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Fukasawa N, Tsunoda J, Sunaga S, Kiyohara H, Nakamoto N, Teratani T, Mikami Y, Kanai T. The gut-organ axis: Clinical aspects and immune mechanisms. Allergol Int 2025; 74:197-209. [PMID: 39979198 DOI: 10.1016/j.alit.2025.01.004] [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: 12/19/2024] [Revised: 12/29/2024] [Accepted: 01/04/2025] [Indexed: 02/22/2025] Open
Abstract
The gut-brain axis exemplifies the bidirectional connection between the intestines and the brain, as evidenced by the impact of severe stress on gastrointestinal symptoms including abdominal pain and diarrhea, and conversely, the influence of abdominal discomfort on mood. Clinical observations support the notion of the gut-brain connection, including an increased prevalence of inflammatory bowel disease (IBD) in patients with depression and anxiety, as well as the association of changes in the gut microbiota with neurological disorders such as multiple sclerosis, Parkinson's disease, stroke and Alzheimer's disease. The gut and brain communicate via complex mechanisms involving inflammatory cytokines, immune cells, autonomic nerves, and gut microbiota, which contribute to the pathogenesis in certain gut and brain diseases. Two primary pathways mediate the bidirectional information exchange between the intestinal tract and the brain: signal transduction through bloodstream factors, such as bacterial metabolites and inflammatory cytokines, and neural pathways, such as neurotransmitters and inflammatory cytokines within the autonomic nervous system through the interaction between the nerve cells and beyond. In recent years, the basic mechanisms of the pathophysiology of the gut-brain axis have been gradually elucidated. Beyond the gut-brain interaction, emerging evidence suggests the influence of the gut extends to other organs, such as the liver and lungs, through intricate inter-organ communication pathways. An increasing number of reports on this clinical and basic cross-organ interactions underscore the potential for better understanding and novel therapeutic strategies targeting inter-organs networks. Further clarification of interactions between multiorgans premises transformative insights into cross-organ therapeutic strategies.
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Affiliation(s)
- Naoto Fukasawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Junya Tsunoda
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Shogo Sunaga
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Hiroki Kiyohara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Nobuhiro Nakamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Toshiaki Teratani
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Yohei Mikami
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, Japan.
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Balthazard R, Drouin‐Engler R, Bertrand S, Zine‐Eddine F, Li J, Tastet O, Daigneault A, Mamane VH, Ortega‐Delgado GG, Sreng Flores AM, Kaufmann DE, Major P, House AA, Létourneau‐Guillon L, Arbour N, Keezer MR, Larochelle C. Distinct peripheral pro-inflammatory profile associated with tuberous sclerosis complex and epilepsy. Epilepsia 2025; 66:1288-1303. [PMID: 39817839 PMCID: PMC11997944 DOI: 10.1111/epi.18261] [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: 06/05/2024] [Revised: 12/20/2024] [Accepted: 12/31/2024] [Indexed: 01/18/2025]
Abstract
OBJECTIVE Tuberous sclerosis complex (TSC) is a monogenetic disorder associated with sustained mechanistic target of rapamycin (mTOR) activation, leading to heterogeneous clinical manifestations. Epilepsy and renal angiomyolipoma are the most important causes of morbidity in adult people with TSC (pwTSC). mTOR is a key player in inflammation, which in turn could influence TSC-related clinical manifestations. Reliable biomarkers are lacking to monitor and predict evolution and response to treatment for epilepsy in pwTSC. Inflammation has been implicated in epileptogenesis in non-TSC-related epilepsy. We aimed to characterize the relation between markers of neuroglial activation/injury, markers of peripheral inflammation, and active epilepsy in pwTSC to identify accessible biomarkers and potential new therapeutic targets. METHODS We performed a cross-sectional study to investigate markers of central nervous system (CNS) (neurofilament light [NfL] and glial fibrillary acidic protein [GFAP]) and peripheral (45 cytokines) inflammation in the peripheral blood of pwTSC (n = 46) vs age- and sex-matched healthy controls (HCs) (n = 26). In pwTSC, markers associated with active epilepsy (n = 23/46) were compared to non-TSC epilepsy controls (n = 18). Observations on markers of neuroglial activation/injury (GFAP, NfL) were confirmed in an independent TSC cohort (n = 45; 69% with active epilepsy). RESULTS We report that TSC is characterized by elevated serum levels of marker of astrogliosis (GFAP), pro-inflammatory molecules (interleukin 1β [IL-1β], CXCL8) and trophic factor (epidermal growth factor [EGF]) compared to HCs and to non-TSC-related epilepsy controls. Among pwTSC, renal angiomyolipoma presence and size was associated with IL-15. It is notable that active epilepsy in pwTSC was associated with higher levels of GFAP compared to pwTSC without epilepsy, which was confirmed in an external validation cohort, and with elevated levels of pro-inflammatory cytokines (IL-17A, IL-17C, tumor necrosis factor α [TNF-α]), not significantly related to seizure activity or treatment with mTOR inhibitor. These associations remained significant after adjusting for age and sex. SIGNIFICANCE These results suggest that key inflammatory mediators could contribute to epileptogenesis and represent novel biomarkers and therapeutic targets in TSC.
