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Xie K, Royer J, Rodriguez‐Cruces R, Horwood L, Ngo A, Arafat T, Auer H, Sahlas E, Chen J, Zhou Y, Valk SL, Hong S, Frauscher B, Pana R, Bernasconi A, Bernasconi N, Concha L, Bernhardt BC. Temporal Lobe Epilepsy Perturbs the Brain-Wide Excitation-Inhibition Balance: Associations with Microcircuit Organization, Clinical Parameters, and Cognitive Dysfunction. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2406835. [PMID: 39806576 PMCID: PMC11884548 DOI: 10.1002/advs.202406835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 10/23/2024] [Indexed: 01/16/2025]
Abstract
Excitation-inhibition (E/I) imbalance is theorized as a key mechanism in the pathophysiology of epilepsy, with ample research focusing on elucidating its cellular manifestations. However, few studies investigate E/I imbalance at the macroscale, whole-brain level, and its microcircuit-level mechanisms and clinical significance remain incompletely understood. Here, the Hurst exponent, an index of the E/I ratio, is computed from resting-state fMRI time series, and microcircuit parameters are simulated using biophysical models. A broad decrease in the Hurst exponent is observed in pharmaco-resistant temporal lobe epilepsy (TLE), suggesting more excitable network dynamics. Connectome decoders point to temporolimbic and frontocentral cortices as plausible network epicenters of E/I imbalance. Furthermore, computational simulations reveal that enhancing cortical excitability in TLE reflects atypical increases in recurrent connection strength of local neuronal ensembles. Mixed cross-sectional and longitudinal analyses show stronger E/I ratio elevation in patients with longer disease duration, more frequent electroclinical seizures as well as interictal epileptic spikes, and worse cognitive functioning. Hurst exponent-informed classifiers discriminate patients from healthy controls with high accuracy (72.4% [57.5%-82.5%]). Replicated in an independent dataset, this work provides in vivo evidence of a macroscale shift in E/I balance in TLE patients and points to progressive functional imbalances that relate to cognitive decline.
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Affiliation(s)
- Ke Xie
- McConnell Brain Imaging CentreMontreal Neurological Institute and HospitalMcGill UniversityMontrealQCH3A 2B4Canada
| | - Jessica Royer
- McConnell Brain Imaging CentreMontreal Neurological Institute and HospitalMcGill UniversityMontrealQCH3A 2B4Canada
| | - Raul Rodriguez‐Cruces
- McConnell Brain Imaging CentreMontreal Neurological Institute and HospitalMcGill UniversityMontrealQCH3A 2B4Canada
| | - Linda Horwood
- McConnell Brain Imaging CentreMontreal Neurological Institute and HospitalMcGill UniversityMontrealQCH3A 2B4Canada
| | - Alexander Ngo
- McConnell Brain Imaging CentreMontreal Neurological Institute and HospitalMcGill UniversityMontrealQCH3A 2B4Canada
| | - Thaera Arafat
- McConnell Brain Imaging CentreMontreal Neurological Institute and HospitalMcGill UniversityMontrealQCH3A 2B4Canada
| | - Hans Auer
- McConnell Brain Imaging CentreMontreal Neurological Institute and HospitalMcGill UniversityMontrealQCH3A 2B4Canada
| | - Ella Sahlas
- McConnell Brain Imaging CentreMontreal Neurological Institute and HospitalMcGill UniversityMontrealQCH3A 2B4Canada
| | - Judy Chen
- McConnell Brain Imaging CentreMontreal Neurological Institute and HospitalMcGill UniversityMontrealQCH3A 2B4Canada
| | - Yigu Zhou
- McConnell Brain Imaging CentreMontreal Neurological Institute and HospitalMcGill UniversityMontrealQCH3A 2B4Canada
| | - Sofie L. Valk
- Otto Hahn Research Group for Cognitive NeurogeneticsMax Planck Institute for Human Cognitive and Brain Sciences04103LeipzigGermany
- Institute of Neurosciences and Medicine (INM‐7)Research Centre Jülich52428JülichGermany
- Institute of Systems NeuroscienceHeinrich Heine University Düsseldorf40225DüsseldorfGermany
| | - Seok‐Jun Hong
- Center for Neuroscience Imaging ResearchInstitute for Basic ScienceSungkyunkwan UniversitySuwon34126South Korea
- Department of Biomedical EngineeringSungkyunkwan UniversitySuwon16419South Korea
- Center for the Developing BrainChild Mind InstituteNew York CityNY10022USA
| | - Birgit Frauscher
- Department of Neurology and Department of Biomedical EngineeringDuke UniversityDurhamNC27704USA
| | - Raluca Pana
- Montreal Neurological Institute and HospitalMcGill UniversityMontrealQCH3A 2B4Canada
| | - Andrea Bernasconi
- McConnell Brain Imaging CentreMontreal Neurological Institute and HospitalMcGill UniversityMontrealQCH3A 2B4Canada
| | - Neda Bernasconi
- McConnell Brain Imaging CentreMontreal Neurological Institute and HospitalMcGill UniversityMontrealQCH3A 2B4Canada
| | - Luis Concha
- Institute of NeurobiologyUniversidad Nacional Autónoma de MexicoQueretaro76230Mexico
| | - Boris C. Bernhardt
- McConnell Brain Imaging CentreMontreal Neurological Institute and HospitalMcGill UniversityMontrealQCH3A 2B4Canada
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Wang W, Yin J. Exosomal miR-203 from bone marrow stem cells targets the SOCS3/NF-κB pathway to regulate neuroinflammation in temporal lobe epilepsy. World J Stem Cells 2025; 17:101395. [DOI: 10.4252/wjsc.v17.i2.101395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 12/27/2024] [Accepted: 02/11/2025] [Indexed: 02/24/2025] Open
Abstract
BACKGROUND Epilepsy is a prevalent chronic neurological disorder affecting 50 million individuals globally, with temporal lobe epilepsy (TLE) being the most common form. Despite advances in antiepileptic drug development, over 30% of patients suffer from drug-resistant epilepsy, which can lead to severe cognitive impairments and adverse psychosocial outcomes.
AIM To explore the role of bone marrow mesenchymal stem cell (BMSC)-derived exosomal miR-203 in the regulation of neuroinflammation in a mouse model of epilepsy, providing a theoretical basis for the development of targeted microRNA delivery therapies for drug-resistant epilepsy.
METHODS Adult male C57BL/6 mice were divided into a control group and a TLE model of 30 mice each, and the TLE model group was established by injecting kainic acid. BMSCs were isolated from the mice, and exosomes were purified using ultracentrifugation. Exosomal miR-203 was identified and characterized using high-throughput sequencing and quantitative reverse-transcription polymerase chain reaction. The uptake of exosomes by hippocampal neurons and the subsequent effects on neuroinflammatory markers were assessed using in vitro cell culture models.
RESULTS Exosomal miR-203 exhibited a significant upregulation in BMSCs derived from epileptic mice. In vitro investigations demonstrated the efficient internalization of these exosomes by hippocampal neurons, resulting in downregulation of suppressor of cytokine signaling 3 expression and activation of the nuclear factor kappaB pathway, ultimately leading to enhanced secretion of pro-inflammatory cytokines.
CONCLUSION Our study identifies exosomal miR-203 as a key regulator of neuroinflammation in a mouse model of epilepsy. The findings suggest that targeting miR-203 may offer a novel therapeutic strategy for epilepsy by modulating the suppression of cytokine signaling 3/nuclear factor kappaB pathway, thus providing a potential avenue for the development of cell-free therapeutics.
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Affiliation(s)
- Wei Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Jian Yin
- Department of Neurosurgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
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Priyadarshini S, Goyal K, R R, Gupta S, Roy A, Biswas R, Patra S, Chauhan P, Wadhwa K, Singh G, Kamal M, Iqbal D, Alsaweed M, Nuli MV, Abomughaid MM, Almutary AG, Sinha JK, Bansal P, Rani B, Walia C, Sivaprasad GV, Ojha S, Nelson VK, Jha NK. Polypharmacology and Neuroprotective Effects of Gingerol in Alzheimer's Disease. Mol Neurobiol 2025:10.1007/s12035-024-04484-y. [PMID: 39982688 DOI: 10.1007/s12035-024-04484-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 07/22/2024] [Indexed: 02/22/2025]
Abstract
Alzheimer's disease (AD) is a neurodegenerative condition that results in brain shrinkage and the death of brain cells. The search for new treatment agents with many targets is now crucial due to the insufficient effectiveness, and adverse effects, including pharmacokinetic issues of traditional AD medications. Although phytochemicals have anti-disease characteristics and thus are widely used and accepted by people, researchers have also determined some of their most beneficial functions. Sesquiterpenes, volatile oils, and aromatic ketones (gingerols) are abundant in ginger. The most pharmacologically active components of ginger are considered to be gingerols. These gingerols are the compounds that impart spicy characteristics to the plant. Besides, gingerols readily undergo dehydration and produce another class of compounds, shogaols. These gingerols, shogaols, and other compounds, like zingerone, are mainly responsible for their distinctive aroma and pharmacological effects. This review aims to delineate the therapeutic potentials of gingerol in different AD models by assessing available literature reporting its effect on various cellular and molecular pathways. Although ginger is well recognized as a non-toxic nutraceutical, existing clinical research lacks robust evidence to support its efficacy in treating NDs, including AD. Clinical studies did not provide sufficient data that supports its use in treating various NDs including AD. Therefore, further research is essential to establish the safety and effectiveness of ginger and its constituents, ultimately paving the way for its development as a potential therapeutic agent for AD.
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Affiliation(s)
- Sakthi Priyadarshini
- Faculty of Biology, Ludwig Maximilian University, Großhaderner Straße 2-4, 82152, Planegg Martinsried, Munich, Germany
| | - Keshav Goyal
- Faculty of Biology, Ludwig Maximilian University, Großhaderner Straße 2-4, 82152, Planegg Martinsried, Munich, Germany
| | - Roopashree R
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Saurabh Gupta
- Department of Biotechnology, GLA University, Uttar Pradesh, Mathura, India
| | - Aatreyi Roy
- Faculty of Biology, Ludwig Maximilian University, Großhaderner Straße 2-4, 82152, Planegg Martinsried, Munich, Germany
| | - Ritabrata Biswas
- Faculty of Biology, Ludwig Maximilian University, Großhaderner Straße 2-4, 82152, Planegg Martinsried, Munich, Germany
| | - Sandeep Patra
- Department of Microbiology, Ram Lal Anand College, University of Delhi, Benito Juarez Marg, New Delhi, 110021, India
| | - Payal Chauhan
- Department of Pharmaceutical Sciences, Maharshi Dayanad University, Rohtak, Haryana, 124001, India
| | - Karan Wadhwa
- Department of Pharmaceutical Sciences, Maharshi Dayanad University, Rohtak, Haryana, 124001, India
| | - Govind Singh
- Department of Pharmaceutical Sciences, Maharshi Dayanad University, Rohtak, Haryana, 124001, India
| | - Mehnaz Kamal
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, 11942, Al-Kharj, Saudi Arabia
| | - Danish Iqbal
- Department of Health Information Management, College of Applied Medical Sciences, Buraydah Private Colleges, 51418, Buraydah, Saudi Arabia
| | - Mohammed Alsaweed
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, 11952, Majmaah, Saudi Arabia
| | - Mohana Vamsi Nuli
- Raghavendra Institute of Pharmaceutical Education and Research, Anantapur, India
| | - Mosleh Mohammad Abomughaid
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, 61922, Bisha, Saudi Arabia
| | - Abdulmajeed G Almutary
- Department of Biomedical Sciences, College of Health Sciences, Abu Dhabi University, P.O. Box 59911, Abu Dhabi, United Arab Emirates
| | | | - Pooja Bansal
- Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, Rajasthan, 303012, India
| | - Bindu Rani
- Department of Medicine, National Institute of Medical Sciences, NIMS University Rajasthan, Jaipur, India
| | - Chakshu Walia
- Chandigarh Pharmacy College, Chandigarh Group of Colleges-Jhanjeri, Mohali, 140307, Punjab, India
| | - G V Sivaprasad
- Department of Basic Science & Humanities, Raghu Engineering College, Visakhapatnam, India
| | - Shreesh Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 15551, Al Ain, United Arab Emirates
| | - Vinod Kumar Nelson
- Department of Natural Products and Drug Discovery, Centre for global health research, Saveetha medical college and Hospital, Saveetha institute of medical and technical sciences, Chennai, Tamil Nadu, India.
| | - Niraj Kumar Jha
- Department of Biotechnology & Bioengineering, School of Biosciences & Technology, Galgotias University, Greater Noida, India.
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, India.
- School of Bioengineering & Biosciences, Lovely Professional University, Phagwara, 144411, India.
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Meng Q, Zhang X, Chen Y, Yang H, Liu J, Yang Z, Lei J, Lu F, Hao D, Feng L, Wang Y. Nanoparticles modified with glucose analogs to enhance the permeability of the blood-brain barrier and their accumulation in the epileptic brain. J Mater Chem B 2025; 13:2810-2819. [PMID: 39871635 DOI: 10.1039/d4tb02476a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2025]
Abstract
Drug delivery for epilepsy treatment faces enormous challenges, where the sole focus on enhancing the ability of drugs to penetrate the blood-brain barrier (BBB) through ligand modification is insufficient because of the absence of seizure-specific drug accumulation. In this study, an amphipathic drug carrier with a glucose transporter (GLUT)-targeting capability was synthesised by conjugating 2-deoxy-2-amino-D-glucose (2-DG) to the model carrier DSPE-PEG2k. A 2-DG-modified nano drug delivery system (NDDS) possessing robust stability and favourable biocompatibility was then fabricated using the nanoprecipitation method. The results showed that the 2-DG-modified NDDS exhibited enhanced cellular uptake by brain capillary endothelial cells and neuronal cells. Most importantly, the 2-DG-modified NDDS exhibited enhanced BBB penetration and brain accumulation, especially in the epileptic brain, thus achieving seizure-based on-demand drug delivery. Our study provides a simple and smart strategy for the delivery of anti-seizure medicines.
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Affiliation(s)
- Qian Meng
- Department of Neurology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, P. R. China.
| | - Xiaoyu Zhang
- Department of Neurology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, P. R. China.
- Anhui Public Health Clinical Center, Hefei 230041, Anhui, P. R. China
| | - Yuwen Chen
- Department of Neurology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, P. R. China.
| | - Hao Yang
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui, P. R. China.
| | - Jinshuai Liu
- Department of Neurology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, P. R. China.
| | - Zifan Yang
- Department of Neurology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, P. R. China.
| | - Jianxiang Lei
- Department of Neurology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, P. R. China.
| | - Fengqing Lu
- Department of Neurology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, P. R. China.
| | - Dengyuan Hao
- State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, Jilin, P. R. China
| | - Lijie Feng
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui, P. R. China.
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei 230032, Anhui, P. R. China
| | - Yu Wang
- Department of Neurology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, P. R. China.
- Anhui Public Health Clinical Center, Hefei 230041, Anhui, P. R. China
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Wooley J, Zachery-Savella A, Le M, Scofield S, Jay K, Mosse-Robinson J, West PJ, Wilcox KS, Anderson DN. DynamoSort: Using machine learning approaches for the automatic classification of seizure dynamotypes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.12.637999. [PMID: 40027820 PMCID: PMC11870418 DOI: 10.1101/2025.02.12.637999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
Objective Epilepsy is characterised by unprovoked and recurring seizures, which can be electrically measured using electroencephalograms (EEG). To better understand the underlying mechanisms of seizures, researchers are exploring their temporal dynamics through the lens of dynamical systems modelling. Seizure initiation and termination patterns of spiking amplitude and frequency can be sorted into "dynamotypes", which may be able to serve as biomarkers for intervention. However, manual classification of these dynamotypes requires trained raters and is prone to variability. To address this, we developed DynamoSort, a machine-learning algorithm for automatic seizure onset and offset classification. Methods We used approximately 2100 seizures from an intra-amygdala kainic acid (IAK) mouse model of mesial temporal lobe epilepsy, categorized by five trained raters. MATLAB's classification learner application was used to create an ensemble model to score and label dynamotypes of individual seizures based on spiking and frequency features. Results Dynamotype classification of real EEG data lacks a definitive ground truth, with mean inter-rater agreement at 73.4% for onset and 64.2% for offset types. Despite this, DynamoSort achieved a mean area under the curve (AUC) of 0.81 for onset and a mean AUC of 0.75 for offset types. Machine-human agreement was not significantly different from human-to-human agreement. To address the lack of ground truth in ratings, DynamoSort assigns probabilistic scores (-20 to 20), to indicate similarity to each seizure dynamotype based on spiking features, allowing for a characterization of seizure dynamics on a spectrum rather than the traditional qualitative taxonomy. Significance Automating the classification of dynamotypes is a critical step for their inclusion as a biomarker in clinical and research applications. DynamoSort is a straightforward, open-access tool that uses automatic labelling and probabilistic scoring to quantify subtle changes in seizure onset and offset dynamics. Key Points Dynamotypes are a promising seizure categorization system, but is prone to interrater variability and lacks a ground truth.Machine learning can be used to automatically classify seizure onsets and offsets into appropriate dynamotypes based on spike features.Agreement between DynamoSort and human raters rivals typical agreement rates in trained human raters.DynamoSort uses probabilistic scoring to quantify subtle changes in seizure onset and offset, allowing for a quantitative characterisation.
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Affiliation(s)
- Josh Wooley
- School of Biomedical Engineering, University of Sydney, Sydney, Australia
| | | | - Michelle Le
- Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, USA
| | - Sally Scofield
- Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, USA
| | - Kishore Jay
- Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, USA
| | | | - Peter J. West
- Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, USA
| | - Karen S. Wilcox
- Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, USA
| | - Daria Nesterovich Anderson
- School of Biomedical Engineering, University of Sydney, Sydney, Australia
- Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, USA
- Department of Neurosurgery, University of Utah, Salt Lake City, UT
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Thergarajan P, O'Brien TJ, Jones NC, Ali I. Ligand-receptor interactions: A key to understanding microglia and astrocyte roles in epilepsy. Epilepsy Behav 2025; 163:110219. [PMID: 39693861 DOI: 10.1016/j.yebeh.2024.110219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 11/30/2024] [Accepted: 12/07/2024] [Indexed: 12/20/2024]
Abstract
Epilepsy continues to pose significant social and economic challenges on a global scale. Existing therapeutic approaches predominantly revolve around neurocentric mechanisms, and fail to control seizures in approximately one-third of patients. This underscores the pressing need for novel and complementary treatment approaches to address this gap. An increasing body of literature points to a role for glial cells, including microglia and astrocytes, in the pathogenesis of epilepsy. Notably, microglial cells, which serve as pivotal inflammatory mediators within the epileptic brain, have received increasing attention over recent years. These immune cells react to epileptogenic insults, regulate neuronal processes, and play diverse roles during the process of epilepsy development. Additionally, astrocytes, another integral non-neuronal brain cells, have garnered increasing recognition for their dynamic contributions to the pathophysiology of epilepsy. Their complex interactions with neurons and other glial cells involve modulating synaptic activity and neuronal excitability, thereby influencing the aberrant networks formed during epileptogenesis. This review explores the alterations in microglial and astrocytic function and their mechanisms of communication following an epileptogenic insult, examining their contribution to epilepsy development. By comprehensively studying these mechanisms, potential avenues could emerge for refining therapeutic strategies and ameliorating the impact of this complex neurological disease.
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Affiliation(s)
- Peravina Thergarajan
- Department of Neuroscience, School of Translational Medicine, Monash University, Melbourne, Victoria, 3004, Australia
| | - Terence J O'Brien
- Department of Neuroscience, School of Translational Medicine, Monash University, Melbourne, Victoria, 3004, Australia; Department of Neurology, The Alfred Hospital, Melbourne, Victoria, 3004, Australia; Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Victoria, 3000, Australia
| | - Nigel C Jones
- Department of Neuroscience, School of Translational Medicine, Monash University, Melbourne, Victoria, 3004, Australia; Department of Neurology, The Alfred Hospital, Melbourne, Victoria, 3004, Australia; Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Victoria, 3000, Australia
| | - Idrish Ali
- Department of Neuroscience, School of Translational Medicine, Monash University, Melbourne, Victoria, 3004, Australia; Department of Neurology, The Alfred Hospital, Melbourne, Victoria, 3004, Australia; Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Victoria, 3000, Australia
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Wu C, Zheng J, Pan Y, Tao R, Zhong Z, Qian C, Liang H, Wu H. Genetic and non-genetic factors influencing the therapeutic response of valproic acid in pediatric epileptic patients. Per Med 2025; 22:11-19. [PMID: 39711059 DOI: 10.1080/17410541.2024.2441655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 12/10/2024] [Indexed: 12/24/2024]
Abstract
AIMS Considerable inter-individual variability in the efficacy of valproic acid (VPA) has been reported, with approximately 20-45% of patients failing to achieve satisfactory seizure control after VPA monotherapy. The aim of this study was to investigate the influence of non-genetic and genetic factors on 12-month VPA-response in a cohort of 194 pediatric patients. MATERIALS & METHODS Trough concentrations were determined, and a panel of 48 variants located in pharmacokinetic and pharmacodynamic gene were genotyped. RESULTS Aetiology was highlighted as a significant factor for the response to VPA. Specifically, patients with idiopathic epilepsy demonstrated poorer 12-month outcomes (p < 0.001). Trough VPA concentrations did not significantly affect outcomes. Marginal association was found between VPA efficacy and the following genetic variants: GABRA1 rs10068980 (p = 0.02), SLC16A1 rs7169 (p = 0.02), ABCC2 rs1885301 (p = 0.092), ACADM rs1251079 (p = 0.061) and GABRA1 rs6883877 (p = 0.085), as indicated by Fisher's exact test. A significant cumulative effect of two genetic factors (GABRA1 rs10068980 and SLC16A1 rs7169) was observed after a multiple logistic analysis, with ORs of 2.828 (1.213, 6.594) and 4.066 (1.148,14.398), respectively. CONCLUSION Our study indicated that GABRA1 rs10068980 and SLC16A1 rs7169 might serve as potential biomarkers for predicting the 12-month VPA treatment outcomes in pediatric patients with epilepsy.
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Affiliation(s)
- Changsong Wu
- Department of Neurology, The Second Affiliated Hospital of Guizhou Medical University, Kaili City, Guizhou, China
| | - Jianghuan Zheng
- Department of Neurology, The Second Affiliated Hospital of Guizhou Medical University, Kaili City, Guizhou, China
| | - Yanling Pan
- Department of Neurology, The Second Affiliated Hospital of Guizhou Medical University, Kaili City, Guizhou, China
| | - Ruyu Tao
- Department of Neurology, The Second Affiliated Hospital of Guizhou Medical University, Kaili City, Guizhou, China
| | - Zhijun Zhong
- Department of Neurosurgery, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang City, Guizhou, China
| | - Chaozhi Qian
- Department of Neurosurgery, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang City, Guizhou, China
| | - Heng Liang
- School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou City, Guangdong, China
| | - Haijun Wu
- Department of Neurosurgery, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang City, Guizhou, China
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Zhang X, Xiang F, Wang Z, Li Y, Shao C, Lan X, Lang S, Wang X. Clinical characteristics, etiology, and treatment of young adult-onset epilepsy: A 24-year retrospective study. Epilepsia Open 2025; 10:298-306. [PMID: 39736142 PMCID: PMC11803278 DOI: 10.1002/epi4.13126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 12/14/2024] [Accepted: 12/18/2024] [Indexed: 01/01/2025] Open
Abstract
OBJECTIVE To analyze the clinical characteristics, etiology, drug treatment, and related factors of patients with young adult-onset epilepsy. METHODS The study included patients with epilepsy aged between 18 and 44 years and aimed to analyze the clinical characteristics of epilepsy in young people and their response to antiseizure medication (ASM) over a 24-year period (February 1999 and March 2023). RESULTS A total of 4227 patients experienced epilepsy onset between 18 and 44 years of age. The median age of onset was 26 years (interquartile range [IQR]: 21-33), and the median duration from the first seizure to starting treatment was 3 months (IQR: 1.0-6.0). Structural etiology was the most common cause of epilepsy, accounting for 43.2% (1827/4227) of cases, of which head trauma and a history of craniotomy accounted for 64.9% (1186/1827). However, these two causes did not necessarily result in prompt medication or poor epilepsy control. Co-morbid cognitive decline was more prevalent than headache and anxiety/depression. Multifactorial regression analysis showed that the factors associated with poor seizure control included longer seizure duration (odds ratio [OR] 1.85; 95% confidence interval [CI] 1.58-2.16; p < 0.001), electroencephalography (EEG) epileptic discharge (OR 1.37; 95% CI 1.17-1.67; p < 0.001), focal seizure (OR 1.69; 95% CI 1.38-2.07; p < 0.001), and seizure clusters (OR 3.35; 95% CI 2.70-4.15; p < 0.001). Initiating treatment after two seizures (OR, 1.18; 95% CI 0.98-1.15; p = .08) or 6 months after the first seizure (OR 0.84; 95% CI 0.67-1.03; p = .09) did not worsen effectiveness. SIGNIFICANCE Young adult-onset epilepsy was frequently caused by head trauma or craniotomies. Co-morbid cognitive decline was more prevalent than headache and anxiety/depression. The median time from the first seizure to follow-up treatment was 3 months (IQR: 1.0-6.0). Initiating treatment after two seizures did not necessarily indicate poor drug effectiveness. PLAIN LANGUAGE SUMMARY In this article, we observed that young adult-onset epilepsy was mainly caused by head trauma and craniotomy; co-morbid cognitive decline was more common. The median duration from first seizure to initiation of treatment for young-onset epilepsy was 3 months, and more than one-third of patients experienced more than two seizures prior to treatment, but this factor had no effect on the drug effectiveness.
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Affiliation(s)
- Xu Zhang
- Department of NeurologyThe First Medical Center of Chinese PLA General HospitalBeijingChina
| | - Feng Xiang
- Department of NeurologyThe First Medical Center of Chinese PLA General HospitalBeijingChina
| | - Ziyu Wang
- Department of Electrophysiology, Beijing Jishuitan HospitalCapital Medical UniversityBeijingChina
| | - Yang Li
- Department of NeurologyThe First Medical Center of Chinese PLA General HospitalBeijingChina
| | | | - Xiaoyang Lan
- Department of NeurologyThe First Medical Center of Chinese PLA General HospitalBeijingChina
| | - Senyang Lang
- Department of NeurologyHainan Hospital of Chinese PLA General HospitalSanyaChina
| | - Xiangqing Wang
- Department of NeurologyThe First Medical Center of Chinese PLA General HospitalBeijingChina
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Wang L, Kong Q, Leng X, Leung H, Li Y. The sphingosine-1-phosphate signaling pathway (sphingosine-1-phosphate and its receptor, sphingosine kinase) and epilepsy. Epilepsia Open 2025; 10:55-73. [PMID: 39727628 PMCID: PMC11803289 DOI: 10.1002/epi4.13112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 11/08/2024] [Accepted: 11/20/2024] [Indexed: 12/28/2024] Open
Abstract
Epilepsy is one of the common chronic neurological diseases, affecting more than 70 million people worldwide. The brains of people with epilepsy exhibit a pathological and persistent propensity for recurrent seizures. Epilepsy often coexists with cardiovascular disease, cognitive dysfunction, depression, etc., which seriously affects the patient's quality of life. Although our understanding of epilepsy has advanced, the pathophysiological mechanisms leading to epileptogenesis, drug resistance, and associated comorbidities remain largely unknown. The use of newer antiepileptic drugs has increased, but this has not improved overall outcomes. We need to deeply study the pathogenesis of epilepsy and find drugs that can not only prevent the epileptogenesis and interfere with the process of epileptogenesis but also treat epilepsy comorbidities. Sphingosine-1-phosphate (S1P) is an important lipid molecule. It not only forms the basis of cell membranes but is also an important bioactive mediator. It can not only act as a second messenger in cells to activate downstream signaling pathways but can also exert biological effects by being secreted outside cells and binding to S1P receptors on the cell membrane. Fingolimod (FTY720) is the first S1P receptor modulator developed and approved for the treatment of multiple sclerosis. More and more studies have proven that the S1P signaling pathway is closely related to epilepsy, drug-resistant epilepsy, epilepsy comorbidities, or other epilepsy-causing diseases. However, there is much controversy over the role of certain natural molecules in the pathway and receptor modulators (such as FTY720) in epilepsy. Here, we summarize and analyze the role of the S1P signaling pathway in epilepsy, provide a basis for finding potential therapeutic targets and/or epileptogenic biomarkers, analyze the reasons for these controversies, and put forward our opinions. PLAIN LANGUAGE SUMMARY: This article combines the latest research literature at home and abroad to review the sphingosine 1-phosphate signaling pathway and epileptogenesis, drug-resistant epilepsy, epilepsy comorbidities, other diseases that can cause epilepsy, as well as the sphingosine-1-phosphate signaling pathway regulators and epilepsy, with the expectation of providing a certain theoretical basis for finding potential epilepsy treatment targets and/or epileptogenic biomarkers in the sphingosine-1-phosphate signaling pathway.
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Affiliation(s)
- Lin Wang
- Department of NeurologyAffiliated Hospital of Jining Medical UniversityJining CityChina
- Epilepsy CenterAffiliated Hospital of Jining Medical UniversityJining CityChina
- The Chinese University of Hong Kong, Department of Medicine and TherapeuticsThe Chinese University of Hong Kong, Central AveHong KongHong Kong
| | - Qingxia Kong
- Department of NeurologyAffiliated Hospital of Jining Medical UniversityJining CityChina
- Epilepsy CenterAffiliated Hospital of Jining Medical UniversityJining CityChina
| | - Xinyi Leng
- The Chinese University of Hong Kong, Department of Medicine and TherapeuticsThe Chinese University of Hong Kong, Central AveHong KongHong Kong
| | - Howan Leung
- Division of Neurology, Department of Medicine and Therapeutics, Prince of Wales Hospital7/F Clinical Science Building, Prince of Wales HospitalHong KongHong Kong
| | - Yang Li
- Department of OncologyAffiliated Hospital of Jining Medical UniversityJining CityChina
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10
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Xiong Z, Deng J, Xie P, Tang C, Wang J, Deng Q, Yang Y, Zhang J, Guo M, Wang X, Guan Y, Luan G, Zhou J, Li T. Deep Brain Stimulation Inhibits Epileptic Seizures via Increase of Adenosine Release and Inhibition of ENT1, CD39, and CD73 Expression. Mol Neurobiol 2025; 62:1800-1812. [PMID: 39042219 DOI: 10.1007/s12035-024-04374-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 07/16/2024] [Indexed: 07/24/2024]
Abstract
Deep brain stimulation (DBS) of the anterior nucleus of the thalamus is an efficacious treatment option for patients with refractory epilepsy. Our previous study demonstrates that adenosine is a potential target of DBS for the treatment of epilepsy. Equilibrative nucleoside transporters-1 (ENT1) and ectonucleotidases (CD39, CD73) function as regulators of extracellular adenosine in the brain. It is unclear whether ENT1, CD39, and CD73 are involved in the mechanism of DBS for epilepsy. A total of 48 SD male rats were divided into four groups: control (naïve rats), Pilo (pilocarpine induced rats with epilepsy), DBS (rats with epilepsy treated with DBS for 8 weeks), and sham. In the present study, video electroencephalogram monitoring, Morris water maze assays, in vivo measurements of adenosine using fiber photometry, histochemistry, and western blot were performed on the hippocampus. DBS markedly attenuated spontaneous recurrent seizures (SRSs) and enhanced spatial learning in rats with epilepsy, assessed through video-EEG and water maze assays. Fibred photometry measurements of an adenosine sensor revealed dynamic increase in extracellular adenosine during DBS. The expressions of ENT1, CD39, and CD73 in Pilo group and sham group increased compared with the control group, while the expressions of ENT1, CD39, and CD73 in DBS group decreased compared to that of Pilo group and sham group. The findings indicate that DBS reduces the number of SRSs and improves spatial memory in rats with epilepsy with concomitant decrease of ENT1, CD39, and CD73 expressions. Adenosine-modulating enzymes might be the potential targets of DBS for the treatment of epilepsy.
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Affiliation(s)
- Zhonghua Xiong
- Department of Brian Institute, Center of Epilepsy, Key Laboratory of Epilepsy Research, Beijing Institute for Brain Disorders, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
- Department of Neurology, Center of Epilepsy, Beijing Institute for Brain Disorders, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
| | - Jiahui Deng
- Department of Brian Institute, Center of Epilepsy, Key Laboratory of Epilepsy Research, Beijing Institute for Brain Disorders, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
| | - Pandeng Xie
- Department of Brian Institute, Center of Epilepsy, Key Laboratory of Epilepsy Research, Beijing Institute for Brain Disorders, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
- Department of Neurosurgery, Center of Epilepsy, Key Laboratory of Epilepsy Research, Beijing Institute for Brain Disorders, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
| | - Chongyang Tang
- Department of Brian Institute, Center of Epilepsy, Key Laboratory of Epilepsy Research, Beijing Institute for Brain Disorders, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
- Department of Neurosurgery, Center of Epilepsy, Key Laboratory of Epilepsy Research, Beijing Institute for Brain Disorders, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
| | - Jing Wang
- Department of Brian Institute, Center of Epilepsy, Key Laboratory of Epilepsy Research, Beijing Institute for Brain Disorders, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
- Department of Neurology, Center of Epilepsy, Beijing Institute for Brain Disorders, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
| | - Qinqin Deng
- Department of Brian Institute, Center of Epilepsy, Key Laboratory of Epilepsy Research, Beijing Institute for Brain Disorders, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
- Department of Neurology, Center of Epilepsy, Beijing Institute for Brain Disorders, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
| | - Yujiao Yang
- Department of Brian Institute, Center of Epilepsy, Key Laboratory of Epilepsy Research, Beijing Institute for Brain Disorders, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
- Department of Neurology, Center of Epilepsy, Beijing Institute for Brain Disorders, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
| | - Jing Zhang
- Department of Brian Institute, Center of Epilepsy, Key Laboratory of Epilepsy Research, Beijing Institute for Brain Disorders, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
- Department of Neurology, Center of Epilepsy, Beijing Institute for Brain Disorders, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
| | - Mengyi Guo
- Department of Brian Institute, Center of Epilepsy, Key Laboratory of Epilepsy Research, Beijing Institute for Brain Disorders, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
- Department of Neurology, Center of Epilepsy, Beijing Institute for Brain Disorders, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
| | - Xiongfei Wang
- Department of Brian Institute, Center of Epilepsy, Key Laboratory of Epilepsy Research, Beijing Institute for Brain Disorders, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
- Department of Neurosurgery, Center of Epilepsy, Key Laboratory of Epilepsy Research, Beijing Institute for Brain Disorders, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
| | - Yuguang Guan
- Department of Brian Institute, Center of Epilepsy, Key Laboratory of Epilepsy Research, Beijing Institute for Brain Disorders, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
- Department of Neurosurgery, Center of Epilepsy, Key Laboratory of Epilepsy Research, Beijing Institute for Brain Disorders, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
| | - Guoming Luan
- Department of Brian Institute, Center of Epilepsy, Key Laboratory of Epilepsy Research, Beijing Institute for Brain Disorders, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
- Department of Neurosurgery, Center of Epilepsy, Key Laboratory of Epilepsy Research, Beijing Institute for Brain Disorders, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
| | - Jian Zhou
- Department of Brian Institute, Center of Epilepsy, Key Laboratory of Epilepsy Research, Beijing Institute for Brain Disorders, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
- Department of Neurosurgery, Center of Epilepsy, Key Laboratory of Epilepsy Research, Beijing Institute for Brain Disorders, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
| | - Tianfu Li
- Department of Brian Institute, Center of Epilepsy, Key Laboratory of Epilepsy Research, Beijing Institute for Brain Disorders, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China.
- Department of Neurology, Center of Epilepsy, Beijing Institute for Brain Disorders, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China.
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Gargus M, Ben-Azu B, Landwehr A, Dunn J, Errico JP, Tremblay MÈ. Mechanisms of vagus nerve stimulation for the treatment of neurodevelopmental disorders: a focus on microglia and neuroinflammation. Front Neurosci 2025; 18:1527842. [PMID: 39881804 PMCID: PMC11774973 DOI: 10.3389/fnins.2024.1527842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 12/27/2024] [Indexed: 01/31/2025] Open
Abstract
The vagus nerve (VN) is the primary parasympathetic nerve, providing two-way communication between the body and brain through a network of afferent and efferent fibers. Evidence suggests that altered VN signaling is linked to changes in the neuroimmune system, including microglia. Dysfunction of microglia, the resident innate immune cells of the brain, is associated with various neurodevelopmental disorders, including schizophrenia, attention deficit hyperactive disorder (ADHD), autism spectrum disorder (ASD), and epilepsy. While the mechanistic understanding linking the VN, microglia, and neurodevelopmental disorders remains incomplete, vagus nerve stimulation (VNS) may provide a better understanding of the VN's mechanisms and act as a possible treatment modality. In this review we examine the VN's important role in modulating the immune system through the inflammatory reflex, which involves the cholinergic anti-inflammatory pathway, which releases acetylcholine. Within the central nervous system (CNS), the direct release of acetylcholine can also be triggered by VNS. Homeostatic balance in the CNS is notably maintained by microglia. Microglia facilitate neurogenesis, oligodendrogenesis, and astrogenesis, and promote neuronal survival via trophic factor release. These cells also monitor the CNS microenvironment through a complex sensome, including groups of receptors and proteins enabling microglia to modify neuroimmune health and CNS neurochemistry. Given the limitations of pharmacological interventions for the treatment of neurodevelopmental disorders, this review seeks to explore the application of VNS as an intervention for neurodevelopmental conditions. Accordingly, we review the established mechanisms of VNS action, e.g., modulation of microglia and various neurotransmitter pathways, as well as emerging preclinical and clinical evidence supporting VNS's impact on symptoms associated with neurodevelopmental disorders, such as those related to CNS inflammation induced by infections. We also discuss the potential of adapting non-invasive VNS for the prevention and treatment of these conditions. Overall, this review is intended to increase the understanding of VN's potential for alleviating microglial dysfunction involved in schizophrenia, ADHD, ASD, and epilepsy. Additionally, we aim to reveal new concepts in the field of CNS inflammation and microglia, which could serve to understand the mechanisms of VNS in the development of new therapies for neurodevelopmental disorders.