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Affiliation(s)
- Renaud Balthazard
- Department of Neurosciences, Faculty of MedicineUniversité de MontréalMontrealQuebecCanada
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)MontrealQuebecCanada
| | - Rose‐Marie Drouin‐Engler
- Department of Neurosciences, Faculty of MedicineUniversité de MontréalMontrealQuebecCanada
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)MontrealQuebecCanada
| | - Samuel Bertrand
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)MontrealQuebecCanada
- Centre Hospitalier de l'Université de Montréal (CHUM)MontrealQuebecCanada
| | - Faycal Zine‐Eddine
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)MontrealQuebecCanada
- Centre Hospitalier de l'Université de Montréal (CHUM)MontrealQuebecCanada
| | - Jimmy Li
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)MontrealQuebecCanada
- Division of NeurologyCentre Hospitalier de l'Université de Sherbrooke (CHUS)SherbrookeQuebecCanada
- School of Public HealthUniversité de MontréalMontrealQuebecCanada
| | | | - Audrey Daigneault
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)MontrealQuebecCanada
| | - Victoria H. Mamane
- Department of Neurosciences, Faculty of MedicineUniversité de MontréalMontrealQuebecCanada
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)MontrealQuebecCanada
| | | | - Alina Maria Sreng Flores
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)MontrealQuebecCanada
- Department of Microbiology, Infectious Diseases and Immunology, Faculty of MedicineUniversité de MontréalMontrealQuebecCanada
| | - Daniel E. Kaufmann
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)MontrealQuebecCanada
- Centre Hospitalier de l'Université de Montréal (CHUM)MontrealQuebecCanada
- Department of Medicine, Faculty of MedicineUniversité de MontréalMontrealQuebecCanada
- Division of Infectious Diseases, Department of MedicineLausanne University Hospital and University of LausanneLausanneSwitzerland
| | - Philippe Major
- Department of Neurosciences, Faculty of MedicineUniversité de MontréalMontrealQuebecCanada
- Division of NeurologyCentre Hospitalier Universitaire (CHU) Sainte JustineMontrealQuebecCanada
| | - Andrew A. House
- Division of Nephrology, Department of MedicineWestern University and London Health Sciences CentreLondonOntarioCanada
| | - Laurent Létourneau‐Guillon
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)MontrealQuebecCanada
- Centre Hospitalier de l'Université de Montréal (CHUM)MontrealQuebecCanada
- Department of Radiology, Faculty of MedicineUniversité de MontréalMontrealQuebecCanada
| | - Nathalie Arbour
- Department of Neurosciences, Faculty of MedicineUniversité de MontréalMontrealQuebecCanada
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)MontrealQuebecCanada
| | - Mark R. Keezer
- Department of Neurosciences, Faculty of MedicineUniversité de MontréalMontrealQuebecCanada
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)MontrealQuebecCanada
- Centre Hospitalier de l'Université de Montréal (CHUM)MontrealQuebecCanada
- School of Public HealthUniversité de MontréalMontrealQuebecCanada
| | - Catherine Larochelle
- Department of Neurosciences, Faculty of MedicineUniversité de MontréalMontrealQuebecCanada
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)MontrealQuebecCanada
- Centre Hospitalier de l'Université de Montréal (CHUM)MontrealQuebecCanada
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Fang S, Hu N, Zhou C, You J, Wu L, Pan X, Xiao Z, Qiu J. The comparison of gut microbiota between different types of epilepsy in children. Microb Cell Fact 2025; 24:64. [PMID: 40082906 PMCID: PMC11908097 DOI: 10.1186/s12934-025-02684-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 02/21/2025] [Indexed: 03/16/2025] Open
Abstract
OBJECTIVE To better understand the variations in gut microbiota in children with different types of epilepsy. METHODS Thirty-seven children with epilepsy were included in the case group, which was further divided into focal (group A, n = 28) and generalized epilepsy groups (group B, n = 9) based on the origin and extent of the seizures. The focal epilepsy group was subdivided into the benign childhood epilepsy with centrotemporal spikes (BECT) (group C, n = 9) and non-BECT groups (group D, n = 19) based on the appearance of typical centrotemporal spikes or spike-wave complexes on the electroencephalogram (EEG). Additionally, 14 healthy children were selected as the control group (group E, n = 14). RESULTS Significant differences were observed in the diversity and composition of gut microbiota between the case and control groups. At the genus level, the abundance of Megamonas (P = 0.001), Streptococcus (P<0.001), Romboutsia (P = 0.001), Bacteroides (P<0.05), and Escherichia/Shigella (P<0.05) was significantly higher in the focal epilepsy group than in the control group (0.027 vs. 0.00009, P = 0.001; 0.016 vs. 0.002, P<0.001; 0.013 vs. 0.002, P = 0.001; 0.030 vs. 0.002, P<0.05, respectively). Additionally, Escherichia/Shigella (P<0.05) was more abundant in the case group compared to the control group (0.033 vs. 0.002, P<0.05). Bacteroides (P<0.05) was more abundant in the control group than in the case group. Megamonas (P<0.001) and Collinsella (P<0.05) were significantly more prevalent in the BECT group than in the control group (0.034 vs. 0.00009, P<0.001; 0.014 vs. 0.001, P<0.05, respectively). In the non-BECT group, compared to the control group, Megamonas (P = 0.013), Streptococcus (P<0.001), Romboutsia (P = 0.001), and Escherichia/Shigella (P<0.05) were found in greater abundance (0.023 vs. 0.00009, P = 0.013; 0.018 vs. 0.002, P<0.001; 0.014 vs. 0.002, P = 0.001; 0.037 vs. 0.002, P<0.05, respectively). CONCLUSIONS Though, there were no statistically significant differences in gut microbiota between the different types of epilepsy, the gut microbiota of children with epilepsy significantly differed from that of healthy controls. The increased abundance of Escherichia/Shigella may lead to the worsening of clinical phenotypes and poor prognosis, and it could be a candidate biomarker to identify the focal epilepsy or even non-benign childhood epilepsy with centrotemporal spikes, potentially providing new therapeutic targets for the future.
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Affiliation(s)
- Siwei Fang
- Pediatrics Research Institute of Hunan Province, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), Changsha, Hunan, 410007, China
- The School of Pediatrics, Hengyang Medical School, University of South China, Hengyang, Hunan, 421099, China
- Department of Emergency Center, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), Changsha, Hunan, 410007, China
| | - Nanfei Hu
- Pediatrics Research Institute of Hunan Province, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), Changsha, Hunan, 410007, China
- Hunan Provincial Brain Hospital, Changsha, Hunan, 410007, China
| | - Changci Zhou
- Pediatrics Research Institute of Hunan Province, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), Changsha, Hunan, 410007, China
- The School of Pediatrics, Hengyang Medical School, University of South China, Hengyang, Hunan, 421099, China
- Department of Emergency Center, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), Changsha, Hunan, 410007, China
| | - Jiajia You
- Pediatrics Research Institute of Hunan Province, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), Changsha, Hunan, 410007, China
- The School of Pediatrics, Hengyang Medical School, University of South China, Hengyang, Hunan, 421099, China
- Department of Emergency Center, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), Changsha, Hunan, 410007, China
| | - Liwen Wu
- Department of Neonatology, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), Changsha, Hunan, 410007, China
| | - Xiongfeng Pan
- Pediatrics Research Institute of Hunan Province, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), Changsha, Hunan, 410007, China
- The School of Pediatrics, Hengyang Medical School, University of South China, Hengyang, Hunan, 421099, China
- Department of Emergency Center, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), Changsha, Hunan, 410007, China
| | - Zhenghui Xiao
- Pediatrics Research Institute of Hunan Province, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), Changsha, Hunan, 410007, China.