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Affiliation(s)
- Makenna Gargus
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| | - Benneth Ben-Azu
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Department of Pharmacology, Faculty of Basic Medical Sciences, Delta State University, Abraka, Nigeria
| | - Antonia Landwehr
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| | - Jaclyn Dunn
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| | | | - Marie-Ève Tremblay
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, BC, Canada
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12
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Pang J, Cen C, Tian Y, Cao X, Hao L, Tao X, Cao Z. Targeting Shp2 as a therapeutic strategy for neurodegenerative diseases. Transl Psychiatry 2025; 15:6. [PMID: 39794316 PMCID: PMC11724000 DOI: 10.1038/s41398-024-03222-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 12/12/2024] [Accepted: 12/31/2024] [Indexed: 01/13/2025] Open
Abstract
The incidence of neurodegenerative diseases (NDs) has increased recently. However, most of the current governance strategies are palliative and lack effective therapeutic drugs. Therefore, elucidating the pathological mechanism of NDs is the key to the development of targeted drugs. As a member of the tyrosine phosphatase family, the role of Shp2 has been studied in tumors, but the research in the nervous system is still in a sporadic state. It can be phosphorylated by tyrosine kinases and then positively regulate tyrosine kinase-dependent signaling pathways. It could also be used as an adaptor protein to mediate downstream signaling pathways. Most of the existing studies have shown that Shp2 may be a potential molecular "checkpoint" against NDs, but its role in promoting degenerative lesions is difficult to ignore as well, and its two-way effect of both activation and inhibition is very distinctive. Shp2 is closely related to NDs-related pathogenic factors such as oxidative stress, mitochondrial dysfunction, excitatory toxicity, immune inflammation, apoptosis, and autophagy. Its bidirectional effects interfere with these pathogenic factors, making it a core component of the feedback and crosstalk network between multiple signaling pathways. Therefore, this article reviews the molecular mechanism of Shp2 regulation in NDs and its regulatory role in various pathogenic factors, providing evidence for the treatment of NDs by targeting Shp2 and the development of molecular targeted drugs.
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Affiliation(s)
- Jiao Pang
- Department of Forensic Pathology, School of Forensic Medicine, China Medical University, Shenyang, Liaoning Province, PR China
- Department of Pathology and pathophysiology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian Province, PR China
- College of Life Science, Northwest University, Xi'an City, Shaanxi Province, PR China
| | - Changqian Cen
- Department of Forensic Pathology, School of Forensic Medicine, China Medical University, Shenyang, Liaoning Province, PR China
| | - Yuan Tian
- Department of Biological Sciences, Sookmyung Women's University, Seoul, Republic of Korea
| | - Xingrui Cao
- Department of Chemistry, School of Forensic Medicine, China Medical University, Shenyang, Liaoning Province, PR China
| | - Liang Hao
- Department of Chemistry, School of Forensic Medicine, China Medical University, Shenyang, Liaoning Province, PR China.
| | - Xueshu Tao
- Department of Forensic Pathology, School of Forensic Medicine, China Medical University, Shenyang, Liaoning Province, PR China.
- Department of Pain Medicine, The First Hospital of China Medical University, Shenyang, Liaoning Province, PR China.
| | - Zhipeng Cao
- Department of Forensic Pathology, School of Forensic Medicine, China Medical University, Shenyang, Liaoning Province, PR China.
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13
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Khatoon S, Kalam N. Mechanistic insight of curcumin: a potential pharmacological candidate for epilepsy. Front Pharmacol 2025; 15:1531288. [PMID: 39845785 PMCID: PMC11752882 DOI: 10.3389/fphar.2024.1531288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 12/16/2024] [Indexed: 01/24/2025] Open
Abstract
Recurrent spontaneous seizures with an extended epileptic discharge are the hallmarks of epilepsy. At present, there are several available anti-epileptic drugs (AEDs) in the market. Still no adequate treatment for epilepsy treatment is available. The main disadvantages of AEDs are their associated adverse effects. It is a challenge to develop new therapies that can reduce seizures by modulating the underlying mechanisms with no adverse effects. In the last decade, the neuromodulatory potential of phytoconstituents has sparked their usage in the treatment of central nervous system disorders. Curcumin is an active polyphenolic component that interacts at cellular and molecular levels. Curcumin's neuroprotective properties have been discovered in recent preclinical and clinical studies due to its immunomodulatory effects. Curcumin has the propensity to modulate signaling pathways involved in cell survival and manage oxidative stress, apoptosis, and inflammatory mechanisms. Further, curcumin can persuade epigenetic alterations, including histone modifications (acetylation/deacetylation), which are the changes responsible for the altered expression of genes facilitating the process of epileptogenesis. The bioavailability of curcumin in the brain is a concern that needs to be tackled. Therefore, nanonization has emerged as a novel drug delivery system to enhance the pharmacokinetics of curcumin. In the present review, we reviewed curcumin's modulatory effects on potential biomarkers involved in epileptogenesis including dendritic cells, T cell subsets, cytokines, chemokines, apoptosis mediators, antioxidant mechanisms, and cognition impairment. Also, we have discussed the nanocarrier systems for encapsulating curcumin, offering a promising approach to enhance bioavailability of curcumin.
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Affiliation(s)
- Saima Khatoon
- Department of Obstetrics, Gynecology and Reproductive Sciences, School of Medicine, University of Maryland, Baltimore, MD, United States
| | - Nida Kalam
- Infection and Immunity Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University, Bandar Sunway, Malaysia
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14
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Dhiman V, Karan K, Satischandra P, Mahadevan A, Arimappamagan A, Bharath RD, Raj D, Thennarasu K, Viswanathan LG, Mundlamuri R, Kenchaiah R, Asranna A, Saini J, Rajeswaran JR, Kumar K, Rao MB, Anand A, Sinha S. Clinico-genetic Analysis of Adenosine Signaling Pathway in Drug-Resistant Epilepsy. Ann Indian Acad Neurol 2025; 28:49-57. [PMID: 39951024 DOI: 10.4103/aian.aian_358_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Accepted: 12/22/2024] [Indexed: 02/21/2025] Open
Abstract
BACKGROUND AND OBJECTIVES The adenosine pathway in drug-resistant epilepsy (DRE) due to hippocampal sclerosis (HS) is largely unexplored. The present study aims to provide new insights into the role of adenosine pathway in patients with DRE associated with HS (DRE-HS). METHODS Quantitative polymerase chain reaction and immunohistochemistry were used to analyze 10 genes involved in adenosine pathway ( ADARB1 , ADK , NT5E , ADORA1 , C-FOS, C-MYC, CREB1, C-JUN, NF-kB1, and MAPK ) in surgically resected sclerosed hippocampi (n = 37) and compare their expressions with control hippocampi (n = 38) obtained from the autopsy. Expression analyses were also carried out in peripheral blood of 20 matched patients and 30 healthy controls. RESULTS C-JUN , NT5E , C-FOS , ADARB1 , and ADORA1 were significantly upregulated in the hippocampus, whereas in blood, C-JUN , NT5E , C-FOS , and ADORA1 were significantly downregulated. ADARB1 , NF-kB1 , MAPK1, C-FOS, and CREB1 showed the reverse direction of expressions in post-surgery blood samples. On clinico-genetic analysis, MAPK1 and ADARB1 correlated with neuronal dispersion in the dentate gyrus ( P = 0.02 and 0.03, respectively) and C-JUN correlated with neuronal loss in CA1 ( P = 0.01) and CA4 ( P = 0.04) areas. In blood, MAPK1 , NF-kB1 , and C-FOS expressions correlated negatively with the age of onset of seizures ( P = 0.02, 0.03, and 0.03, respectively). In addition, ADARB1 expression correlated with neuronal loss in CA3 and CA4 areas ( P ≤ 0.001 and 0.04, respectively). CONCLUSION Genes with similar expression patterns in the brain and peripheral blood are potential biomarkers in DRE-HS. Significant clinico-genetic correlations warrant further studies for developing novel therapeutic interventions.
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Affiliation(s)
- Vikas Dhiman
- Department of Clinical Neurosciences, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
- Indian Council of Medical Research Headquarters, New Delhi, India
| | - Kalpita Karan
- Human Molecular Genetics Laboratory, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, Karnataka, India
| | - Parthasarathy Satischandra
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
| | - Anita Mahadevan
- Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
| | - Arivazhagan Arimappamagan
- Department of Neurosurgery, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
| | - Rose D Bharath
- Department of Neuroimaging and Interventional Radiology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
| | - Dharma Raj
- Department of Biostatistics and Bioinformatics, ICMR-National Institute for Research in Environmental Health, Bhopal, Madhya Pradesh, India
| | - Kandavel Thennarasu
- Department of Biostatistics, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
| | | | - Ravindranadh Mundlamuri
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
| | - Raghavendra Kenchaiah
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
| | - Ajay Asranna
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
| | - Jitender Saini
- Department of Neuroimaging and Interventional Radiology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
| | - Jamuna R Rajeswaran
- Department of Neuropsychology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
| | - Keshav Kumar
- Department of Neuropsychology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
| | - Malla Bhaskara Rao
- Department of Neurosurgery, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
| | - Anuranjan Anand
- Human Molecular Genetics Laboratory, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, Karnataka, India
| | - Sanjib Sinha
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
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15
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Zhao J, Qin X, Yang L, Guo H, Chen S, Tian K, Guo Q, Zhao W, Zhang P, Jia Z, Yang Z, Kong D, Zhang W. Application of TCM network pharmacology and experimental verification to explore the mechanism of kaempferol against epilepsy. Brain Res Bull 2025; 220:111150. [PMID: 39608614 DOI: 10.1016/j.brainresbull.2024.111150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 10/12/2024] [Accepted: 11/25/2024] [Indexed: 11/30/2024]
Abstract
BACKGROUND Kaempferol (KF), the main active ingredient in identifying the authenticity of safflower, has a variety of pharmacological activities and neuroprotective effects. However, the mechanism of KF in the treatment of epilepsy remains unclear. This study aimed to investigate the protective effects of KF on epilepsy and its related mechanisms. METHODS Network pharmacology was used to explore the targets and mechanisms of safflower antiepileptic action. The protective effect of KF on epilepsy was assessed in the behavior and tissues of epileptic mice. Additionally, the impact of KF on the excitability and calcium transients of rat cortical neurons and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionicacid receptor (AMPAR) were investigated using patch clamp and calcium imaging techniques. RESULTS Network pharmacology indicated safflower could be involved in calcium signaling pathways and calcium channel inhibitor activity. Experimental validation demonstrated that KF delayed seizure onset and mitigated neuronal damage in the prefrontal cortex of mice. It also reduced neuronal excitability, as indicated by action potential parameters, and suppressed Glutamate (Glu)-induced calcium transients. In tsA201 cells, KF inhibited AMPAR-mediated currents, suggesting a role in regulating [Ca2+]i homeostasis. CONCLUSION These results indicate that KF's anticonvulsant properties may arise from its neuroprotection against cell injury, edema, and necrosis, its reduction of neuronal hyperexcitability, and its prevention of calcium-induced cytotoxicity, potentially involving AMPAR modulation. This study positions KF as a promising candidate for epilepsy therapy, offering a scientific foundation for its clinical investigation.
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Affiliation(s)
- Jiaojiao Zhao
- Department of Pharmacology of Chinese Materia Medica, Institution of Chinese Integrative Medicine, School of Chinese Integrative Medicine, Hebei Medical University, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei Province 050017, China
| | - Xia Qin
- Department of Pharmacology of Chinese Materia Medica, Institution of Chinese Integrative Medicine, School of Chinese Integrative Medicine, Hebei Medical University, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei Province 050017, China
| | - Lei Yang
- Department of Pharmacology of Chinese Materia Medica, Institution of Chinese Integrative Medicine, School of Chinese Integrative Medicine, Hebei Medical University, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei Province 050017, China
| | - Han Guo
- Department of Pharmacology of Chinese Materia Medica, Institution of Chinese Integrative Medicine, School of Chinese Integrative Medicine, Hebei Medical University, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei Province 050017, China
| | - Siruan Chen
- Department of Pharmacology of Chinese Materia Medica, Institution of Chinese Integrative Medicine, School of Chinese Integrative Medicine, Hebei Medical University, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei Province 050017, China
| | - Keying Tian
- Department of Pharmacology of Chinese Materia Medica, Institution of Chinese Integrative Medicine, School of Chinese Integrative Medicine, Hebei Medical University, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei Province 050017, China
| | - Qinghui Guo
- Department of Pharmacology of Chinese Materia Medica, Institution of Chinese Integrative Medicine, School of Chinese Integrative Medicine, Hebei Medical University, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei Province 050017, China
| | - Wenya Zhao
- Department of Pharmacology of Chinese Materia Medica, Institution of Chinese Integrative Medicine, School of Chinese Integrative Medicine, Hebei Medical University, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei Province 050017, China
| | - Panpan Zhang
- Department of Pharmacology of Chinese Materia Medica, Institution of Chinese Integrative Medicine, School of Chinese Integrative Medicine, Hebei Medical University, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei Province 050017, China
| | - Zhanfeng Jia
- Department of Pharmacology, Hebei Medical University, Shijiazhuang, Hebei Province 050017, China
| | - Zuxiao Yang
- Department of Pharmacology of Chinese Materia Medica, Institution of Chinese Integrative Medicine, School of Chinese Integrative Medicine, Hebei Medical University, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei Province 050017, China
| | - Dezhi Kong
- Department of Pharmacology of Chinese Materia Medica, Institution of Chinese Integrative Medicine, School of Chinese Integrative Medicine, Hebei Medical University, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei Province 050017, China
| | - Wei Zhang
- Department of Pharmacology of Chinese Materia Medica, Institution of Chinese Integrative Medicine, School of Chinese Integrative Medicine, Hebei Medical University, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei Province 050017, China.
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Anand A, Shrivastava A, Singh K, Barik R, Gayakwad D, Jailani S, Shamim, Dwivedi S. Neuroprotective Efficacy and Complementary Treatment with Medicinal Herbs: A Comprehensive Review of Recent Therapeutic Approaches in Epilepsy Management. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2025; 24:60-73. [PMID: 39069797 DOI: 10.2174/0118715273332140240724093837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 06/25/2024] [Accepted: 07/10/2024] [Indexed: 07/30/2024]
Abstract
Central Nervous System (CNS) disorders affect millions of people worldwide, with a significant proportion experiencing drug-resistant forms where conventional medications fail to provide adequate seizure control. This abstract delves into recent advancements and innovative therapies aimed at addressing the complex challenge of CNS-related drug-resistant epilepsy (DRE) management. The idea of precision medicine has opened up new avenues for epilepsy treatment. Herbs such as curcumin, ginkgo biloba, panax ginseng, bacopa monnieri, ashwagandha, and rhodiola rosea influence the BDNF pathway through various mechanisms. These include the activation of CREB, inhibition of NF-κB, modulation of neurotransmitters, reduction of oxidative stress, and anti- inflammatory effects. By promoting BDNF expression and activity, these herbs support neuroplasticity, cognitive function, and overall neuronal health. Novel antiepileptic drugs (AEDs) with distinct mechanisms of action demonstrate efficacy in refractory cases where traditional medications falter. Additionally, repurposing existing drugs for antiepileptic purposes presents a cost-effective strategy to broaden therapeutic choices. Cannabidiol (CBD), derived from cannabis herbs, has garnered attention for its anticonvulsant properties, offering a potential adjunctive therapy for refractory seizures. In conclusion, recent advances and innovative therapies represent a multifaceted approach to managing drug-resistant epilepsy. Leveraging precision medicine, neurostimulation technologies, novel pharmaceuticals, and complementary therapies, clinicians can optimize treatment outcomes and improve the life expectancy of patients living with refractory seizures. Genetic testing and biomarker identification now allow for personalized therapeutic approaches tailored to individual patient profiles. Utilizing next-generation sequencing techniques, researchers have elucidated genetic mutations.
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Affiliation(s)
- Amit Anand
- Department of Pharmacognosy, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India
| | - Aman Shrivastava
- Department of Pharmacology, Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India
| | - Kuldeep Singh
- Department of Pharmacology, Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India
| | - Rakesh Barik
- GITAM School of Pharmacy, GITAM University, Hyderabad, Telangana, India
| | - Devshree Gayakwad
- Acropolis Institute of Pharmaceutical Education and Research, Indore, Madhya Pradesh, India
| | - S Jailani
- Formulation R&D Department, Alpha Pharma, KAEC, Rabigh, Kingdom of Saudi Arabia
| | - Shamim
- IIMT College of Medical Sciences, IIMT University, Ganga Nagar, Meerut, Uttar Pradesh, India
| | - Sumeet Dwivedi
- Acropolis Institute of Pharmaceutical Education and Research, Indore, Madhya Pradesh, India
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Hu D, Yu C, Zhang X, Zhong Y, Zhu Y, Tian M, Zhang H. [ 18F]FDG PET for mapping the cerebral glucose metabolic characteristics of drug-sensitive and drug-resistant epilepsy in pediatric patients. Eur J Nucl Med Mol Imaging 2025; 52:564-573. [PMID: 39373899 DOI: 10.1007/s00259-024-06933-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 09/28/2024] [Indexed: 10/08/2024]
Abstract
OBJECTIVE This study aimed to investigate [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG PET) mapping for cerebral glucose metabolism in drug-sensitive and drug-resistant pediatric epilepsy patients. METHODS This retrospective study enrolled 40 patients and 25 controls. Patients were categorized into drug-sensitive epilepsy (n = 22) and drug-resistant epilepsy (n = 18) according to the seizure frequency at follow-up. All patients underwent two [18F]FDG PET scans separated by a minimum of one year. Absolute asymmetry index (|AI|) was calculated for assessing metabolic differences and changes in epileptic foci. Statistical Parametric Mapping (SPM) was utilized to reveal voxel-wise metabolic characteristics and alterations throughout the brain. Network analysis based on graph theory was used to investigate network-level differences between the two patient groups. RESULTS The drug-sensitive group showed a lower |AI| at both baseline (P = 0.038) and follow-up (P = 0.003) PET scans than the drug-resistant group. |AI| decreased in the drug-sensitive group and increased in the drug-resistant group across scans, but these trends were not statistically significant (P = 0.240 and P = 0.450, respectively). Both groups exhibited hypometabolism at baseline. The drug-sensitive group showed less hypometabolic brain regions than the drug-resistant group. The drug-sensitive maintained stable level of hypometabolism between the two scans, whereas the drug-resistant group showed an increasing hypometabolism. Network analysis demonstrated that the drug-sensitive group had a higher global efficiency, average degree, and clustering, along with a shorter characteristic path length compared to the drug-resistant group. CONCLUSIONS For the first time, this study revealed in vivo cerebral glucose metabolic pattern of nonsurgical pediatric epilepsy patients treated by antiepileptic drugs. Especially, drug-resistant epilepsy patients represented significantly extensive and progressive hypometabolism with inefficient brain network connectivity compared with drug-sensitive epilepsy. [18F]FDG PET imaging may be a potential visual approach for theranostics of epilepsy patients.
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Affiliation(s)
- Daoyan Hu
- College of Biomedical Engineering & Instrument Science, Zhejiang University, Hangzhou, 310014, Zhejiang, China
- Department of Nuclear Medicine and Medical PET Center, The Second Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
- Institute of Nuclear Medicine and Molecular, Imaging of Zhejiang University, Hangzhou, 310009, Zhejiang, China
- Key Laboratory of Medical Molecular Imaging of Zhejiang Province, Hangzhou, 310009, Zhejiang, China
| | - Congcong Yu
- Department of Nuclear Medicine and Medical PET Center, The Second Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
- Institute of Nuclear Medicine and Molecular, Imaging of Zhejiang University, Hangzhou, 310009, Zhejiang, China
- Key Laboratory of Medical Molecular Imaging of Zhejiang Province, Hangzhou, 310009, Zhejiang, China
| | - Xiaohui Zhang
- Department of Nuclear Medicine and Medical PET Center, The Second Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
- Institute of Nuclear Medicine and Molecular, Imaging of Zhejiang University, Hangzhou, 310009, Zhejiang, China
- Key Laboratory of Medical Molecular Imaging of Zhejiang Province, Hangzhou, 310009, Zhejiang, China
| | - Yan Zhong
- Department of Nuclear Medicine and Medical PET Center, The Second Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
- Institute of Nuclear Medicine and Molecular, Imaging of Zhejiang University, Hangzhou, 310009, Zhejiang, China
- Key Laboratory of Medical Molecular Imaging of Zhejiang Province, Hangzhou, 310009, Zhejiang, China
| | - Yuankai Zhu
- Department of Nuclear Medicine and PET Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Mei Tian
- Department of Nuclear Medicine and Medical PET Center, The Second Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
- Institute of Nuclear Medicine and Molecular, Imaging of Zhejiang University, Hangzhou, 310009, Zhejiang, China.
- Key Laboratory of Medical Molecular Imaging of Zhejiang Province, Hangzhou, 310009, Zhejiang, China.
- Huashan Hospital and Human Phenome Institute, Fudan University, Shanghai, 200040, China.
| | - Hong Zhang
- College of Biomedical Engineering & Instrument Science, Zhejiang University, Hangzhou, 310014, Zhejiang, China.
- Department of Nuclear Medicine and Medical PET Center, The Second Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
- Institute of Nuclear Medicine and Molecular, Imaging of Zhejiang University, Hangzhou, 310009, Zhejiang, China.
- Key Laboratory of Medical Molecular Imaging of Zhejiang Province, Hangzhou, 310009, Zhejiang, China.
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Zhao T, Li HJ, Zhang HL, Yu J, Feng J, Cui L, Sun KF, Sun Y, Yu LH. Effects of CYP2C19 and CYP2C9 polymorphisms on the efficacy and plasma concentration of lacosamide in pediatric patients with epilepsy in China. Eur J Pediatr 2024; 184:73. [PMID: 39658609 DOI: 10.1007/s00431-024-05897-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 11/03/2024] [Accepted: 11/20/2024] [Indexed: 12/12/2024]
Abstract
To evaluate the effects of cytochrome P450 family 2 subfamily C member 9 (CYP2C9) and cytochrome P450 family 2 subfamily C member 19 (CYP2C19) polymorphisms on the plasma concentrations, efficacy, and safety of lacosamide (LCM) among pediatric patients with epilepsy. This prospective study was conducted at two institutions. It included 215 pediatric patients with epilepsy who were under LCM. LCM plasma concentrations were quantified using validated ultra-performance liquid chromatography. CYP2C9 and CYP2C19 polymorphisms were analyzed in all pediatric patients in our hospital's Institute of Clinical Pharmacy research laboratory through polymerase chain reaction, agarose gel electrophoresis detection, gel recovery, and other steps. Seizure frequencies were recorded 3, 6, and 12 months after initiating LCM therapy and compared with the baseline monthly frequency. Clinical information, including efficacy, toxicity, and concomitant drugs, was collected. A total of 158 pediatric patients (73.5%) responded to LCM therapy. Of them, 77 patients reported adverse events while under LCM. The LCM plasma concentration was linearly correlated with its daily dose (r = 0.26, p < 0.001). Patients with adverse events reported higher LCM plasma concentrations (7.9 ± 4.0 µg/mL) than patients without adverse events (6.8 ± 3.0 µg/mL; p < 0.05). The poor metabolizer (PM) group demonstrated the highest concentration-to-dose ratio (1.7 ± 0.7 μg·mL-1·kg·mg-1) than the extensive metabolizer, intermediate metabolizer, and ultra-rapid metabolizer groups (0.8 ± 0.4, 1.0 ± 0.5, and 0.8 ± 0.4 μg·mL-1·kg·mg-1, respectively). The PM group comprised the highest proportion of patients with effective LCM (9/11, 81.8%) and adverse events (7/11, 63.6%). CONCLUSION LCM plasma concentrations were strongly associated with its clinical efficacy and toxicity. CYP2C19 polymorphisms affect the plasma concentration and treatment efficacy in pediatric patients with epilepsy. CYP2C19 PMs with two no-function alleles are likely to have higher LCM plasma concentrations. WHAT IS KNOWN • LCM is metabolized by CYP2C19, CYP2C9, and CYP3A4 into pharmacologically inactive O-desmethyl-lacosamide; it primarily undergoes renal elimination. • Plasma LCM concentrations in patients treated with the recommended dose vary widely between and within individuals variability. WHAT IS NEW • CYP2C19 polymorphisms affect the plasma concentration and treatment efficacy in Chinese pediatric patients with epilepsy. • CYP2C19 PMs with two no-function alleles are likely to have higher plasma LCM concentrations.
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Affiliation(s)
- Ting Zhao
- Department of Pharmacy, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, 830001, Xinjiang, China
- Institute of Clinical Pharmacy, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, 830001, Xinjiang, China
| | - Hong-Jian Li
- Department of Pharmacy, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, 830001, Xinjiang, China
- Institute of Clinical Pharmacy, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, 830001, Xinjiang, China
| | - Hui-Lan Zhang
- Department of Pharmacy, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, 830001, Xinjiang, China
- Institute of Clinical Pharmacy, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, 830001, Xinjiang, China
| | - Jing Yu
- Department of Pediatrics, Children's Hospital of Xinjiang Uygur Autonomous Region, Xinjiang Hospital of Beijing Children's Hospital, Urumqi, 830001, Xinjiang, China
| | - Jie Feng
- Department of Pharmacy, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, 830001, Xinjiang, China
- Institute of Clinical Pharmacy, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, 830001, Xinjiang, China
| | - Long Cui
- Department of Pharmacy, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, 830001, Xinjiang, China
- Institute of Clinical Pharmacy, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, 830001, Xinjiang, China
| | - Ke-Fang Sun
- Medicine, Zhejiang University School, Hangzhou, Zhejiang, China
| | - Yan Sun
- Department of Pediatrics, Children's Hospital of Xinjiang Uygur Autonomous Region, Xinjiang Hospital of Beijing Children's Hospital, Urumqi, 830001, Xinjiang, China.
| | - Lu-Hai Yu
- Department of Pharmacy, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, 830001, Xinjiang, China.
- Institute of Clinical Pharmacy, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, 830001, Xinjiang, China.
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Sun YH, Hu BW, Tan LH, Lin L, Cao SX, Wu TX, Wang H, Yu B, Wang Q, Lian H, Chen J, Li XM. Posterior Basolateral Amygdala is a Critical Amygdaloid Area for Temporal Lobe Epilepsy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2407525. [PMID: 39476381 DOI: 10.1002/advs.202407525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 10/06/2024] [Indexed: 12/28/2024]
Abstract
The amygdaloid complex consists of multiple nuclei and is a key node in controlling temporal lobe epilepsy (TLE) in both human and animal model studies. However, the specific nucleus in the amygdaloid complex and the neural circuitry governing seizures remain unknown. Here, it is discovered that activation of glutamatergic neurons in the posterior basolateral amygdala (pBLA) induces severe seizures and even mortality. The pBLA glutamatergic neurons project collateral connections to multiple brain regions, including the insular cortex (IC), bed nucleus of the stria terminalis (BNST), and central amygdala (CeA). Stimulation of pBLA-targeted IC neurons triggers seizures, whereas ablation of IC neurons suppresses seizures induced by activating pBLA glutamatergic neurons. GABAergic neurons in the BNST and CeA establish feedback inhibition on pBLA glutamatergic neurons. Deleting GABAergic neurons in the BNST or CeA leads to sporadic seizures, highlighting their role in balancing pBLA activity. Furthermore, pBLA neurons receive glutamatergic inputs from the ventral hippocampal CA1 (vCA1). Ablation of pBLA glutamatergic neurons mitigates both acute and chronic seizures in the intrahippocampal kainic acid-induced mouse model of TLE. Together, these findings identify the pBLA as a pivotal nucleus in the amygdaloid complex for regulating epileptic seizures in TLE.
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Affiliation(s)
- Yan-Hui Sun
- Department of Neurology and Department of Psychiatry of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310058, China
- NHC and CAMS Key Laboratory of Medical Neurobiology, Ministry of Education Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Bo-Wu Hu
- Department of Neurology and Department of Psychiatry of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310058, China
- NHC and CAMS Key Laboratory of Medical Neurobiology, Ministry of Education Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Li-Heng Tan
- Department of Neurology and Department of Psychiatry of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310058, China
- NHC and CAMS Key Laboratory of Medical Neurobiology, Ministry of Education Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Lin Lin
- Department of Neurology and Department of Psychiatry of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310058, China
- NHC and CAMS Key Laboratory of Medical Neurobiology, Ministry of Education Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Shu-Xia Cao
- Department of Neurobiology of Sir Run Shaw Hospital, Zhejiang University, Hangzhou, 310058, China
| | - Tan-Xia Wu
- Department of Neurobiology of Sir Run Shaw Hospital, Zhejiang University, Hangzhou, 310058, China
| | - Hao Wang
- Nanhu Brain-computer Interface Institute, Hangzhou, 311100, China
- Affiliated Mental Health Center and Hangzhou Seventh People's Hospital, Zhejiang University, Hangzhou, 310013, China
| | - Bin Yu
- Key Laboratory of Novel Targets, Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, 310015, China
| | - Qin Wang
- Department of Neurology and Department of Psychiatry of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310058, China
- NHC and CAMS Key Laboratory of Medical Neurobiology, Ministry of Education Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Hong Lian
- Research Center of System Medicine, School of Basic Medical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Jiadong Chen
- Department of Neurology and Department of Psychiatry of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310058, China
- NHC and CAMS Key Laboratory of Medical Neurobiology, Ministry of Education Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Xiao-Ming Li
- Department of Neurology and Department of Psychiatry of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310058, China
- NHC and CAMS Key Laboratory of Medical Neurobiology, Ministry of Education Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, 310058, China
- Nanhu Brain-computer Interface Institute, Hangzhou, 311100, China
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Yang Y, Shang J, Xia Y, Gui Y. Fluorescent probes for sensing peroxynitrite: biological applications. Redox Rep 2024; 29:2430157. [PMID: 39581574 PMCID: PMC11587728 DOI: 10.1080/13510002.2024.2430157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2024] Open
Abstract
Peroxynitrite (ONOO-) is a quintessential reactive oxygen species (ROS) and reactive nitrogen species (RNS), renowned for its potent oxidizing and nitrifying capabilities. Under normal physiological conditions, a baseline level of ONOO- is present within the body. However, its production escalates significantly in response to oxidative stress. ONOO- is highly reactive with various biomolecules in vivo, particularly proteins, lipids, and nucleic acids, thereby playing a role in a spectrum of physiological and pathological processes, such as inflammation, cancer, neurodegenerative diseases, and cardiovascular diseases. Consequently, detecting ONOO- in vivo is of paramount importance for understanding the etiology of various diseases and facilitating early diagnosis. Fluorescent probes have become a staple in the identification of biomolecules due to their ease of use, convenience, and superior sensitivity and specificity. This review highlights the recent advancements in the development of fluorescent probes for the detection of ONOO- in diverse disease models and provides an in-depth examination of their design and application.
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Affiliation(s)
- Yan Yang
- Hubei Key Laboratory of Cognitive and Affective Disorders, Jianghan University, Wuhan, Hubei, People’s Republic of China
- Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, Hubei, People’s Republic of China
| | - Jinting Shang
- Hubei Key Laboratory of Cognitive and Affective Disorders, Jianghan University, Wuhan, Hubei, People’s Republic of China
- Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, Hubei, People’s Republic of China
| | - Yiyuan Xia
- Hubei Key Laboratory of Cognitive and Affective Disorders, Jianghan University, Wuhan, Hubei, People’s Republic of China
- Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, Hubei, People’s Republic of China
- Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, Hubei, People’s Republic of China
| | - Yuran Gui
- Hubei Key Laboratory of Cognitive and Affective Disorders, Jianghan University, Wuhan, Hubei, People’s Republic of China
- Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, Hubei, People’s Republic of China
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Wang J, Wu T, Zhao Y, Mao L, Ding J, Wang X. IL-17A Aggravated Blood-Brain Barrier Disruption via Activating Src Signaling in Epilepsy Mice. Mol Neurobiol 2024; 61:11012-11025. [PMID: 38819634 DOI: 10.1007/s12035-024-04203-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Accepted: 04/25/2024] [Indexed: 06/01/2024]
Abstract
Inflammation is an important pathogenic driving force in the genesis and development of epilepsy. The latest researches demonstrated that IL-17A mediated blood-brain barrier (BBB) dysfunction through disruption of tight junction protein expression. To investigate whether IL-17A is involved in BBB disruption after acute seizure attack, the pilocarpine model was established with C57BL/6 J (wild type, WT) and IL-17R-deficient mice in vivo and with primary cultured rat brain microvascular endothelial cells in vitro. The mortality rate and brain water content were evaluated at 24 h after status epilepticus, and IL-17A concentration, endothelial tight junction, adherens junction proteins, and albumin leakage were assessed at 0 h, 4 h, 12 h, and 24 h after status epilepticus (SE). IL-17R-deficient mice showed lessen severity of epilepsy than WT mice, accompanied by less albumin leakage, reduced brain water content, decreased IL-17A, and upregulated expression of target proteins (ZO-1, Occludin and VE-cadherin). IL-17R knockout abrogated abnormal upregulation of Src kinase and phosphorylated Src kinase in the setting of SE, and Src kinase inhibitor PP1 abrogated IL-17A-induced SE related endothelial injury in vitro. In conclusion, IL-17A inhibition might be a promising therapeutic option to attenuate endothelial cell injury and further BBB disruption by reducing Src kinase activation.
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Affiliation(s)
- Jing Wang
- Department of Neurology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Tingting Wu
- Department of Neurology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Yanan Zhao
- Department of Neurology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
- Department of Neurology, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lingyan Mao
- Department of Neurology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Jing Ding
- Department of Neurology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
- CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai, China.
| | - Xin Wang
- Department of Neurology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
- CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai, China
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Buchanan GF. Who's Down With UDP?-Not Epilepsy; Purinergic Microglial Ca 2+ Signaling Mediates Epileptogenesis. Epilepsy Curr 2024:15357597241293849. [PMID: 39545019 PMCID: PMC11558650 DOI: 10.1177/15357597241293849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2024] Open
Abstract
Purinergic mechanisms mediate microglial Ca 2 + signaling in epileptogenesis Umpierre, AD, Li, B, Katayoun, A, Simon, WL, Zhao, S, Xie, M, Thyen, G, Hur, B, Zheng, J, Liang, Y, Bosco, DB, Maynes, MA, Wu, Z, Yu, X, Sung, J, Johnson, AJ, Li, Y, Wu,J-L. 2024. Microglial P2Y6 calcium signaling promotes phagocytosis and shapes neuroimmune responses in epileptogenesis. Neuron 112:1959-1977. Microglial calcium signaling is rare in a baseline state but strongly engaged during early epilepsy development. The mechanism(s) governing microglial calcium signaling are not known. By developing an in vivo uridine diphosphate (UDP) fluorescent sensor, GRABUDP1.0, we discovered that UDP release is a conserved response to seizures and excitotoxicity across brain regions. UDP can signal through the microglial-enriched P2Y6 receptor to increase calcium activity during epileptogenesis. P2Y6 calcium activity is associated with lysosome biogenesis and enhanced production of NF-kB-related cytokines. In the hippocampus, knockout of the P2Y6 receptor prevents microglia from fully engulfing neurons. Attenuating microglial calcium signaling through calcium extruder (“CalEx”) expression recapitulates multiple features of P2Y6 knockout, including reduced lysosome biogenesis and phagocytic interactions. Ultimately, P2Y6 knockout mice retain more CA3 neurons and better cognitive task performance during epileptogenesis. Our results demonstrate that P2Y6 signaling impacts multiple aspects of myeloid cell immune function during epileptogenesis.