- The School of Pediatrics, Hengyang Medical School, University of South China, Hengyang, Hunan, 421099, China.
- Department of Emergency Center, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), Changsha, Hunan, 410007, China.
| | - Jun Qiu
- Pediatrics Research Institute of Hunan Province, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), Changsha, Hunan, 410007, China.
- The School of Pediatrics, Hengyang Medical School, University of South China, Hengyang, Hunan, 421099, China.
- Department of Emergency Center, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), Changsha, Hunan, 410007, China.
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Ashtiani SH, Akel S, Berger E, Zelano J. Plasma proteomics in epilepsy: Network-based identification of proteins associated with seizures. Epilepsy Res 2025; 209:107480. [PMID: 39626528 DOI: 10.1016/j.eplepsyres.2024.107480] [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: 04/22/2024] [Revised: 10/31/2024] [Accepted: 11/14/2024] [Indexed: 01/11/2025]
Abstract
PURPOSE Identification of potential biomarkers of seizures. METHODS In this exploratory study, we quantified plasma protein intensities in 15 patients with recent seizures compared to 15 patients with long-standing seizure freedom. Using TMT-based proteomics we found fifty-one differentially expressed proteins. RESULTS Network analyses including co-expression networks and protein-protein interaction networks, using the STRING database, followed by network centrality and modularity analyses revealed 22 protein modules, with one module showing a significant association with seizures. The protein-protein interaction network centered around this module identified a subnetwork of 125 proteins, grouped into four clusters. Notably, one cluster (mainly enriching inflammatory pathways and Gene Ontology terms) demonstrated the highest enrichment of known epilepsy-related genes. CONCLUSION Overall, our network-based approach identified a protein module linked with seizures. The module contained known markers of epilepsy and inflammation. The results also demonstrate the potential of network analysis in discovering new biomarkers for improved epilepsy management.
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Affiliation(s)
- Saman Hosseini Ashtiani
- Department of Clinical Neuroscience, Sahlgrenska Academy, University of Gothenburg, Sweden; Wallenberg Center of Molecular and Translational Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
| | - Sarah Akel
- Department of Clinical Neuroscience, Sahlgrenska Academy, University of Gothenburg, Sweden; Wallenberg Center of Molecular and Translational Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden
| | - Evelin Berger
- Proteomics Core Facility, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Johan Zelano
- Department of Clinical Neuroscience, Sahlgrenska Academy, University of Gothenburg, Sweden; Wallenberg Center of Molecular and Translational Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden; Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden
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Viswas A, Dabla PK, Gupta S, Yadav M, Tanwar A, Upreti K, Koner BC. SCN1A Genetic Alterations and Oxidative Stress in Idiopathic Generalized Epilepsy Patients: A Causative Analysis in Refractory Cases. Indian J Clin Biochem 2025; 40:105-110. [PMID: 39835235 PMCID: PMC11741965 DOI: 10.1007/s12291-023-01164-x] [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: 09/01/2023] [Accepted: 11/09/2023] [Indexed: 08/27/2024]
Abstract
Single Nucleotide Polymorphisms (SNPs) have found it be associated with drug resistance in epilepsy. The purpose of this study was to determine the role of SCN1A gene polymorphism in developing drug resistance in idiopathic generalized epilepsy (IGE) patients, along with increased oxidative stress. The study was conducted at a tertiary care hospital in Delhi, India. We recruited 100 patients diagnosed with IGE patients, grouped as drug-resistant and drug-responsive, and then further compared the SCN1A SNP rs10167228 A*/T analysis between the two groups. We utilized the PCR-RFLP technique to investigate the association between polymorphisms and refractory epilepsy. Serum HMGB1 levels were estimated using the ELISA technique to analyze oxidative stress in both groups. rs10167228 A*/T polymorphism genotypes AT and AA genotypes are significantly associated with an increased risk of developing drug resistance. Serum HMGB1, IL-1β, and IL-6 levels were significantly higher in drug-resistant cases, compared to the drug-responsive group. The association of SCN1A gene polymorphisms, in conjunction with raised oxidative stress, may be predictive of the development of drug-resistant epilepsy. The AT and AA genotypes of rs10167228 may pose a risk factor for developing drug-resistant epilepsy.