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Affiliation(s)
- Gordon F Buchanan
- Department of Neurology, Iowa Neuroscience Institute, Neuroscience Program, and Medical Scientist Training Program, Carver College of Medicine, University of Iowa
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Cai Y, He X, Ao L, Liu Y, Zhang Y, Yang H, Zhang L. Efficacy and safety of traditional Chinese medicine for the treatment of epilepsy by wind quenching and phlegm resolving: A systematic review and meta-analysis. Medicine (Baltimore) 2024; 103:e39942. [PMID: 39470546 PMCID: PMC11521077 DOI: 10.1097/md.0000000000039942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 09/05/2024] [Accepted: 09/13/2024] [Indexed: 10/30/2024] Open
Abstract
BACKGROUND Using wind-quenching and phlegm-resolving (WQPR) therapy for epilepsy has yielded beneficial results in various clinical studies. However, a comprehensive analysis of the WQPR approach to epilepsy has not yet conducted to date. This study aimed to evaluate the effectiveness and safety of the WQPR method in traditional Chinese medicine (TCM) for epilepsy. METHODS Eight databases, including The Cochrane Library, Web of Science, PubMed, Embase, Chinese Biomedical Database, Chinese National Knowledge Infrastructure, Chinese Science and Technology Periodical Database (VIP), and WanFang Database, were comprehensively searched to include randomized controlled trials (RCTs) investigating the WQPR approach in epilepsy. Quality was evaluated by the Cochrane Handbook for Systematic Reviews of Interventions, and meta-analysis was conducted using the RevMan 5.4 and Stata 14.0 software. For the outcome indicators with the number of studies ≥ 10, funnel chart and Egger test were used to evaluate the bias, and the evidence quality was evaluated according to GRADEpro system. RESULTS We included 19 randomized controlled trials with 1475 participants. Compared to the control group, the WQPR approach showed clinical efficacy for epilepsy (odds ratio = 3.23, 95% confidence interval [CI] [2.19, 4.77], Z = 5.90, P < .00001), reduced seizure frequency (standardized mean differences = -1.24, 95% CI [-1.62, -0.85], Z = 6.26, P < .00001), shortened seizure duration (standardized mean differences = -2.07, 95% CI [-2.99, -1.14], Z = 4.39, P < .0001), improved patient's quality of life (mean difference = 2.60, 95% CI [2.16, 3.03], Z = 11.62, P < .00001), and ameliorated TCM syndromes (mean difference = -4.37, 95% CI [-6.19, -2.56], Z = 4.72, P < .00001). The reduced rate of adverse reactions (odds ratio = 0.56, 95% CI [0.37, 0.85], Z = 2.71, P = .007). CONCLUSION WQPR therapy appears to be an effective and safe approach for treating epilepsy, increasing clinical efficacy, reducing seizures' frequency and duration, improving patients' quality of life, ameliorating TCM syndromes, and reducing adverse reaction rates.
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Affiliation(s)
- Yufen Cai
- Guilin Hospital of Traditional Chinese Medicine, Guangxi, China
- Guizhou University of Chinese Medicine, Guiyang, China
| | - Xiaofang He
- Department of Pediatric Intensive Care Unit, Guizhou Provincial People's Hospital, Guiyang, China
- Wuxi School of Medicine, Jiangnan University, Beijing, China
| | - Liting Ao
- Guizhou University of Chinese Medicine, Guiyang, China
| | - Yibo Liu
- Guizhou University of Chinese Medicine, Guiyang, China
| | - Yanju Zhang
- Guizhou University of Chinese Medicine, Guiyang, China
| | - Hui Yang
- Department of Neurology, The Second Affiliated Hospital of Guizhou University of Chinese Medicine, Guiyang, China
| | - Lin Zhang
- Department of Neurology, The Second Affiliated Hospital of Guizhou University of Chinese Medicine, Guiyang, China
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Zhang X, Xiang F, Shi X, Wang Z, Li Y, Zhang S, Lan X, Lang S, Wang X. Characteristics and treatment of midlife-onset epilepsy: A 24-year single-center, retrospective study. Epileptic Disord 2024; 26:600-608. [PMID: 38896014 DOI: 10.1002/epd2.20253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 05/27/2024] [Accepted: 06/02/2024] [Indexed: 06/21/2024]
Abstract
OBJECTIVE This study aimed to analyze the clinical characteristics, etiology, and treatment of midlife-onset epilepsy in a real-world setting at a single center in China. METHODS The clinical data of patients who attended the epilepsy clinic of the Department of Neurology, First Medical Center of Chinese PLA General Hospital from February 1999 to March 2023 were retrospectively analyzed. The clinical characteristics, etiology, and risk factors for midlife-onset epilepsy over the past 24 years were analyzed. RESULTS Of the 969 patients with onset at 45-64 years of age, 914 were diagnosed with epilepsy with at least two unprovoked seizures 24 h apart. Of those, 99.7% (911) were of focal origin. The median duration from the initial seizure to follow-up treatment was 2 months (interquartile range [IQR]: 1.0-6.0 months). Before commencing treatment, 30.2% (207/683) of patients experienced more than two seizures. A structural etiology was found in 66.3% (606/914) of patients. Cerebrovascular disease (CVD) and traumatic brain injury (TBI) accounted for 19.9% (182/914) and 16.6% (152/914) of the cases, respectively. Logistic regression analysis showed that patients with abnormal imaging (odds ratio [OR] 2.04; 95% confidence interval [CI] 1.25-3.32; p = .004), focal seizures (OR 2.98; 95%CI 1.82-4.87; p < .001), and seizure clusters (OR 2.40; 95%CI 1.21-4.73; p = .01) had poor drug responses. Treatment outcomes were generally better in patients with epilepsy after CVD (OR .49; 95%CI .28-.85; p = .01). Treatment initiation after two seizures (OR .70; 95%CI .42-1.15; p = .16) or 6 months after the first seizure (OR 1.17; 95%CI .66-2.09; p = .58) did not result in poor drug effectiveness. SIGNIFICANCE Midlife-onset epilepsy is typically of focal etiology, with CVD being the most common cause, and tends to respond well to medication. The median duration from the initial seizure to follow-up treatment was 2 months. Over 30% of patients experienced more than two seizures before commencing treatment, but this did not affect subsequent outcomes.
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Affiliation(s)
- Xu Zhang
- Department of Neurology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Feng Xiang
- Department of Neurology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xiaobing Shi
- Department of Neurology, The Second Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Ziyu Wang
- Department of Electrophysiology, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China
| | - Yang Li
- Department of Neurology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Shimin Zhang
- Department of Neurology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xiaoyang Lan
- Department of Neurology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Senyang Lang
- Department of Neurology, Hainan Hospital of Chinese PLA General Hospital, Sanya, China
| | - Xiangqing Wang
- Department of Neurology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
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Liu Z, De Schutter E, Li Y. GABA-Induced Seizure-Like Events Caused by Multi-ionic Interactive Dynamics. eNeuro 2024; 11:ENEURO.0308-24.2024. [PMID: 39443111 PMCID: PMC11524612 DOI: 10.1523/eneuro.0308-24.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 09/17/2024] [Indexed: 10/25/2024] Open
Abstract
Experimental evidence showed that an increase in intracellular chloride concentration [Formula: see text] caused by gamma-aminobutyric acid (GABA) input can promote epileptic firing activity, but the actual mechanisms remain elusive. Here in this theoretical work, we show that influx of chloride and concomitant bicarbonate ion [Formula: see text] efflux upon GABA receptor activation can induce epileptic firing activity by transition of GABA from inhibition to excitation. We analyzed the intrinsic property of neuron firing states as a function of [Formula: see text] We found that as [Formula: see text] increases, the system exhibits a saddle-node bifurcation, above which the neuron exhibits a spectrum of intensive firing, periodic bursting interrupted by depolarization block (DB) state, and eventually a stable DB through a Hopf bifurcation. We demonstrate that only GABA stimuli together with [Formula: see text] efflux can switch GABA's effect to excitation which leads to a series of seizure-like events (SLEs). Exposure to a low [Formula: see text] can drive neurons with high concentrations of [Formula: see text] downward to lower levels of [Formula: see text], during which it could also trigger SLEs depending on the exchange rate with the bath. Our analysis and simulation results show how the competition between GABA stimuli-induced accumulation of [Formula: see text] and [Formula: see text] application-induced decrease of [Formula: see text] regulates the neuron firing activity, which helps to understand the fundamental ionic dynamics of SLE.
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Affiliation(s)
- Zichao Liu
- School of Systems Science, Beijing Normal University, Beijing 100875, China
| | - Erik De Schutter
- Computational Neuroscience Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa 904-0495, Japan
| | - Yinyun Li
- School of Systems Science, Beijing Normal University, Beijing 100875, China
- Computational Neuroscience Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa 904-0495, Japan
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26
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Gao Y, Ma L, Yuan J, Huang Y, Ban Y, Zhang P, Tan D, Liang M, Li Z, Gong C, Xu T, Yang X, Chen Y. GLS2 reduces the occurrence of epilepsy by affecting mitophagy function in mouse hippocampal neurons. CNS Neurosci Ther 2024; 30:e70036. [PMID: 39404053 PMCID: PMC11474837 DOI: 10.1111/cns.70036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 07/21/2024] [Accepted: 07/26/2024] [Indexed: 10/19/2024] Open
Abstract
BACKGROUND Altered mitophagy has been observed in various neurological disorders, such as epilepsy. The role of mitophagy in causing neuronal damage during epileptic episodes is significant, and recent research has indicated that GLS2 plays a crucial role in regulating autophagy. However, exactly how GLS2 affects epilepsy is still unclear. AIMS To investigate the expression and distribution characteristics of GLS2 in epilepsy, and then observed the changes in behavior and electrophysiology caused by overexpression of GLS2 in epileptic mice, and determined whether GLS2 regulated seizure-like changes in the mouse model through the protective mechanism of mitophagy. RESULTS The expression of GLS2 in a kainic acid (KA)-induced epileptic mouse model and aglutamate-inducedneuronal excitatory damage in HT22 cells model was downregulation. In brief, overexpression of GLS2 can alleviate epileptic activity. Subsequently, we demonstrated that GLS2 interacts with mitophagy-related proteins in a KA-induced epilepsy mouse model. Mechanistically, overexpression of GLS2 inhibited mitophagy in epileptic mice, downregulating the expression of LC3 and reducing ROS production. CONCLUSIONS This study proves the GLS2 expression pattern is abnormal in epileptic mice. The function of mitophagy in hippocampal neurons is affected by GLS2, and overexpression of GLS2 can reduce the occurrence of seizure-like events (SLEs) by altering mitophagy function. Thus, GLS2 might control seizures, and our findings provide a fresh avenue for antiepileptic treatment and offer novel insights into treating and preventing epilepsy.
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Affiliation(s)
- Yuan Gao
- Department of NeurologyThe Second Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Limin Ma
- Department of NeurologyThe Second Affiliated Hospital of Chongqing Medical UniversityChongqingChina
- Department of GerontologyChongqing University Three Gorges HospitalChongqingChina
| | - Jinxian Yuan
- Department of NeurologyThe Second Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Yunyi Huang
- Department of NeurologyThe Second Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Yuenan Ban
- Department of NeurologyThe Second Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Peng Zhang
- Department of NeurologyThe Second Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Dandan Tan
- Department of NeurologyThe Second Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Minxue Liang
- Department of NeurologyThe Second Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Zhipeng Li
- Department of NeurologyThe Second Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Chen Gong
- Department of NeurologyThe Second Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Tao Xu
- Department of NeurologyThe Second Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Xiaolan Yang
- Department of NeurologyThe Second Affiliated Hospital of Chongqing Medical UniversityChongqingChina
- Department of NeurologyChongqing Medical University Affiliated Second Hospital Affiliated Fengjie HospitalChongqingChina
| | - Yangmei Chen
- Department of NeurologyThe Second Affiliated Hospital of Chongqing Medical UniversityChongqingChina
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27
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Wang H, Qiao Z, Luan K, Xiang W, Chang X, Zhang Y, Wei N, Wang K. Identification of a new retigabine derivative with improved photostability for selective activation of neuronal Kv7 channels and antiseizure activity. Epilepsia 2024; 65:2923-2934. [PMID: 39140981 DOI: 10.1111/epi.18092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 07/27/2024] [Accepted: 07/29/2024] [Indexed: 08/15/2024]
Abstract
OBJECTIVE Pharmacological activation of neuronal Kv7 channels by the antiepileptic drug retigabine (RTG; ezogabine) has been proven effective in treating partial epilepsy. However, RTG was withdrawn from the market due to the toxicity caused by its phenazinium dimer metabolites, leading to peripheral skin discoloration and retinal abnormalities. To address the undesirable metabolic properties of RTG and prevent the formation of phenazinium dimers, we made chemical modifications to RTG, resulting in a new RTG derivative, 1025c, N,N'-{4-[(4-fluorobenzyl) (prop-2-yn-1-yl)amino]-1,2-phenylene}bis(3,3-dimethylbutanamide). METHODS Whole-cell recordings were used to evaluate Kv7 channel openers. Site-directed mutagenesis and molecular docking were adopted to investigate the molecular mechanism underlying 1025c and Kv7.2 interactions. Mouse seizure models of maximal electroshock (MES), subcutaneous pentylenetetrazol (scPTZ), and PTZ-induced kindling were utilized to test compound antiepileptic activity. RESULTS The novel compound 1025c selectively activates whole-cell Kv7.2/7.3 currents in a concentration-dependent manner, with half-maximal effective concentration of .91 ± .17 μmol·L-1. The 1025c compound also causes a leftward shift in Kv7.2/7.3 current activation toward a more hyperpolarized membrane potential, with a shift of the half voltage of maximal activation (ΔV1/2) of -18.6 ± 3.0 mV. Intraperitoneal administration of 1025c demonstrates dose-dependent antiseizure activities in assays of MES, scPTZ, and PTZ-induced kindling models. Moreover, through site-directed mutagenesis combined with molecular docking, a key residue Trp236 has been identified as critical for 1025c-mediated activation of Kv7.2 channels. Photostability experiments further reveal that 1025c is more photostable than RTG and is unable to dimerize. SIGNIFICANCE Our findings demonstrate that 1025c exhibits potent and selective activation of neuronal Kv7 channels without being metabolized to phenazinium dimers, suggesting its developmental potential as an antiseizure agent for therapy.
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Affiliation(s)
- Hongbin Wang
- Departments of Pharmacology and Pharmaceutical Analysis, School of Pharmacy, Qingdao University Medical College, Qingdao, China
| | - Zhen Qiao
- School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, China
- Qingdao Key Laboratory of Neurorehabilitation, University of Health and Rehabilitation Sciences, Qingdao, China
| | - Kun Luan
- Departments of Pharmacology and Pharmaceutical Analysis, School of Pharmacy, Qingdao University Medical College, Qingdao, China
| | - Wei Xiang
- Departments of Pharmacology and Pharmaceutical Analysis, School of Pharmacy, Qingdao University Medical College, Qingdao, China
| | - Xiuying Chang
- Departments of Pharmacology and Pharmaceutical Analysis, School of Pharmacy, Qingdao University Medical College, Qingdao, China
| | - Yanru Zhang
- Departments of Pharmacology and Pharmaceutical Analysis, School of Pharmacy, Qingdao University Medical College, Qingdao, China
- Institute of Innovative Drug Discovery, Qingdao University Medical College, Qingdao, China
| | - Ningning Wei
- Departments of Pharmacology and Pharmaceutical Analysis, School of Pharmacy, Qingdao University Medical College, Qingdao, China
- Institute of Innovative Drug Discovery, Qingdao University Medical College, Qingdao, China
| | - KeWei Wang
- Departments of Pharmacology and Pharmaceutical Analysis, School of Pharmacy, Qingdao University Medical College, Qingdao, China
- Institute of Innovative Drug Discovery, Qingdao University Medical College, Qingdao, China
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28
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Lu T, Chen X, Zhang Q, Shang K, Yang X, Xiang W. Vitamin D Relieves Epilepsy Symptoms and Neuroinflammation in Juvenile Mice by Activating the mTOR Signaling Pathway via RAF1: Insights from Network Pharmacology and Molecular Docking Studies. Neurochem Res 2024; 49:2379-2392. [PMID: 38837094 DOI: 10.1007/s11064-024-04176-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 03/15/2024] [Accepted: 05/22/2024] [Indexed: 06/06/2024]
Abstract
Epilepsy is a common neurological disorder, and the exploration of potential therapeutic drugs for its treatment is still ongoing. Vitamin D has emerged as a promising treatment due to its potential neuroprotective effects and anti-epileptic properties. This study aimed to investigate the effects of vitamin D on epilepsy and neuroinflammation in juvenile mice using network pharmacology and molecular docking, with a focus on the mammalian target of rapamycin (mTOR) signaling pathway. Experimental mouse models of epilepsy were established through intraperitoneal injection of pilocarpine, and in vitro injury models of hippocampal neurons were induced by glutamate (Glu) stimulation. The anti-epileptic effects of vitamin D were evaluated both in vivo and in vitro. Network pharmacology and molecular docking analysis were used to identify potential targets and regulatory pathways of vitamin D in epilepsy. The involvement of the mTOR signaling pathway in the regulation of mouse epilepsy by vitamin D was validated using rapamycin (RAPA). The levels of inflammatory cytokines (TNF-α, IL-1β, and IL-6) were assessed by enzyme-linked immunosorbent assay (ELISA). Gene and protein expressions were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot, respectively. The terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) staining was used to analyze the apoptosis of hippocampal neurons. In in vivo experiments, vitamin D reduced the Racine scores of epileptic mice, prolonged the latency of epilepsy, and inhibited the production of TNF-α, IL-1β, and IL-6 in the hippocampus. Furthermore, network pharmacology analysis identified RAF1 as a potential target of vitamin D in epilepsy, which was further confirmed by molecular docking analysis. Additionally, the mTOR signaling pathway was found to be involved in the regulation of mouse epilepsy by vitamin D. In in vitro experiments, Glu stimulation upregulated the expressions of RAF1 and LC3II/LC3I, inhibited mTOR phosphorylation, and induced neuronal apoptosis. Mechanistically, vitamin D activated the mTOR signaling pathway and alleviated mouse epilepsy via RAF1, while the use of the pathway inhibitor RAPA reversed this effect. Vitamin D alleviated epilepsy symptoms and neuroinflammation in juvenile mice by activating the mTOR signaling pathway via RAF1. These findings provided new insights into the molecular mechanisms underlying the anti-epileptic effects of vitamin D and further supported its use as an adjunctive therapy for existing anti-epileptic drugs.
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Affiliation(s)
- Tiantian Lu
- School of Pediatrics, Hainan Medical University, Haikou, 571199, China
- Department of Neonatology, Haikou Maternal and Child Health Hospital, Haikou, 570203, China
| | - Xiuling Chen
- Department of Pediatric Medicine, Affiliated Haikou Hospital of Xiangya Medical School Central South University, Haikou, 570208, China
| | - Qin Zhang
- Department of Neurosurgery, Hainan Women and Children's Medical Center, Haikou, 570312, China
| | - Kun Shang
- Institute of Deep-sea Science and Engineering, Chinese Academy of Science, Sanya, 572000, China
| | - Xiaogui Yang
- Department of Neonatology, Haikou Maternal and Child Health Hospital, Haikou, 570203, China
| | - Wei Xiang
- School of Pediatrics, Hainan Medical University, Haikou, 571199, China.
- Hainan Women and Children's Medical Center, Hainan Medical University, Haikou, 570312, China.
- National Health Commission (NHC) Key Laboratory of Tropical Disease Control, Hainan Medical University, Haikou, 570216, China.
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29
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Siddiqui MS, Shahi MH, Castresana JS. The role of the adenylate kinase 5 gene in various diseases and cancer. J Clin Transl Sci 2024; 8:e96. [PMID: 39655021 PMCID: PMC11626602 DOI: 10.1017/cts.2024.536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 03/21/2024] [Accepted: 05/01/2024] [Indexed: 12/12/2024] Open
Abstract
Adenylate kinases (AKs) are important enzymes involved in cellular energy metabolism. Among AKs, AK5 (adenylate kinase 5), a cytosolic protein, is emerging as a significant contributor to various diseases and cellular processes. This comprehensive review integrates findings from various research groups on AK5 since its discovery, shedding light on its multifaceted roles in nucleotide metabolism, energy regulation, and cellular differentiation. We investigate its implications in a spectrum of diseases, including autoimmune encephalitis, epilepsy, neurodegenerative disorders such as Alzheimer's and Parkinson's, diabetes, lower extremity arterial disease, celiac disease, and various cancers. Notably, AK5's expression levels and methylation status have been associated with cancer progression and patient outcomes, indicating its potential as a prognostic indicator. Furthermore, AK5 is implicated in regulating cellular processes in breast cancer, gastric cancer, colorectal carcinoma, prostate cancer, and colon adenocarcinoma, suggesting its relevance across different cancer types. However, a limitation lies in the need for more robust clinical validation and a deeper understanding of AK5's precise mechanisms in disease pathogenesis, despite its association with various pathophysiological conditions. Nonetheless, AK5 holds promise as a therapeutic target, with emerging evidence suggesting its potential in therapy development.
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Affiliation(s)
- M. Sarim Siddiqui
- Interdisciplinary Brain Research Centre, Faculty of Medicine, Aligarh Muslim University, Aligarh202002, India
| | - Mehdi H. Shahi
- Interdisciplinary Brain Research Centre, Faculty of Medicine, Aligarh Muslim University, Aligarh202002, India
| | - Javier S. Castresana
- Department of Biochemistry and Genetics, University of Navarra School of Sciences, Pamplona31008, Spain
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30
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Han J, Wang Y, Wei P, Lu D, Shan Y. Unveiling the hidden connection: the blood-brain barrier's role in epilepsy. Front Neurol 2024; 15:1413023. [PMID: 39206290 PMCID: PMC11349696 DOI: 10.3389/fneur.2024.1413023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Accepted: 07/18/2024] [Indexed: 09/04/2024] Open
Abstract
Epilepsy is characterized by abnormal synchronous electrical activity of neurons in the brain. The blood-brain barrier, which is mainly composed of endothelial cells, pericytes, astrocytes and other cell types and is formed by connections between a variety of cells, is the key physiological structure connecting the blood and brain tissue and is critical for maintaining the microenvironment in the brain. Physiologically, the blood-brain barrier controls the microenvironment in the brain mainly by regulating the passage of various substances. Disruption of the blood-brain barrier and increased leakage of specific substances, which ultimately leading to weakened cell junctions and abnormal regulation of ion concentrations, have been observed during the development and progression of epilepsy in both clinical studies and animal models. In addition, disruption of the blood-brain barrier increases drug resistance through interference with drug trafficking mechanisms. The changes in the blood-brain barrier in epilepsy mainly affect molecular pathways associated with angiogenesis, inflammation, and oxidative stress. Further research on biomarkers is a promising direction for the development of new therapeutic strategies.
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Affiliation(s)
| | | | | | | | - Yongzhi Shan
- Department of Neurosurgery, Xuanwu Hospital Capital Medical University, Beijing, China
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31
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Mello F, Sampaio TB, Neuberger B, Mallmann MP, Fighera MR, Royes LFF, Furian AF, Larrick JW, Oliveira MS. Electroencephalographic and Behavioral Effects of Intranasal Administration of a Na +, K +-ATPase-Activating Antibody after Status Epilepticus. ACS Chem Neurosci 2024; 15:2695-2702. [PMID: 38989663 PMCID: PMC11311123 DOI: 10.1021/acschemneuro.4c00141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 06/11/2024] [Accepted: 07/08/2024] [Indexed: 07/12/2024] Open
Abstract
Status epilepticus (SE) is a medical emergency associated with high mortality and morbidity. Na+, K+-ATPase, is a promising therapeutic target for SE, given its critical role in regulation of neuron excitability and cellular homeostasis. We investigated the effects of a Na+, K+-ATPase-activating antibody (DRRSAb) on short-term electrophysiological and behavioral consequences of pilocarpine-induced SE. Rats were submitted to pilocarpine-induced SE, followed by intranasal administration (2 μg/nostril). The antibody increased EEG activity following SE, namely, EEG power in theta, beta, and gamma frequency bands, assessed by quantitative analysis of EEG power spectra. One week later, DRRSAb-treated animals displayed less behavioral hyperreactivity in pick-up tests and better performance in novel object recognition tests, indicating that the intranasal administration of this Na+, K+-ATPase activator immediately after SE improves behavioral outcomes at a later time point. These results suggest that Na+, K+-ATPase activation warrants further investigation as an adjunctive therapeutic strategy for SE.
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Affiliation(s)
- Fernanda
Kulinski Mello
- Graduate
Program in Pharmacology, Federal University
of Santa Maria, Santa Maria 97105-900, Brazil
| | - Tuane Bazanella Sampaio
- Graduate
Program in Pharmacology, Federal University
of Santa Maria, Santa Maria 97105-900, Brazil
| | - Bruna Neuberger
- Graduate
Program in Pharmacology, Federal University
of Santa Maria, Santa Maria 97105-900, Brazil
| | - Michele Pereira Mallmann
- Graduate
Program in Pharmacology, Federal University
of Santa Maria, Santa Maria 97105-900, Brazil
| | - Michele Rechia Fighera
- Department
of Neuropsychiatry, Federal University of
Santa Maria, Santa Maria 97105-900, Brazil
| | - Luiz Fernando Freire Royes
- Department
of Sports Methods and Techniques, Federal
University of Santa Maria, Santa
Maria 97105-900, Brazil
| | - Ana Flávia Furian
- Graduate
Program in Pharmacology, Federal University
of Santa Maria, Santa Maria 97105-900, Brazil
| | - James W. Larrick
- Panorama
Research Institute, 1230
Bordeaux Dr., Sunnyvale, California 94089, United States
| | - Mauro Schneider Oliveira
- Graduate
Program in Pharmacology, Federal University
of Santa Maria, Santa Maria 97105-900, Brazil
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32
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Lessa VCC, Martins MBM, Vidal ASC, Araujo LA, D'Andrea Meira I. The reality of epilepsy in primary care in Rio de Janeiro: the importance of educational projects for better patient care. ARQUIVOS DE NEURO-PSIQUIATRIA 2024; 82:1-5. [PMID: 39038804 DOI: 10.1055/s-0044-1787796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/24/2024]
Abstract
BACKGROUND The Basic Health Unit (Unidade Básica de Saúde - UBS, in Portuguese) is the first point of contact in the public healthcare system for people with epilepsy. Primary care professionals need to appropriately diagnose, treat, and refer, if necessary, to tertiary services. OBJECTIVE To evaluate the knowledge of UBS professionals on the management of patients with epilepsy in Rio de Janeiro. METHODS Online questionnaires were performed on the topic of epilepsy before and after exposure to classes taught by epileptologists. RESULTS A total of 66 doctors participated, 54.5% of whom were residents or trained in family medicine. The majority had from 1 to 3 years of practice. Insecurity prevailed in the management of pregnant women and the elderly. Around 59.1% of the participants referred patients with seizures without examinations. A total of 78% of the participants did not correctly classify seizure types, and 2/3 did not define drug-resistant epilepsy. Induction and broad-spectrum drugs were common. The therapeutic decision depended on availability in the basic health unit (UBS) (81.8%), dosage (60.6%), side effects (34.8%), and age (36.4%). Comorbidities and sex influenced 1/4 of the sample. For 23% of the participants, the type of crisis did not affect the choice. Regarding typical non-pharmacological options, 75% of the participants were aware of cannabidiol, 40.9% of surgery, 22.7% of ketogenic diet, and 22.8% of deep brain stimulation/vagus nerve stimulation (DBS/VNS). A total of 90.2% indicated the need for training. CONCLUSION There are deficits in the knowledge of UBS professionals in the management of epilepsy. Specialized training is imperative to optimize the care offered within SUS.
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Affiliation(s)
- Vanessa Cristina Colares Lessa
- Instituto Estadual do Cérebro Paulo Niemeyer, Departamento de Epilepsia, Rio de Janeiro RJ, Brazil
- Santa Casa da Misericórdia de São Paulo, Departamento de Epilepsia, São Paulo SP, Brazil
| | - Marília Bezerra Magalhães Martins
- Instituto Estadual do Cérebro Paulo Niemeyer, Departamento de Epilepsia, Rio de Janeiro RJ, Brazil
- Hospital Universitário Gaffrée e Guinle, Departamento de Pediatria, Rio de Janeiro RJ, Brazil
| | | | - Leonardo Alves Araujo
- Instituto Estadual do Cérebro Paulo Niemeyer, Departamento de Epilepsia, Rio de Janeiro RJ, Brazil
| | - Isabella D'Andrea Meira
- Instituto Estadual do Cérebro Paulo Niemeyer, Departamento de Epilepsia, Rio de Janeiro RJ, Brazil
- Universidade Federal Fluminense, Faculdade de Medicina, Programa de Pós-Graduação em Neurologia/Neurociências, Niterói RJ, Brazil
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33
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Glazyrin YE, Veprintsev DV, Timechko EE, Minic Z, Zamay TN, Dmitrenko DV, Berezovski MV, Kichkailo AS. Comparative Proteomic Profiling of Blood Plasma Revealed Marker Proteins Involved in Temporal Lobe Epilepsy. Int J Mol Sci 2024; 25:7935. [PMID: 39063177 PMCID: PMC11276668 DOI: 10.3390/ijms25147935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 07/15/2024] [Accepted: 07/19/2024] [Indexed: 07/28/2024] Open
Abstract
Temporal lobe epilepsy has various origins, involving or not involving structural changes in brain tissue. The mechanisms of epileptogenesis are associated with cell regulation and signaling disruptions expressed in varied levels of proteins. The blood plasma proteomic profiling of temporal lobe epilepsy patients (including magnetic resonance imaging (MRI)-positive and MRI-negative ones) and healthy volunteers using mass spectrometry and label-free quantification revealed a list of differently expressed proteins. Several apolipoproteins (APOA1, APOD, and APOA4), serpin protease inhibitors (SERPINA3, SERPINF1, etc.), complement components (C9, C8, and C1R), and a total of 42 proteins were found to be significantly upregulated in the temporal lobe epilepsy group. A classification analysis of these proteins according to their biological functions, as well as a review of the published sources, disclosed the predominant involvement of the processes mostly affected during epilepsy such as neuroinflammation, intracellular signaling, lipid metabolism, and oxidative stress. The presence of several proteins related to the corresponding compensatory mechanisms has been noted. After further validation, the newly identified temporal lobe epilepsy biomarker candidates may be used as epilepsy diagnostic tools, in addition to other less specific methods such as electroencephalography or MRI.
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Affiliation(s)
- Yury E. Glazyrin
- Laboratory for Digital Controlled Drugs and Theranostics, Federal Research Center “Krasnoyarsk Science Center of the Siberian Branch of the Russian Academy of Science”, Akademgorodok 50, 660036 Krasnoyarsk, Russia; (D.V.V.); (T.N.Z.); (A.S.K.)
- Laboratory for Biomolecular and Medical Technologies, Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, Partizana Zheleznyaka 1, 660022 Krasnoyarsk, Russia
| | - Dmitry V. Veprintsev
- Laboratory for Digital Controlled Drugs and Theranostics, Federal Research Center “Krasnoyarsk Science Center of the Siberian Branch of the Russian Academy of Science”, Akademgorodok 50, 660036 Krasnoyarsk, Russia; (D.V.V.); (T.N.Z.); (A.S.K.)
| | - Elena E. Timechko
- Department of Medical Genetics and Clinical Neurophysiology, Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, Partizana Zheleznyaka 1, 660022 Krasnoyarsk, Russia; (E.E.T.); (D.V.D.)
| | - Zoran Minic
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie-Curie, Ottawa, ON K1N 6N5, Canada; (Z.M.); (M.V.B.)
| | - Tatiana N. Zamay
- Laboratory for Digital Controlled Drugs and Theranostics, Federal Research Center “Krasnoyarsk Science Center of the Siberian Branch of the Russian Academy of Science”, Akademgorodok 50, 660036 Krasnoyarsk, Russia; (D.V.V.); (T.N.Z.); (A.S.K.)
- Laboratory for Biomolecular and Medical Technologies, Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, Partizana Zheleznyaka 1, 660022 Krasnoyarsk, Russia
| | - Diana V. Dmitrenko
- Department of Medical Genetics and Clinical Neurophysiology, Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, Partizana Zheleznyaka 1, 660022 Krasnoyarsk, Russia; (E.E.T.); (D.V.D.)
| | - Maxim V. Berezovski
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie-Curie, Ottawa, ON K1N 6N5, Canada; (Z.M.); (M.V.B.)
| | - Anna S. Kichkailo
- Laboratory for Digital Controlled Drugs and Theranostics, Federal Research Center “Krasnoyarsk Science Center of the Siberian Branch of the Russian Academy of Science”, Akademgorodok 50, 660036 Krasnoyarsk, Russia; (D.V.V.); (T.N.Z.); (A.S.K.)
- Laboratory for Biomolecular and Medical Technologies, Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, Partizana Zheleznyaka 1, 660022 Krasnoyarsk, Russia
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Bezerra DF, Alessi R, Andrade DM, Wajnsztejn R, Akerman M. Translation to Portuguese and cross-cultural adaptation of the epilepsy transition readiness checklist for use in Brazil. Clinics (Sao Paulo) 2024; 79:100432. [PMID: 39013275 PMCID: PMC11305199 DOI: 10.1016/j.clinsp.2024.100432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 06/10/2024] [Accepted: 06/12/2024] [Indexed: 07/18/2024] Open
Abstract
OBJECTIVES Planning for the child and adolescent to have a safe handling in the epilepsy transition process is essential. In this work, the authors translated the "Readiness Checklists" and applied them to a group of patients and their respective caregivers in the transition process to assess the possibility of using them as a monitoring and instructional instrument. METHODS The "Readiness Checklists" were applied to thirty adolescents with epilepsy and their caregivers. The original English version of this instrument underwent a process of translation and cultural adaptation by a translator with knowledge of English and epilepsy. Subsequently, it was carried out the back-translation and the Portuguese version was compared to the original, analyzing discrepancies, thus obtaining the final version for the Brazilian population. RESULTS Participants were able to answer the questions. In four questions there was an association between the teenagers' educational level and the response pattern to the questionnaires. The authors found a strong positive correlation between the responses of adolescents and caregivers (RhoSpearman = 0.837; p < 0.001). The application of the questionnaire by the health team was feasible for all interviewed patients and their respective caregivers. CONCLUSION The translation and application of the "Readiness Checklists" is feasible in Portuguese. Patients with lower educational levels felt less prepared for the transition than patients with higher educational levels, independently of age. Adolescents and caregivers showed similar perceptions regarding patients' abilities. The lists can be very useful tools to assess and plan the follow-up of the population of patients with epilepsy in the process of transition.
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Affiliation(s)
| | - Rudá Alessi
- Neurology Discipline, Faculdade de Medicina do ABC, Santo André, SP, Brazil
| | - Danielle Molinari Andrade
- Adult Genetic Epilepsy Program, Division of Neurology, Krembil Brain Institute, Toronto Western Hospital, University of Toronto, Toronto, Canada
| | - Rubens Wajnsztejn
- Neurology Discipline, Faculdade de Medicina do ABC, Santo André, SP, Brazil
| | - Marco Akerman
- Department of Politics, Management and Health, Faculdade de Saúde Pública, Universidade de São Paulo, São Paulo, SP, Brazil
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Swami P, Maheshwari J, Kumar M, Bhatia M. Evolutionary transfer optimization-based approach for automated ictal pattern recognition using brain signals. Front Hum Neurosci 2024; 18:1386168. [PMID: 39055535 PMCID: PMC11269234 DOI: 10.3389/fnhum.2024.1386168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 05/01/2024] [Indexed: 07/27/2024] Open
Abstract
The visual scrutinization process for detecting epileptic seizures (ictal patterns) is time-consuming and prone to manual errors, which can have serious consequences, including drug abuse and life-threatening situations. To address these challenges, expert systems for automated detection of ictal patterns have been developed, yet feature engineering remains problematic due to variability within and between subjects. Single-objective optimization approaches yield less reliable results. This study proposes a novel expert system using the non-dominated sorting genetic algorithm (NSGA)-II to detect ictal patterns in brain signals. Employing an evolutionary multi-objective optimization (EMO) approach, the classifier minimizes both the number of features and the error rate simultaneously. Input features include statistical features derived from phase space transformations, singular values, and energy values of time-frequency domain wavelet packet transform coefficients. Through evolutionary transfer optimization (ETO), the optimal feature set is determined from training datasets and passed through a generalized regression neural network (GRNN) model for pattern detection of testing datasets. The results demonstrate high accuracy with minimal computation time (<0.5 s), and EMO reduces the feature set matrix by more than half, suggesting reliability for clinical applications. In conclusion, the proposed model offers promising advancements in automating ictal pattern recognition in EEG data, with potential implications for improving epilepsy diagnosis and treatment. Further research is warranted to validate its performance across diverse datasets and investigate potential limitations.
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Affiliation(s)
- Piyush Swami
- Section for Visual Computing, Department of Applied Mathematics and Computer Science, Technical University of Denmark, Kongens Lyngby, Denmark
- Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital – Amager and Hvidovre, Copenhagen, Denmark
- Biomedical Engineering Techies, Broendby, Denmark
| | - Jyoti Maheshwari
- School of Behavioural Forensics, National Forensic Sciences University, Gandhinagar, Gujarat, India
| | - Mohit Kumar
- School of Electronics Engineering, VIT-AP University, Amaravati, India
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Dong P, Bakhurin K, Li Y, Mikati MA, Cui J, Grill WM, Yin HH, Yang H. Attenuating midline thalamus bursting to mitigate absence epilepsy. Proc Natl Acad Sci U S A 2024; 121:e2403763121. [PMID: 38968111 PMCID: PMC11252967 DOI: 10.1073/pnas.2403763121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 05/31/2024] [Indexed: 07/07/2024] Open
Abstract
Advancing the mechanistic understanding of absence epilepsy is crucial for developing new therapeutics, especially for patients unresponsive to current treatments. Utilizing a recently developed mouse model of absence epilepsy carrying the BK gain-of-function channelopathy D434G, here we report that attenuating the burst firing of midline thalamus (MLT) neurons effectively prevents absence seizures. We found that enhanced BK channel activity in the BK-D434G MLT neurons promotes synchronized bursting during the ictal phase of absence seizures. Modulating MLT neurons through pharmacological reagents, optogenetic stimulation, or deep brain stimulation effectively attenuates burst firing, leading to reduced absence seizure frequency and increased vigilance. Additionally, enhancing vigilance by amphetamine, a stimulant medication, or physical perturbation also effectively suppresses MLT bursting and prevents absence seizures. These findings suggest that the MLT is a promising target for clinical interventions. Our diverse approaches offer valuable insights for developing next generation therapeutics to treat absence epilepsy.