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Affiliation(s)
- Aroop Viswas
- Department of Biochemistry, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research, New Delhi, India
| | - Pradeep Kumar Dabla
- Department of Biochemistry, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research, New Delhi, India
| | - Swapan Gupta
- Department of Neurology, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research, New Delhi, India
| | - Manisha Yadav
- Multi-disciplinary Research Unit, Maulana Azad Medical College, New Delhi, India
| | - Alokit Tanwar
- Multi-disciplinary Research Unit, Maulana Azad Medical College, New Delhi, India
- Manav Rachna International Institute of Research and Studies, Faridabad, Haryana India
| | - Kamal Upreti
- Department of Computer Science, CHRIST (Deemed to be University), Ghaziabad, Delhi NCR India
| | - B C Koner
- Multi-disciplinary Research Unit, Maulana Azad Medical College, New Delhi, India
- Department of Biochemistry, Maulana Azad Medical College, New Delhi, India
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Antar A, Abdel-Rehiem ES, Al-Khalaf AA, Abuelsaad ASA, Abdel-Gabbar M, Shehab GMG, Abdel-Aziz AM. Therapeutic Efficacy of Lavandula dentata's Oil and Ethanol Extract in Regulation of the Neuroinflammation, Histopathological Alterations, Oxidative Stress, and Restoring Balance Treg Cells Expressing FoxP3+ in a Rat Model of Epilepsy. Pharmaceuticals (Basel) 2024; 18:35. [PMID: 39861097 PMCID: PMC11768170 DOI: 10.3390/ph18010035] [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: 11/24/2024] [Revised: 12/26/2024] [Accepted: 12/27/2024] [Indexed: 01/27/2025] Open
Abstract
Background/Objectives: Despite the availability of antiepileptic drugs (AEDs) that can manage seizures, they often come with cognitive side effects. Furthermore, the role of oxidative stress and neuroinflammatory responses in epilepsy and the limitations of current AEDs necessitate exploring alternative therapeutic options. Medicinal plants, e.g., Lavandula dentata L., are rich in phenolic compounds and may provide neuroprotective and anti-inflammatory benefits. However, limited research evaluates their effectiveness in modulating neuroinflammation and histopathological changes in epilepsy models. Therefore, the current study hypothesized that treating Lavandula dentata L. extract or essential oils may reduce neuroinflammatory responses and mitigate histopathological changes in the brain, providing a natural alternative or adjunct therapy for epilepsy management. Methods: Five groups of male Wistar rats were used: control, pilocarpine-treated epileptic, valproic acid (VPA-treated epileptic), L. dentata extract, and essential oils. Numerous electrolyte levels, monoamine levels, neurotransmitter levels, and the mRNA expression of specific gate channel subtypes were evaluated in homogenate brain tissue. Additionally, histological changes in various brain regions were investigated. Results: The investigation revealed that the extract and essential oils obtained from L. dentata L. exhibited the ability to improve the modulation of electrolytes and ions across voltage- and ligand-gated ion channels. Furthermore, it was revealed that they could decrease neuronal excitability by facilitating repolarization. Moreover, L. dentata's oil and ethanol extract re-balances T-reg/Th-17 cytokines, restoring the pro/anti-inflammatory cytokines and Treg markers, e.g., FOXP3 and CTLA-4, to their normal level. Conclusions: The present work confirms that the extract and essential oils of L. dentata L. have different activities to ameliorate the progression of histopathological alterations. Therefore, when used in conjunction with other AEDs, the extract and essential oils of L. dentata can slow the progression of epileptogenesis.
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Affiliation(s)
- Aziza Antar
- Biochemistry Department, Faculty of Science, Beni-Suef University, Beni-Suef 62521, Egypt; (A.A.); (M.A.-G.)
| | - Eman S. Abdel-Rehiem
- Molecular Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef 62521, Egypt;
| | - Areej A. Al-Khalaf
- Biology Department, College of Science, Princess Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia;
| | - Abdelaziz S. A. Abuelsaad
- Immunology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef 62521, Egypt
| | - Mohamed Abdel-Gabbar
- Biochemistry Department, Faculty of Science, Beni-Suef University, Beni-Suef 62521, Egypt; (A.A.); (M.A.-G.)
| | - Gaber M. G. Shehab
- Department of Biochemistry, College of Medicine, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia;
| | - Ayman M. Abdel-Aziz
- Zoology Department, Faculty of Science, Fayoum University, Fayoum 63514, Egypt;
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Li M, Tong F, Wu B, Dong X. Radiation-Induced Brain Injury: Mechanistic Insights and the Promise of Gut-Brain Axis Therapies. Brain Sci 2024; 14:1295. [PMID: 39766494 PMCID: PMC11674909 DOI: 10.3390/brainsci14121295] [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: 11/06/2024] [Revised: 12/17/2024] [Accepted: 12/19/2024] [Indexed: 01/11/2025] Open
Abstract
Radiation therapy is widely recognized as an efficacious modality for treating neoplasms located within the craniofacial region. Nevertheless, this approach is not devoid of risks, predominantly concerning potential harm to the neural structures. Adverse effects may encompass focal cerebral necrosis, cognitive function compromise, cerebrovascular pathology, spinal cord injury, and detriment to the neural fibers constituting the brachial plexus. With increasing survival rates among oncology patients, evaluating post-treatment quality of life has become crucial in assessing the benefits of radiation therapy. Consequently, it is imperative to investigate therapeutic strategies to mitigate cerebral complications from radiation exposure. Current management of radiation-induced cerebral damage involves corticosteroids and bevacizumab, with preclinical research on antioxidants and thalidomide. Despite these efforts, an optimal treatment remains elusive. Recent studies suggest the gut microbiota's involvement in neurologic pathologies. This review aims to discuss the causes and existing treatments for radiation-induced cerebral injury and explore gut microbiota modulation as a potential therapeutic strategy.
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Affiliation(s)
- Mengting Li
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan 430022, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Fan Tong
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan 430022, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Bian Wu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan 430022, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiaorong Dong
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan 430022, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, 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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9
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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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10
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Du Y, Xiao X, You HZ, Hou ZY, Yang XD, Wang J, Tang J, Wang Y. Association of High Plasma Levels of Serpin E1, IGFBP2, and CCL5 With Refractory Epilepsy in Children by Cytokine Profiling. Clin Pediatr (Phila) 2024; 63:953-962. [PMID: 37731223 DOI: 10.1177/00099228231201245] [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] [Indexed: 09/22/2023]
Abstract
Inflammatory cytokines participate in the pathology of epilepsy and the development of drug resistance. In this study, we combined a cytokine array and enzyme-linked immunosorbent assay to identify new cytokines in the plasma from children on early stage of the onset of epilepsy (EOE) and children with drug-resistant epilepsy (DRE). Compared with healthy controls, a broad up-regulation of cytokines was observed in patients with EOE, and many of the cytokines were not previously reported. In patients with DRE, most of these up-regulated cytokines maintained at relatively low levels close to those in controls; only a few of them, including CCL5, Serpin E1, and IGFBP2, remained at high levels. The dramatic difference in cytokine profile could be a strong clue for the incidence of DRE, and DRE-associated cytokines appeared to have the potential to be new biomarkers for epilepsy prognosis and therapeutic targets.