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Affiliation(s)
- Ping Dong
- Department of Biochemistry, Duke University Medical Center, Durham, NC27710
| | | | - Yuhui Li
- Department of Biomedical Engineering, Duke University, Durham, NC27708
| | - Mohamad A. Mikati
- Department of Neurobiology, Duke University Medical Center, Durham, NC27710
- Department of Pediatrics, Duke University Medical Center, Durham, NC27710
| | - Jianmin Cui
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO63130
| | - Warren M. Grill
- Department of Biomedical Engineering, Duke University, Durham, NC27708
- Department of Neurobiology, Duke University Medical Center, Durham, NC27710
- Department of Neurosurgery, Duke University Medical Center, Durham, NC27710
| | - Henry H. Yin
- Department of Psychology and Neuroscience, Duke University, Durham, NC27708
- Department of Neurobiology, Duke University Medical Center, Durham, NC27710
| | - Huanghe Yang
- Department of Biochemistry, Duke University Medical Center, Durham, NC27710
- Department of Neurobiology, Duke University Medical Center, Durham, NC27710
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Ahmad I, Wang X, Li L, Liu Z, Huang J, Aboyeji ST, Li G, Mukhopadhyay SC, Liu Z, Zhao G, Guo Y, Chen S. An Attention-Based Hybrid Deep Learning Approach for Patient-Specific, Cross-Patient, and Patient-Independent Seizure Detection. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2024; 2024:1-4. [PMID: 40031456 DOI: 10.1109/embc53108.2024.10782346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
Automatic detection of epilepsy plays a crucial role in diagnosing and treatment of patients, while most current methods rely on patient-specific models and have shown promising results, which is not suitable for clinical application, especially when new patient data are used for diagnosis in EEG epileptic seizure detection (ESD). Therefore, the proposed study introduces a novel hybrid deep learning approach consisting of a one-dimensional convolutional neural network (1D CNN), a Multi-Long Short-Term Memory Network (MLSTM) with a multi-attention layer (MAT) for patient-specific, cross-patient, and patient-independent seizure detection. The 1D CNN model extracts spatial features, while the MLSTM extracts temporal features from segmented EEG data. Moreover, the MAT layer conducts feature fusion and identifies relevant patterns. Experiments conducted using the CHB-MIT EEG dataset confirm our method's superiority over other sibling and state-of-the-art methods by an average of 2% in classification accuracy, recall, specificity, and G.mean of using patient-specific, cross-patient, and patient-independent seizure detection, demonstrating a robust and effective framework in EEG ESD.
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Cheng T, Hu Y, Qin X, Ma J, Zha D, Xie H, Ji T, Liu Q, Wang Z, Hao H, Wu Y, Li L. A predictive model combining connectomics and entropy biomarkers to discriminate long-term vagus nerve stimulation efficacy for pediatric patients with drug-resistant epilepsy. CNS Neurosci Ther 2024; 30:e14751. [PMID: 39015946 PMCID: PMC11252558 DOI: 10.1111/cns.14751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 04/22/2024] [Accepted: 04/23/2024] [Indexed: 07/18/2024] Open
Abstract
AIMS To predict the vagus nerve stimulation (VNS) efficacy for pediatric drug-resistant epilepsy (DRE) patients, we aim to identify preimplantation biomarkers through clinical features and electroencephalogram (EEG) signals and thus establish a predictive model from a multi-modal feature set with high prediction accuracy. METHODS Sixty-five pediatric DRE patients implanted with VNS were included and followed up. We explored the topological network and entropy features of preimplantation EEG signals to identify the biomarkers for VNS efficacy. A Support Vector Machine (SVM) integrated these biomarkers to distinguish the efficacy groups. RESULTS The proportion of VNS responders was 58.5% (38/65) at the last follow-up. In the analysis of parieto-occipital α band activity, higher synchronization level and nodal efficiency were found in responders. The central-frontal θ band activity showed significantly lower entropy in responders. The prediction model reached an accuracy of 81.5%, a precision of 80.1%, and an AUC (area under the receiver operating characteristic curve) of 0.838. CONCLUSION Our results revealed that, compared to nonresponders, VNS responders had a more efficient α band brain network, especially in the parieto-occipital region, and less spectral complexity of θ brain activities in the central-frontal region. We established a predictive model integrating both preimplantation clinical and EEG features and exhibited great potential for discriminating the VNS responders. This study contributed to the understanding of the VNS mechanism and improved the performance of the current predictive model.
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Affiliation(s)
- Tung‐yang Cheng
- National Engineering Research Center of Neuromodulation, School of Aerospace EngineeringTsinghua UniversityBeijingChina
| | - Yingbing Hu
- National Engineering Research Center of Neuromodulation, School of Aerospace EngineeringTsinghua UniversityBeijingChina
- Tsinghua‐Berkeley Shenzhen InstituteTsinghua UniversityShenzhenChina
| | - Xiaoya Qin
- National Engineering Research Center of Neuromodulation, School of Aerospace EngineeringTsinghua UniversityBeijingChina
- Tsinghua‐Berkeley Shenzhen InstituteTsinghua UniversityShenzhenChina
| | - Jiayi Ma
- Department of PediatricsPeking University First HospitalBeijingChina
| | - Daqi Zha
- National Engineering Research Center of Neuromodulation, School of Aerospace EngineeringTsinghua UniversityBeijingChina
| | - Han Xie
- Department of PediatricsPeking University First HospitalBeijingChina
| | - Taoyun Ji
- Department of PediatricsPeking University First HospitalBeijingChina
- Pediatric Epilepsy CenterPeking University First HospitalBeijingChina
| | - Qingzhu Liu
- Pediatric Epilepsy CenterPeking University First HospitalBeijingChina
| | - Zhiyan Wang
- CAS Key Laboratory of Mental Health, Institute of PsychologyChinese Academy of SciencesBeijingChina
- Department of PsychologyUniversity of Chinese Academy of SciencesBeijingChina
| | - Hongwei Hao
- National Engineering Research Center of Neuromodulation, School of Aerospace EngineeringTsinghua UniversityBeijingChina
| | - Ye Wu
- Department of PediatricsPeking University First HospitalBeijingChina
- Pediatric Epilepsy CenterPeking University First HospitalBeijingChina
| | - Luming Li
- National Engineering Research Center of Neuromodulation, School of Aerospace EngineeringTsinghua UniversityBeijingChina
- IDG/McGovern Institute for Brain Research at Tsinghua UniversityBeijingChina
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Thakku Sivakumar D, Jain K, Alfehaid N, Wang Y, Teng X, Fischer W, Engel T. The Purinergic P2X7 Receptor as a Target for Adjunctive Treatment for Drug-Refractory Epilepsy. Int J Mol Sci 2024; 25:6894. [PMID: 39000004 PMCID: PMC11241490 DOI: 10.3390/ijms25136894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 06/06/2024] [Accepted: 06/17/2024] [Indexed: 07/14/2024] Open
Abstract
Epilepsy is one of the most common neurological diseases worldwide. Anti-seizure medications (ASMs) with anticonvulsants remain the mainstay of epilepsy treatment. Currently used ASMs are, however, ineffective to suppress seizures in about one third of all patients. Moreover, ASMs show no significant impact on the pathogenic mechanisms involved in epilepsy development or disease progression and may cause serious side-effects, highlighting the need for the identification of new drug targets for a more causal therapy. Compelling evidence has demonstrated a role for purinergic signalling, including the nucleotide adenosine 5'-triphosphate (ATP) during the generation of seizures and epilepsy. Consequently, drugs targeting specific ATP-gated purinergic receptors have been suggested as promising treatment options for epilepsy including the cationic P2X7 receptor (P27XR). P2X7R protein levels have been shown to be increased in the brain of experimental models of epilepsy and in the resected brain tissue of patients with epilepsy. Animal studies have provided evidence that P2X7R blocking can reduce the severity of acute seizures and the epileptic phenotype. The current review will provide a brief summary of recent key findings on P2X7R signalling during seizures and epilepsy focusing on the potential clinical use of treatments based on the P2X7R as an adjunctive therapeutic strategy for drug-refractory seizures and epilepsy.
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Affiliation(s)
- Divyeshz Thakku Sivakumar
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, D02 YN77 Dublin, Ireland
| | - Krishi Jain
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, D02 YN77 Dublin, Ireland
| | - Noura Alfehaid
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, D02 YN77 Dublin, Ireland
| | - Yitao Wang
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, D02 YN77 Dublin, Ireland
- International College of Pharmaceutical Innovation, Soochow University, Suzhou 215123, China
| | - Xinchen Teng
- International College of Pharmaceutical Innovation, Soochow University, Suzhou 215123, China
| | | | - Tobias Engel
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, D02 YN77 Dublin, Ireland
- FutureNeuro, Science Foundation Ireland Research Centre for Chronic and Rare Neurological Diseases, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, D02 YN77 Dublin, Ireland
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Li YS, Yeh WC, Chang YH, Hsu CY. Restless legs syndrome in patients with epilepsy: risk analysis, polysomnography, and quality of life evaluation. Sleep 2024; 47:zsad054. [PMID: 36861219 DOI: 10.1093/sleep/zsad054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 01/14/2023] [Indexed: 03/03/2023] Open
Abstract
STUDY OBJECTIVES Restless legs syndrome (RLS) is a circadian rhythm related sensorimotor disorder due to brain iron deficiency, with lesion sites at the putamen and substantia nigra. However, epilepsy is a disease with abnormal electric discharge from the cortex and can be triggered with iron disequilibrium. We designed a case-control study to discover the association between epilepsy and RLS. METHODS A total of 24 patients with epilepsy and RLS and 72 patients with epilepsy without RLS were included. Most of the patients underwent polysomnography and video electroencephalogram tests and took sleep questionnaires. We collected information on seizure characteristics, including general or focal onset, epileptogenic focus, current antiseizure medications, medically responsive epilepsy or refractory epilepsy, and nocturnal attacks. The sleep architectures of the two groups were compared. We analyzed the risk factors for RLS using multivariate logistic regression. RESULTS Among the patients with epilepsy, the occurrence of RLS was associated with refractory epilepsy (OR 6.422, p = 0.002) and nocturnal seizures (OR 4.960, p = 0.005). Sleep parameters were not significantly associated with RLS status. Quality of life was significantly impaired in the group with RLS in both the physical and mental domains. CONCLUSIONS Refractory epilepsy and nocturnal seizures were strongly correlated with RLS in patients with epilepsy. RLS should be considered a predictable comorbidity in patients with epilepsy. The management of RLS not only led to better control of the patient's epilepsy but also improved their quality of life.
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Affiliation(s)
- Ying-Sheng Li
- Sleep Disorders Center, Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung City, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan
| | - Wei-Chih Yeh
- Department of Neurology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung City, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan
| | - Ya-Hsien Chang
- Department of Pediatrics, Yucheng Otolaryngological and Pediatric Clinic, Kaohsiung City, Taiwan
| | - Chung-Yao Hsu
- Sleep Disorders Center, Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung City, Taiwan
- Department of Neurology, College of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan
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Wang X, Ding Q, Groleau RR, Wu L, Mao Y, Che F, Kotova O, Scanlan EM, Lewis SE, Li P, Tang B, James TD, Gunnlaugsson T. Fluorescent Probes for Disease Diagnosis. Chem Rev 2024; 124:7106-7164. [PMID: 38760012 PMCID: PMC11177268 DOI: 10.1021/acs.chemrev.3c00776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 04/09/2024] [Accepted: 04/10/2024] [Indexed: 05/19/2024]
Abstract
The identification and detection of disease-related biomarkers is essential for early clinical diagnosis, evaluating disease progression, and for the development of therapeutics. Possessing the advantages of high sensitivity and selectivity, fluorescent probes have become effective tools for monitoring disease-related active molecules at the cellular level and in vivo. In this review, we describe current fluorescent probes designed for the detection and quantification of key bioactive molecules associated with common diseases, such as organ damage, inflammation, cancers, cardiovascular diseases, and brain disorders. We emphasize the strategies behind the design of fluorescent probes capable of disease biomarker detection and diagnosis and cover some aspects of combined diagnostic/therapeutic strategies based on regulating disease-related molecules. This review concludes with a discussion of the challenges and outlook for fluorescent probes, highlighting future avenues of research that should enable these probes to achieve accurate detection and identification of disease-related biomarkers for biomedical research and clinical applications.
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Affiliation(s)
- Xin Wang
- College
of Chemistry, Chemical Engineering and Materials Science, Key Laboratory
of Molecular and Nano Probes, Ministry of Education, Collaborative
Innovation Center of Functionalized Probes for Chemical Imaging in
Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University, Jinan 250014, People’s Republic of China
| | - Qi Ding
- College
of Chemistry, Chemical Engineering and Materials Science, Key Laboratory
of Molecular and Nano Probes, Ministry of Education, Collaborative
Innovation Center of Functionalized Probes for Chemical Imaging in
Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University, Jinan 250014, People’s Republic of China
| | | | - Luling Wu
- Department
of Chemistry, University of Bath, Bath BA2 7AY, U.K.
| | - Yuantao Mao
- College
of Chemistry, Chemical Engineering and Materials Science, Key Laboratory
of Molecular and Nano Probes, Ministry of Education, Collaborative
Innovation Center of Functionalized Probes for Chemical Imaging in
Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University, Jinan 250014, People’s Republic of China
| | - Feida Che
- College
of Chemistry, Chemical Engineering and Materials Science, Key Laboratory
of Molecular and Nano Probes, Ministry of Education, Collaborative
Innovation Center of Functionalized Probes for Chemical Imaging in
Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University, Jinan 250014, People’s Republic of China
| | - Oxana Kotova
- School
of Chemistry and Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, The University of Dublin, Dublin 2 D02 R590, Ireland
- Advanced
Materials and BioEngineering Research (AMBER) Centre, Trinity College
Dublin, The University of Dublin, Dublin 2 D02 W9K7, Ireland
| | - Eoin M. Scanlan
- School
of Chemistry and Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, The University of Dublin, Dublin 2 D02 R590, Ireland
- Synthesis
and Solid-State Pharmaceutical Centre (SSPC), School of Chemistry, Trinity College Dublin, The University of Dublin, Dublin 2 , Ireland
| | - Simon E. Lewis
- Department
of Chemistry, University of Bath, Bath BA2 7AY, U.K.
| | - Ping Li
- College
of Chemistry, Chemical Engineering and Materials Science, Key Laboratory
of Molecular and Nano Probes, Ministry of Education, Collaborative
Innovation Center of Functionalized Probes for Chemical Imaging in
Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University, Jinan 250014, People’s Republic of China
| | - Bo Tang
- College
of Chemistry, Chemical Engineering and Materials Science, Key Laboratory
of Molecular and Nano Probes, Ministry of Education, Collaborative
Innovation Center of Functionalized Probes for Chemical Imaging in
Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University, Jinan 250014, People’s Republic of China
- Laoshan
Laboratory, 168 Wenhai
Middle Road, Aoshanwei Jimo, Qingdao 266237, Shandong, People’s Republic of China
| | - Tony D. James
- Department
of Chemistry, University of Bath, Bath BA2 7AY, U.K.
- School
of Chemistry and Chemical Engineering, Henan
Normal University, Xinxiang 453007, People’s
Republic of China
| | - Thorfinnur Gunnlaugsson
- School
of Chemistry and Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, The University of Dublin, Dublin 2 D02 R590, Ireland
- Advanced
Materials and BioEngineering Research (AMBER) Centre, Trinity College
Dublin, The University of Dublin, Dublin 2 D02 W9K7, Ireland
- Synthesis
and Solid-State Pharmaceutical Centre (SSPC), School of Chemistry, Trinity College Dublin, The University of Dublin, Dublin 2 , Ireland
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Alzamanan MZ, Lim KS, Ismail MA, Ghani NA. Development of an epilepsy self-management mobile health app framework: Content validity study results. PLoS One 2024; 19:e0302844. [PMID: 38848353 PMCID: PMC11161114 DOI: 10.1371/journal.pone.0302844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Accepted: 04/14/2024] [Indexed: 06/09/2024] Open
Abstract
BACKGROUND Mobile health (mHealth) applications (apps) show promise in supporting epilepsy self-management (eSM). To delve deeper into this potential, we conducted a systematic review of epilepsy mHealth apps available on both iOS and Android platforms, examining articles related to eSM. This review allowed us to identify important domains related to eSM. Furthermore, based on the findings, we developed an epilepsy mHealth app framework that aims to improve self-management for the local population. This study aims to assess the practicality and usability of the proposed mHealth app framework designed to improve eSM. We will conduct an expert panel review to evaluate the effectiveness and feasibility of the framework. MATERIAL AND METHODS Content validity was assessed by an expert panel comprising epileptologists and pharmacists. The validation process involved scoring the items within each domain of the framework to evaluate their practicality and usability (quantitative component). In addition, a panel discussion was conducted to further explore and discuss the qualitative aspects of the items. RESULTS A total of 4 domains with 15 items were highly rated for their practicality and usefulness in eSM. CONCLUSIONS The locally validated framework will be useful for developing eSM mobile apps. Seizure Tracking, Medication Adherence, Treatment Management, and Healthcare Communication emerged as the most crucial domains for enhancing eSM.
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Affiliation(s)
| | - Kheng-Seang Lim
- Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Maizatul Akmar Ismail
- Department of Information Systems, Faculty of Computer Science and Information Technology, University of Malaya, Kuala Lumpur, Malaysia
| | - Norjihan Abdul Ghani
- Department of Information Systems, Faculty of Computer Science and Information Technology, University of Malaya, Kuala Lumpur, Malaysia
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Ikegaya N, Aung T, Mallela A, Hect JL, Damiani A, Gonzalez-Martinez JA. Thalamic stereoelectroencephalography for neuromodulation target selection: Proof of concept and review of literature of pulvinar direct electrical stimulation. Epilepsia 2024; 65:e79-e86. [PMID: 38625609 DOI: 10.1111/epi.17986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 04/01/2024] [Accepted: 04/02/2024] [Indexed: 04/17/2024]
Abstract
In patients with drug-resistant epilepsy (DRE) who are not candidates for resective surgery, various thalamic nuclei, including the anterior, centromedian, and pulvinar nuclei, have been extensively investigated as targets for neuromodulation. However, the therapeutic effects of different targets for thalamic neuromodulation on various types of epilepsy are not well understood. Here, we present a 32-year-old patient with multifocal bilateral temporoparieto-occipital epilepsy and bilateral malformations of cortical development (MCDs) who underwent bilateral stereoelectroencephalographic (SEEG) recordings of the aforementioned three thalamic nuclei bilaterally. The change in the rate of interictal epileptiform discharges (IEDs) from baseline were compared in temporal, central, parietal, and occipital regions after direct electrical stimulation (DES) of each thalamic nucleus. A significant decrease in the rate of IEDs (33% from baseline) in the posterior quadrant regions was noted in the ipsilateral as well as contralateral hemisphere following DES of the pulvinar. A scoping review was also performed to better understand the current standpoint of pulvinar thalamic stimulation in the treatment of DRE. The therapeutic effect of neuromodulation can differ among thalamic nuclei targets and epileptogenic zones (EZs). In patients with multifocal EZs with extensive MCDs, personalized thalamic targeting could be achieved through DES with thalamic SEEG electrodes.
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Affiliation(s)
- Naoki Ikegaya
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Neurosurgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Thandar Aung
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Neurology, Epilepsy Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Arka Mallela
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Jasmine L Hect
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Arianna Damiani
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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Fikry H, Saleh LA, Mahmoud FA, Gawad SA, Abd-Alkhalek HA. CoQ10 targeted hippocampal ferroptosis in a status epilepticus rat model. Cell Tissue Res 2024; 396:371-397. [PMID: 38499882 PMCID: PMC11144258 DOI: 10.1007/s00441-024-03880-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/15/2024] [Indexed: 03/20/2024]
Abstract
Status epilepticus (SE), the most severe form of epilepsy, leads to brain damage. Uncertainty persists about the mechanisms that lead to the pathophysiology of epilepsy and the death of neurons. Overloading of intracellular iron ions has recently been identified as the cause of a newly recognized form of controlled cell death called ferroptosis. Inhibiting ferroptosis has shown promise as a treatment for epilepsy, according to recent studies. So, the current study aimed to assess the possible antiepileptic impact of CoQ10 either alone or with the standard antiepileptic drug sodium valproate (SVP) and to evaluate the targeted effect of COQ10 on hippocampal oxidative stress and ferroptosis in a SE rat model. Using a lithium-pilocarpine rat model of epilepsy, we evaluated the effect of SVP, CoQ10, or both on seizure severity, histological, and immunohistochemical of the hippocampus. Furthermore, due to the essential role of oxidative stress and lipid peroxidation in inducing ferroptosis, we evaluated malonaldehyde (MDA), reduced glutathione (GSH), glutathione peroxidase 4 (GPX4), and ferritin in tissue homogenate. Our work illustrated that ferroptosis occurs in murine models of lithium-pilocarpine-induced seizures (epileptic group). Nissl staining revealed significant neurodegeneration. A significant increase in the number of astrocytes stained with an astrocyte-specific marker was observed in the hippocampus. Effective seizure relief can be achieved in the seizure model by administering CoQ10 alone compared to SVP. This was accomplished by lowering ferritin levels and increasing GPX4, reducing MDA, and increasing GSH in the hippocampus tissue homogenate. In addition, the benefits of SVP therapy for regulating iron stores, GPX4, and oxidative stress markers were amplified by incorporating CoQ10 as compared to SVP alone. It was concluded that CoQ10 alone has a more beneficial effect than SVP alone in restoring histological structures and has a targeted effect on hippocampal oxidative stress and ferroptosis. In addition, COQ10 could be useful as an adjuvant to SVP in protecting against oxidative damage and ferroptosis-related damage that result from epileptic seizures.
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Affiliation(s)
- Heba Fikry
- Department of Histology and Cell Biology, Faculty of Medicine, Ain Shams University, Khalifa El-Maamon st, Abbasiya sq., Cairo, 11566, Egypt.
| | - Lobna A Saleh
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Khalifa El-Maamon st, Abbasiya sq., Cairo, 11566, Egypt
| | - Faten A Mahmoud
- Department of Histology and Cell Biology, Faculty of Medicine, Ain Shams University, Khalifa El-Maamon st, Abbasiya sq., Cairo, 11566, Egypt
| | - Sara Abdel Gawad
- Department of Histology and Cell Biology, Faculty of Medicine, Ain Shams University, Khalifa El-Maamon st, Abbasiya sq., Cairo, 11566, Egypt
| | - Hadwa Ali Abd-Alkhalek
- Department of Histology and Cell Biology, Faculty of Medicine, Ain Shams University, Khalifa El-Maamon st, Abbasiya sq., Cairo, 11566, Egypt
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Ahmad I, Zhu M, Li G, Javeed D, Kumar P, Chen S. A Secure and Interpretable AI for Smart Healthcare System: A Case Study on Epilepsy Diagnosis Using EEG Signals. IEEE J Biomed Health Inform 2024; 28:3236-3247. [PMID: 38507373 DOI: 10.1109/jbhi.2024.3366341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/22/2024]
Abstract
The efficient patient-independent and interpretable framework for electroencephalogram (EEG) epileptic seizure detection (ESD) has informative challenges due to the complex pattern of EEG nature. Automated detection of ES is crucial, while Explainable Artificial Intelligence (XAI) is urgently needed to justify the model detection of epileptic seizures in clinical applications. Therefore, this study implements an XAI-based computer-aided ES detection system (XAI-CAESDs), comprising three major modules, including of feature engineering module, a seizure detection module, and an explainable decision-making process module in a smart healthcare system. To ensure the privacy and security of biomedical EEG data, the blockchain is employed. Initially, the Butterworth filter eliminates various artifacts, and the Dual-Tree Complex Wavelet Transform (DTCWT) decomposes EEG signals, extracting real and imaginary eigenvalue features using frequency domain (FD), time domain (TD) linear feature, and Fractal Dimension (FD) of non-linear features. The best features are selected by using Correlation Coefficients (CC) and Distance Correlation (DC). The selected features are fed into the Stacking Ensemble Classifiers (SEC) for EEG ES detection. Further, the Shapley Additive Explanations (SHAP) method of XAI is implemented to facilitate the interpretation of predictions made by the proposed approach, enabling medical experts to make accurate and understandable decisions. The proposed Stacking Ensemble Classifiers (SEC) in XAI-CAESDs have demonstrated 2% best average accuracy, recall, specificity, and F1-score using the University of California, Irvine, Bonn University, and Boston Children's Hospital-MIT EEG data sets. The proposed framework enhances decision-making and the diagnosis process using biomedical EEG signals and ensures data security in smart healthcare systems.
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Tian N, Kobau R, Friedman D, Liu Y, Eke PI, Greenlund KJ. Mortality and mortality disparities among people with epilepsy in the United States, 2011-2021. Epilepsy Behav 2024; 155:109770. [PMID: 38636143 PMCID: PMC11284737 DOI: 10.1016/j.yebeh.2024.109770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Revised: 03/25/2024] [Accepted: 03/27/2024] [Indexed: 04/20/2024]
Abstract
Studies on epilepsy mortality in the United States are limited. We used the National Vital Statistics System Multiple Cause of Death data to investigate mortality rates and trends during 2011-2021 for epilepsy (defined by the International Classification of Diseases, 10th Revision, codes G40.0-G40.9) as an underlying, contributing, or any cause of death (i.e., either an underlying or contributing cause) for U.S. residents. We also examined epilepsy as an underlying or contributing cause of death by selected sociodemographic characteristics to assess mortality rate changes and disparities in subpopulations. During 2011-2021, the overall age-standardized mortality rates for epilepsy as an underlying (39 % of all deaths) or contributing (61 % of all deaths) cause of death increased 83.6 % (from 2.9 per million to 6.4 per million population) as underlying cause and 144.1 % (from 3.3 per million to 11.0 per million population) as contributing cause (P < 0.001 for both based on annual percent changes). Compared to 2011-2015, in 2016-2020 mortality rates with epilepsy as an underlying or contributing cause of death were higher overall and in nearly all subgroups. Overall, mortality rates with epilepsy as an underlying or contributing cause of death were higher in older age groups, among males than females, among non-Hispanic Black or non-Hispanic American Indian/Alaska Native persons than non-Hispanic White persons, among those living in the West and Midwest than those living in the Northeast, and in nonmetro counties compared to urban regions. Results identify priority subgroups for intervention to reduce mortality in people with epilepsy and eliminate mortality disparity.
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Affiliation(s)
- Niu Tian
- Division of Population Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA.
| | - Rosemarie Kobau
- Division of Population Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA
| | - Daniel Friedman
- Department of Neurology, New York University Grossman School of Medicine, New York, NY 10016 USA
| | - Yong Liu
- Division of Population Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA
| | - Paul I Eke
- Division of Population Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA
| | - Kurt J Greenlund
- Division of Population Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA
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Waris A, Ullah A, Asim M, Ullah R, Rajdoula MR, Bello ST, Alhumaydhi FA. Phytotherapeutic options for the treatment of epilepsy: pharmacology, targets, and mechanism of action. Front Pharmacol 2024; 15:1403232. [PMID: 38855752 PMCID: PMC11160429 DOI: 10.3389/fphar.2024.1403232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 05/09/2024] [Indexed: 06/11/2024] Open
Abstract
Epilepsy is one of the most common, severe, chronic, potentially life-shortening neurological disorders, characterized by a persisting predisposition to generate seizures. It affects more than 60 million individuals globally, which is one of the major burdens in seizure-related mortality, comorbidities, disabilities, and cost. Different treatment options have been used for the management of epilepsy. More than 30 drugs have been approved by the US FDA against epilepsy. However, one-quarter of epileptic individuals still show resistance to the current medications. About 90% of individuals in low and middle-income countries do not have access to the current medication. In these countries, plant extracts have been used to treat various diseases, including epilepsy. These medicinal plants have high therapeutic value and contain valuable phytochemicals with diverse biomedical applications. Epilepsy is a multifactorial disease, and therefore, multitarget approaches such as plant extracts or extracted phytochemicals are needed, which can target multiple pathways. Numerous plant extracts and phytochemicals have been shown to treat epilepsy in various animal models by targeting various receptors, enzymes, and metabolic pathways. These extracts and phytochemicals could be used for the treatment of epilepsy in humans in the future; however, further research is needed to study the exact mechanism of action, toxicity, and dosage to reduce their side effects. In this narrative review, we comprehensively summarized the extracts of various plant species and purified phytochemicals isolated from plants, their targets and mechanism of action, and dosage used in various animal models against epilepsy.
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Affiliation(s)
- Abdul Waris
- Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong SAR, China
| | - Ata Ullah
- Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong SAR, China
| | - Muhammad Asim
- Department of Neurosciences, City University of Hong Kong, Kowloon, Hong Kong SAR, China
- Centre for Regenerative Medicine and Health (CRMH), Hong Kong, Hong Kong SAR, China
| | - Rafi Ullah
- Department of Botany, Bacha Khan University Charsadda, Charsadda, Pakistan
| | - Md. Rafe Rajdoula
- Department of Neurosciences, City University of Hong Kong, Kowloon, Hong Kong SAR, China
| | - Stephen Temitayo Bello
- Department of Neurosciences, City University of Hong Kong, Kowloon, Hong Kong SAR, China
- Centre for Regenerative Medicine and Health (CRMH), Hong Kong, Hong Kong SAR, China
| | - Fahad A. Alhumaydhi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
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Liu ZY, Li YQ, Wang DL, Wang Y, Qiu WT, Qiu YY, Zhang HL, You QL, Liu SM, Liang QN, Wu EJ, Hu BJ, Sun XD. Agrin-Lrp4 pathway in hippocampal astrocytes restrains development of temporal lobe epilepsy through adenosine signaling. Cell Biosci 2024; 14:66. [PMID: 38783336 PMCID: PMC11112884 DOI: 10.1186/s13578-024-01241-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 04/27/2024] [Indexed: 05/25/2024] Open
Abstract
BACKGROUND Human patients often experience an episode of serious seizure activity, such as status epilepticus (SE), prior to the onset of temporal lobe epilepsy (TLE), suggesting that SE can trigger the development of epilepsy. Yet, the underlying mechanisms are not fully understood. The low-density lipoprotein receptor related protein (Lrp4), a receptor for proteoglycan-agrin, has been indicated to modulate seizure susceptibility. However, whether agrin-Lrp4 pathway also plays a role in the development of SE-induced TLE is not clear. METHODS Lrp4f/f mice were crossed with hGFAP-Cre and Nex-Cre mice to generate brain conditional Lrp4 knockout mice (hGFAP-Lrp4-/-) and pyramidal neuron specific knockout mice (Nex-Lrp4-/-). Lrp4 was specifically knocked down in hippocampal astrocytes by injecting AAV virus carrying hGFAP-Cre into the hippocampus. The effects of agrin-Lrp4 pathway on the development of SE-induced TLE were evaluated on the chronic seizure model generated by injecting kainic acid (KA) into the amygdala. The spontaneous recurrent seizures (SRS) in mice were video monitored. RESULTS We found that Lrp4 deletion from the brain but not from the pyramidal neurons elevated the seizure threshold and reduced SRS numbers, with no change in the stage or duration of SRS. More importantly, knockdown of Lrp4 in the hippocampal astrocytes after SE induction decreased SRS numbers. In accord, direct injection of agrin into the lateral ventricle of control mice but not mice with Lrp4 deletion in hippocampal astrocytes also increased the SRS numbers. These results indicate a promoting effect of agrin-Lrp4 signaling in hippocampal astrocytes on the development of SE-induced TLE. Last, we observed that knockdown of Lrp4 in hippocampal astrocytes increased the extracellular adenosine levels in the hippocampus 2 weeks after SE induction. Blockade of adenosine A1 receptor in the hippocampus by DPCPX after SE induction diminished the effects of Lrp4 on the development of SE-induced TLE. CONCLUSION These results demonstrate a promoting role of agrin-Lrp4 signaling in hippocampal astrocytes in the development of SE-induced development of epilepsy through elevating adenosine levels. Targeting agrin-Lrp4 signaling may serve as a potential therapeutic intervention strategy to treat TLE.
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Affiliation(s)
- Zi-Yang Liu
- School of Basic Medical Sciences, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Institute of Neuroscience and Department of GFNeurology of the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yuan-Quan Li
- School of Basic Medical Sciences, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Institute of Neuroscience and Department of GFNeurology of the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Department of Neurology of the Sixth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Die-Lin Wang
- Guangzhou Medical University-Guangzhou Institute of Biomedicine and Health (GMU-GIBH) Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, China
| | - Ying Wang
- School of Basic Medical Sciences, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Institute of Neuroscience and Department of GFNeurology of the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Wan-Ting Qiu
- School of Basic Medical Sciences, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Institute of Neuroscience and Department of GFNeurology of the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yu-Yang Qiu
- School of Basic Medical Sciences, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Institute of Neuroscience and Department of GFNeurology of the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - He-Lin Zhang
- School of Basic Medical Sciences, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Institute of Neuroscience and Department of GFNeurology of the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qiang-Long You
- School of Basic Medical Sciences, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Institute of Neuroscience and Department of GFNeurology of the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Shi-Min Liu
- School of Basic Medical Sciences, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Institute of Neuroscience and Department of GFNeurology of the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qiu-Ni Liang
- School of Basic Medical Sciences, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Institute of Neuroscience and Department of GFNeurology of the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Er-Jian Wu
- School of Basic Medical Sciences, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Institute of Neuroscience and Department of GFNeurology of the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Bing-Jie Hu
- School of Basic Medical Sciences, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Institute of Neuroscience and Department of GFNeurology of the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
| | - Xiang-Dong Sun
- School of Basic Medical Sciences, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Institute of Neuroscience and Department of GFNeurology of the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
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Chung YG, Cho A, Kim H, Kim KJ. Single-channel seizure detection with clinical confirmation of seizure locations using CHB-MIT dataset. Front Neurol 2024; 15:1389731. [PMID: 38836000 PMCID: PMC11148866 DOI: 10.3389/fneur.2024.1389731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 05/03/2024] [Indexed: 06/06/2024] Open
Abstract
Introduction Long-term electroencephalography (EEG) monitoring is advised to patients with refractory epilepsy who have a failure of anti-seizure medication and therapy. However, its real-life application is limited mainly due to the use of multiple EEG channels. We proposed a patient-specific deep learning-based single-channel seizure detection approach using the long-term scalp EEG recordings of the Children's Hospital Boston-Massachusetts Institute of Technology (CHB-MIT) dataset, in conjunction with neurologists' confirmation of spatial seizure characteristics of individual patients. Methods We constructed 18-, 4-, and single-channel seizure detectors for 13 patients. Neurologists selected a specific channel among four channels, two close to the behind-the-ear and two at the forehead for each patient, after reviewing the patient's distinctive seizure locations with seizure re-annotation. Results Our multi- and single-channel detectors achieved an average sensitivity of 97.05-100%, false alarm rate of 0.22-0.40/h, and latency of 2.1-3.4 s for identification of seizures in continuous EEG recordings. The results demonstrated that seizure detection performance of our single-channel approach was comparable to that of our multi-channel ones. Discussion We suggest that our single-channel approach in conjunction with clinical designation of the most prominent seizure locations has a high potential for wearable seizure detection on long-term EEG recordings for patients with refractory epilepsy.
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Affiliation(s)
- Yoon Gi Chung
- Department of Pediatrics, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Anna Cho
- Department of Pediatrics, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Hunmin Kim
- Department of Pediatrics, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam-si, Gyeonggi-do, Republic of Korea
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Ki Joong Kim
- Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
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Pan X, Huang W, Nie G, Wang C, Wang H. Ultrasound-Sensitive Intelligent Nanosystems: A Promising Strategy for the Treatment of Neurological Diseases. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2303180. [PMID: 37871967 DOI: 10.1002/adma.202303180] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 09/26/2023] [Indexed: 10/25/2023]
Abstract
Neurological diseases are a major global health challenge, affecting hundreds of millions of people worldwide. Ultrasound therapy plays an irreplaceable role in the treatment of neurological diseases due to its noninvasive, highly focused, and strong tissue penetration capabilities. However, the complexity of brain and nervous system and the safety risks associated with prolonged exposure to ultrasound therapy severely limit the applicability of ultrasound therapy. Ultrasound-sensitive intelligent nanosystems (USINs) are a novel therapeutic strategy for neurological diseases that bring greater spatiotemporal controllability and improve safety to overcome these challenges. This review provides a detailed overview of therapeutic strategies and clinical advances of ultrasound in neurological diseases, focusing on the potential of USINs-based ultrasound in the treatment of neurological diseases. Based on the physical and chemical effects induced by ultrasound, rational design of USINs is a prerequisite for improving the efficacy of ultrasound therapy. Recent developments of ultrasound-sensitive nanocarriers and nanoagents are systemically reviewed. Finally, the challenges and developing prospects of USINs are discussed in depth, with a view to providing useful insights and guidance for efficient ultrasound treatment of neurological diseases.
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Affiliation(s)
- Xueting Pan
- CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China
| | - Wenping Huang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China
- School of Nanoscience and Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Guangjun Nie
- CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China
- School of Nanoscience and Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Changyong Wang
- Beijing Institute of Basic Medical Sciences, 27 Taiping Road, Beijing, 100850, China
| | - Hai Wang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China
- School of Nanoscience and Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China
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