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Affiliation(s)
- Yaning Du
- Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao Xiao
- Department of Neurology, The Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Hai-Zhen You
- Department of Traditional Chinese Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Immunology and Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhao-Yuan Hou
- Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao-Dong Yang
- The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosecurity, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Center for Traditional Chinese Medicine and Immunology Research, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiwen Wang
- Department of Neurology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jihong Tang
- Department of Neurology, The Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yingyan Wang
- Department of Neurology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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11
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Dong Y, Zhang X, Wang Y. Interleukins in Epilepsy: Friend or Foe. Neurosci Bull 2024; 40:635-657. [PMID: 38265567 PMCID: PMC11127910 DOI: 10.1007/s12264-023-01170-2] [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: 08/19/2023] [Accepted: 10/28/2023] [Indexed: 01/25/2024] Open
Abstract
Epilepsy is a chronic neurological disorder with recurrent unprovoked seizures, affecting ~ 65 million worldwide. Evidence in patients with epilepsy and animal models suggests a contribution of neuroinflammation to epileptogenesis and the development of epilepsy. Interleukins (ILs), as one of the major contributors to neuroinflammation, are intensively studied for their association and modulatory effects on ictogenesis and epileptogenesis. ILs are commonly divided into pro- and anti-inflammatory cytokines and therefore are expected to be pathogenic or neuroprotective in epilepsy. However, both protective and destructive effects have been reported for many ILs. This may be due to the complex nature of ILs, and also possibly due to the different disease courses that those ILs are involved in. In this review, we summarize the contributions of different ILs in those processes and provide a current overview of recent research advances, as well as preclinical and clinical studies targeting ILs in the treatment of epilepsy.
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Affiliation(s)
- Yuan Dong
- Neuropsychiatry Research Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266000, China.
| | - Xia Zhang
- Neuropsychiatry Research Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266000, China
| | - Ying Wang
- Neuropsychiatry Research Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266000, China.
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, 02115, USA.
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12
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Leonard J, Wei X, Browning J, Gudenschwager-Basso EK, Li J, Harris EA, Olsen ML, Theus MH. Transcriptomic alterations in cortical astrocytes following the development of post-traumatic epilepsy. Sci Rep 2024; 14:8367. [PMID: 38600221 PMCID: PMC11006850 DOI: 10.1038/s41598-024-58904-z] [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: 11/21/2023] [Accepted: 04/04/2024] [Indexed: 04/12/2024] Open
Abstract
Post-traumatic epilepsy (PTE) stands as one of the numerous debilitating consequences that follow traumatic brain injury (TBI). Despite its impact on many individuals, the current landscape offers only a limited array of reliable treatment options, and our understanding of the underlying mechanisms and susceptibility factors remains incomplete. Among the potential contributors to epileptogenesis, astrocytes, a type of glial cell, have garnered substantial attention as they are believed to promote hyperexcitability and the development of seizures in the brain following TBI. The current study evaluated the transcriptomic changes in cortical astrocytes derived from animals that developed seizures as a result of severe focal TBI. Using RNA-Seq and ingenuity pathway analysis (IPA), we unveil a distinct gene expression profile in astrocytes, including alterations in genes supporting inflammation, early response modifiers, and neuropeptide-amidating enzymes. The findings underscore the complex molecular dynamics in astrocytes during PTE development, offering insights into therapeutic targets and avenues for further exploration.
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Affiliation(s)
- John Leonard
- Department of Biomedical Sciences and Pathobiology, Faculty of Health Sciences, Virginia Tech, 970 Washington Street SW, Life Sciences I; Rm 249 (MC0910), Blacksburg, VA, 24061, USA
| | - Xiaoran Wei
- School of Neuroscience, Virginia Tech, Blacksburg, VA, 24061, USA
| | - Jack Browning
- School of Neuroscience, Virginia Tech, Blacksburg, VA, 24061, USA
| | - Erwin Kristobal Gudenschwager-Basso
- Department of Biomedical Sciences and Pathobiology, Faculty of Health Sciences, Virginia Tech, 970 Washington Street SW, Life Sciences I; Rm 249 (MC0910), Blacksburg, VA, 24061, USA
| | - Jiangtao Li
- School of Neuroscience, Virginia Tech, Blacksburg, VA, 24061, USA
| | - Elizabeth A Harris
- Department of Biomedical Sciences and Pathobiology, Faculty of Health Sciences, Virginia Tech, 970 Washington Street SW, Life Sciences I; Rm 249 (MC0910), Blacksburg, VA, 24061, USA
| | - Michelle L Olsen
- School of Neuroscience, Virginia Tech, Blacksburg, VA, 24061, USA
| | - Michelle H Theus
- Department of Biomedical Sciences and Pathobiology, Faculty of Health Sciences, Virginia Tech, 970 Washington Street SW, Life Sciences I; Rm 249 (MC0910), Blacksburg, VA, 24061, USA.
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13
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Zhu H, Wang W, Li Y. The interplay between microbiota and brain-gut axis in epilepsy treatment. Front Pharmacol 2024; 15:1276551. [PMID: 38344171 PMCID: PMC10853364 DOI: 10.3389/fphar.2024.1276551] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Accepted: 01/12/2024] [Indexed: 08/12/2024] Open
Abstract
The brain-gut axis plays a vital role in connecting the cognitive and emotional centers of the brain with the intricate workings of the intestines. An imbalance in the microbiota-mediated brain-gut axis extends far beyond conditions like Irritable Bowel Syndrome (IBS) and obesity, playing a critical role in the development and progression of various neurological disorders, including epilepsy, depression, Alzheimer's disease (AD), and Parkinson's disease (PD). Epilepsy, a brain disorder characterized by unprovoked seizures, affects approximately 50 million people worldwide. Accumulating evidence suggests that rebuilding the gut microbiota through interventions such as fecal microbiota transplantation, probiotics, and ketogenic diets (KD) can benefit drug-resistant epilepsy. The disturbances in the gut microbiota could contribute to the toxic side effects of antiepileptic drugs and the development of drug resistance in epilepsy patients. These findings imply the potential impact of the gut microbiota on epilepsy and suggest that interventions targeting the microbiota, such as the KD, hold promise for managing and treating epilepsy. However, the full extent of the importance of microbiota in epilepsy treatment is not yet fully understood, and many aspects of this field remain unclear. Therefore, this article aims to provide an overview of the clinical and animal evidence supporting the regulatory role of gut microbiota in epilepsy, and of potential pathways within the brain-gut axis that may be influenced by the gut microbiota in epilepsy. Furthermore, we will discuss the recent advancements in epilepsy treatment, including the KD, fecal microbiota transplantation, and antiseizure drugs, all from the perspective of the gut microbiota.
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Affiliation(s)
- Hanxiao Zhu
- Department of Neurology, The First Affiliated Hospital of Dali University, Dali, China
- Clinical Medical School, Dali University, Dali, China
| | - Wei Wang
- Neurobiology Laboratory, China Agricultural University, Beijing, China
| | - Yun Li
- Department of Neurology, The First Affiliated Hospital of Dali University, Dali, China
- Clinical Medical School, Dali University, Dali, China
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14
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Sallam DE, Shaker YS, Mostafa GA, El-Hossiny RM, Taha SI, Ahamed MAEH. Evaluation of serum interleukin-17 A and interleukin-22 levels in pediatric patients with autism spectrum disorder: a pilot study. BMC Pediatr 2024; 24:18. [PMID: 38183030 PMCID: PMC10768424 DOI: 10.1186/s12887-023-04484-2] [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: 11/17/2023] [Accepted: 12/13/2023] [Indexed: 01/07/2024] Open
Abstract
BACKGROUND Many neurodevelopmental abnormalities are connected to autism spectrum disorder (ASD), which can result in inflammation and elevated cytokine levels due to immune system dysregulation. Interleukin (IL)-17 A and IL-22 have been linked to the regulation of host defense against pathogens at the barrier surface, the regeneration of injured tissue, and the integration of the neurological, endocrine, and immune systems. Several studies have investigated the possible connection between IL-17 A and ASD as well as the severity of behavioral symptoms, but few of them included IL-22. OBJECTIVES To measure serum levels of interleukin (IL)-17 A and IL-22 in children with ASD and to investigate their association with disease severity. METHODS This pilot study was performed on 24 children with ASD and 24 matched controls. Childhood Autism Rating Scale (CARS) assessed ASD severity, and serum levels of IL-17 A and IL-22 were assessed by enzyme-linked immunosorbent assay (ELISA). RESULTS In ASD patients, serum levels of IL-17 A and IL-22 showed a significant increase compared to controls (p-values < 0.001). We compared serum levels of IL-17 A and IL-22 according to the severity categories by CARS and could not find any significant differences (p-values > 0.05). Only IL-22 had a significant positive correlation with ASD severity by CARS scores. CONCLUSIONS Raised serum levels of IL-17 A and IL-22 are associated with ASD; only IL-22, not IL-17 A, is correlated with ASD severity. This finding proposes IL-22 as a possible future effective target for ASD treatment. To fully comprehend the significance of these cytokines in ASD and their possible effects on ASD diagnosis and treatment, more research on a wider scale is required.
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Affiliation(s)
- Dina E Sallam
- Department of Pediatrics, Pediatric Nephrology Unit, Faculty of Medicine, Ain Shams University, Abbasia, Cairo, Egypt
| | | | - Gehan A Mostafa
- Department of Pediatrics, Pediatric Allergy, and Immunology Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Reham M El-Hossiny
- Department of Pediatrics, Pediatric Neuropsychiatric Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Sara I Taha
- Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
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15
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Zhou K, Jia L, Mao Z, Si P, Sun C, Qu Z, Wang W. Integrated Macrogenomics and Metabolomics Explore Alterations and Correlation between Gut Microbiota and Serum Metabolites in Adult Epileptic Patients: A Pilot Study. Microorganisms 2023; 11:2628. [PMID: 38004640 PMCID: PMC10672912 DOI: 10.3390/microorganisms11112628] [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: 08/16/2023] [Revised: 10/08/2023] [Accepted: 10/24/2023] [Indexed: 11/26/2023] Open
Abstract
Epilepsy (EP) is a complex brain disorder showing a lot of unknows reasons. Recent studies showed that gut microbiota can influence epilepsy via the brain-gut axis. Nevertheless, the mechanism by which gut microbiota affects adult epilepsy still remains unclear. In this study, fecal and serum samples were obtained from patients with epilepsy and normal controls. Using an integrated analysis, sequencing was performed by macrogenomics and high-throughput targeted metabolomics with various bioinformatics approaches. The macrogenomic sequencing revealed significant changes in microbial structure in patients suffering from epilepsy. For example, at the phylum level, the relative abundance of Actinobacteria, Bacteroidetes and Proteobacteria showed an increase in the patients with epilepsy, whereas that of Firmicutes decreased. In addition, the patients with epilepsy had significantly differential metabolite profiles compared to normal controls, and five clusters with 21 metabolites, mainly containing the upregulation of some fatty acids and downregulation of some amino acids. Tryptophan (AUC = 91.81, p < 0.0001), kynurenine (AUC = 79.09, p < 0.01) and 7Z,10Z,13Z,16Z-Docosatetraenoic acid (AUC = 80.95, p < 0.01) may be used as potential diagnostic markers for epilepsy. Differential serum metabolites have effects on tryptophan metabolism, iron death and other pathways. Furthermore, a multiomic joint analysis observed a statistically significant correlation between the differential flora and the differential serum metabolites. In our findings, a macrogenomic analysis revealed the presence of dysregulated intestinal flora species and function in adult epileptic patients. Deeper metabolomic analyses revealed differences in serum metabolites between patients with epilepsy and healthy populations. Meanwhile, the multiomic combination showed connection between the gut microbes and circulating metabolites in the EP patients, which may be potential therapeutic targets.
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Affiliation(s)
- Kaiping Zhou
- Key Laboratory of Neurology of Hebei Province, Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang 050004, China
| | - Lijing Jia
- Key Laboratory of Neurology of Hebei Province, Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang 050004, China
| | - Zhuofeng Mao
- Key Laboratory of Neurology of Hebei Province, Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang 050004, China
| | - Peipei Si
- Key Laboratory of Neurology of Hebei Province, Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang 050004, China
| | - Can Sun
- Department of Neurology, Peking University Third Hospital, Beijing 100080, China
| | - Zhenzhen Qu
- Key Laboratory of Neurology of Hebei Province, Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang 050004, China
| | - Weiping Wang
- Key Laboratory of Neurology of Hebei Province, Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang 050004, China
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16
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Mengoli M, Conti G, Fabbrini M, Candela M, Brigidi P, Turroni S, Barone M. Microbiota-gut-brain axis and ketogenic diet: how close are we to tackling epilepsy? MICROBIOME RESEARCH REPORTS 2023; 2:32. [PMID: 38045924 PMCID: PMC10688818 DOI: 10.20517/mrr.2023.24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Revised: 08/01/2023] [Accepted: 08/21/2023] [Indexed: 12/05/2023]
Abstract
The microbiota-gut-brain axis refers to the intricate bidirectional communication between commensal microorganisms residing in the digestive tract and the central nervous system, along neuroendocrine, metabolic, immune, and inflammatory pathways. This axis has been suggested to play a role in several neurological disorders, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, and epilepsy, paving the way for microbiome-based intervention strategies for the mitigation and treatment of symptoms. Epilepsy is a multifaceted neurological condition affecting more than 50 million individuals worldwide, 30% of whom do not respond to conventional pharmacological therapies. Among the first-hand microbiota modulation strategies, nutritional interventions represent an easily applicable option in both clinical and home settings. In this narrative review, we summarize the mechanisms underlying the microbiota-gut-brain axis involvement in epilepsy, discuss the impact of antiepileptic drugs on the gut microbiome, and then the impact of a particular dietary pattern, the ketogenic diet, on the microbiota-gut-brain axis in epileptic patients. The investigation of the microbiota response to non-pharmacological therapies is an ever-expanding field with the potential to allow the design of increasingly accessible and successful intervention strategies.
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Affiliation(s)
- Mariachiara Mengoli
- Microbiomics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
| | - Gabriele Conti
- Microbiomics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40126, Italy
| | - Marco Fabbrini
- Microbiomics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40126, Italy
| | - Marco Candela
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40126, Italy
| | - Patrizia Brigidi
- Microbiomics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
| | - Silvia Turroni
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40126, Italy
| | - Monica Barone
- Microbiomics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
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Wang S, Su T, Pang S, Wang J, Lang Y, Zhu M, Cui L. Assessment of the relationship between generalized convulsive epilepsy and systemic inflammatory regulators: a bidirectional Mendelian randomization study. Front Neurol 2023; 14:1206290. [PMID: 37470000 PMCID: PMC10353605 DOI: 10.3389/fneur.2023.1206290] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Accepted: 06/06/2023] [Indexed: 07/21/2023] Open
Abstract
Background Generalized convulsive epilepsy (GCE), an important subtype of epilepsy, is a syndrome of neuronal dysfunction characterized by diffuse abnormal discharge of neurons within the brain. Compounding evidence suggests a correlation between epilepsy and inflammatory factors, for instance, cyclooxygenase-2, interleukin-1β, and interleukin-6. Elevated levels of inflammatory factors have been observed in patients with epilepsy and several animal models. Therefore, inflammation may be closely associated with the pathogenesis and progression of GCE. However, the cause-and-effect relationship between the two is difficult to determine because of small sample sizes and confounding factors. Methods To test for causality of the 41 cytokines on GCE, we conducted a two-sample Mendelian randomization (MR) based on the largest and latest genome-wide association study (GWAS) involving 290 cases and 453,521 European controls and a GWAS meta-analysis consisting of 41 cytokines from 8,293 individuals. Results R confirmed a bidirectional causal link between cytokines and GCE. Genetically predicted increased levels of hepatocyte growth factor and decreased levels of eotaxin and interleukin-18 are associated with an increased risk of GCE (OR = 1.904, 95% CI = 1.019-3.561, p = 0.044; OR = 0.641, 95% CI = 0.417-0.984, p = 0.042; OR = 0.482, 95% CI = 0.251-0.927, p = 0.046). Furthermore, the presence of GCE is related to an increase in levels of multiple cytokines, such as macrophage inflammatory protein-1α, interleukin-12p70, interleukin-17, interleukin-1 receptor antagonist, and basic fibroblast growth factor (OR = 1.038, 95% CI = 1.005-1.073, p = 0.024; OR = 1.031, 95% CI = 1.009-1.054, p = 0.006; OR = 1.027, 95% CI = 1.002-1.053, p = 0.037; OR = 1.037, 95% CI = 1.003-1.072, p = 0.032; OR = 1.032, 95% CI = 1.000-1.066, p = 0.048; OR = 1.025, 95% CI = 1.003-1.048, p = 0026). Conclusion A bidirectional causal link existed between inflammation and GCE. Detecting significantly altered factor concentrations may be of great significance for screening GCE and predicting their occurrence. Moreover, available pharmacological treatments for GCE are focused primarily on suppressing seizures. In future, altering the concentration of these cytokines in the body through targeted anti-inflammatory therapy to modify the epileptogenic mechanism and prevent the recurrence and refractoriness of GCE may become the key to new treatments.
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Affiliation(s)
- Shengnan Wang
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Tengfei Su
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Shuyan Pang
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Jianglong Wang
- First Operating Room, The First Hospital of Jilin University, Changchun, China
| | - Yue Lang
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Mingqin Zhu
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Li Cui
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
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18
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Douglas A, Stevens B, Lynch L. Interleukin-17 as a key player in neuroimmunometabolism. Nat Metab 2023; 5:1088-1100. [PMID: 37488456 PMCID: PMC10440016 DOI: 10.1038/s42255-023-00846-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 06/14/2023] [Indexed: 07/26/2023]
Abstract
In mammals, interleukin (IL)-17 cytokines are produced by innate and adaptive lymphocytes. However, the IL-17 family has widespread expression throughout evolution, dating as far back as cnidaria, molluscs and worms, which predate lymphocytes. The evolutionary conservation of IL-17 suggests that it is involved in innate defence strategies, but also that this cytokine family has a fundamental role beyond typical host defence. Throughout evolution, IL-17 seems to have a major function in homeostatic maintenance at barrier sites. Most recently, a pivotal role has been identified for IL-17 in regulating cellular metabolism, neuroimmunology and tissue physiology, particularly in adipose tissue. Here we review the emerging role of IL-17 signalling in regulating metabolic processes, which may shine a light on the evolutionary role of IL-17 beyond typical immune responses. We propose that IL-17 helps to coordinate the cross-talk among the nervous, endocrine and immune systems for whole-body energy homeostasis as a key player in neuroimmunometabolism.
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Affiliation(s)
- Aaron Douglas
- School of Biochemistry and Immunology, TBSI, Trinity College Dublin, Dublin, Ireland
| | - Brenneth Stevens
- School of Biochemistry and Immunology, TBSI, Trinity College Dublin, Dublin, Ireland
- Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Lydia Lynch
- School of Biochemistry and Immunology, TBSI, Trinity College Dublin, Dublin, Ireland.
- Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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19
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Mohamed KM, Abdelfattah MS, El-khadragy M, Al-Megrin WA, Fehaid A, Kassab RB, Abdel Moneim AE. Rutin-loaded selenium nanoparticles modulated the redox status, inflammatory, and apoptotic pathways associated with pentylenetetrazole-induced epilepsy in mice. GREEN PROCESSING AND SYNTHESIS 2023; 12. [DOI: 10.1515/gps-2023-0010] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2025]
Abstract
Abstract
Worldwide, epilepsy is the second most prevalent neurological disorder. Disappointingly, various adverse effects are being observed with currently used antiepileptic drugs. Nanomedicine represents an effective strategy to overcome these limitations with a better central drug delivery. Hence, our work aimed to unravel the antiepileptic efficacy of rutin (Rut) loaded with selenium nanoparticles (SeNPs) against pentylenetetrazole (PTZ)-challenged mice. Ten days before PTZ (60 mg·kg−1) intraperitoneal injection, mice were orally administered Rut (100 mg·kg−1), sodium selenite (0.5 mg·kg−1), SeNPs (100 mg·kg−1), or sodium valproate (reference drug, 200 mg·kg−1). Remarkably, administration of Rut-loaded SeNPs (Rut-SeNPs) to epileptic mice markedly increased the latency time and decreased the severity and duration of seizures. Remarkable increases were also noticed in acetylcholinesterase, brain-derived neurotrophic factor, dopamine, and norepinephrine levels in epileptic mice treated with Rut-SeNPs. Furthermore, Rut-SeNPs boosted the cellular antioxidant defense by increasing superoxide dismutase, catalase, GSH, Nrf2, and HO-1, along with decreased malondialdehyde and nitric oxide levels. In addition, the nanotherapy successfully mitigated the inflammatory mediators (tumor necrosis factor-α, interleukin-6, cyclooxygenase-2, and nuclear factor kappa B) in mice hippocampus. Rut-SeNPs antagonized neuronal apoptosis by decreasing Bax and caspase-3 and increasing the levels of Bcl-2. Conclusively, the present work suggests Rut-loaded SeNPs as an effective antiepileptic therapy through correction of disturbed neurotransmitters, oxidative status, neuroinflammation, and apoptosis.
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Affiliation(s)
- Kareem M. Mohamed
- Chemistry Department, Faculty of Science, Helwan University , Cairo , Egypt
| | | | - Manal El-khadragy
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University , P.O. Box 84428 , Riyadh 11671 , Saudi Arabia
| | - Wafa A. Al-Megrin
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University , P.O. Box 84428 , Riyadh 11671 , Saudi Arabia
| | - Alaa Fehaid
- Forensic Medicine and Toxicology Department, Faculty of Veterinary Medicine, Mansoura University , Dakahlia , Egypt
| | - Rami B. Kassab
- Zoology and Entomology Department, Faculty of Science, Helwan University , Cairo , Egypt
| | - Ahmed E. Abdel Moneim
- Zoology and Entomology Department, Faculty of Science, Helwan University , Cairo , Egypt
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20
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Cytokines/chemokines and soluble immune checkpoint molecules in anti-GABA B receptor encephalitis. Mult Scler Relat Disord 2022; 68:104234. [PMID: 36270252 DOI: 10.1016/j.msard.2022.104234] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 09/24/2022] [Accepted: 10/02/2022] [Indexed: 11/06/2022]
Abstract
BACKGROUND Anti-gamma-aminobutyric-acid B receptor (anti-GABABR) encephalitis is a rare form of autoimmune limbic encephalitis (ALE) that is closely associated with tumor comorbidity. The purpose of this study is to identify the expressive pattern of cytokines/ chemokines and soluble immune checkpoint molecules (sICMs) in anti-GABABR encephalitis in order to evaluate the clinical condition and provide new treatment options. METHODS A total of 40 cytokines/chemokines and 10 sICMs in the serum of 10 patients with anti-GABABR encephalitis and eight controls were measured. The differentially expressed cytokines/chemokines and sICMs were selected to explore the correlations with disease prognosis, CSF routine and antibody titers. RESULTS Eight cytokines/chemokines were found to be more abundant in patients than in healthy donors (HDs), while 14 were found to be less abundant in patients. In terms of sICMs, patients' serum contained higher level of soluble ICOS and ICOSL but lower level of soluble CD86. Unfavorable prognosis was associated with high serum level of PDGFB, IL-17A, and soluble ICOSL but not with low levels of IL-4. Increased levels of IL-17A, CCL15, and soluble ICOS were found frequently in the patients with CSF-exclusive OCBs, while soluble ICOSL and CCL24 expression was lower in these patients. High levels of IL-1 F2 and TCA-3 were correlated with the presence of tumors in patients. CONCLUSION The majority of patients with anti- GABABR encephalitis had an unfavorable prognosis in one year of follow-up. Serum PDGFB, IL-17A, IL-4 and soluble ICOSL level were associated with the poor clinical outcomes in one-year follow up.
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Bernardini N, Skroza N, Rossi G, Mambrin A, Tolino E, Marraffa F, Caviglia M, Guardo AD, Volpe S, Proietti I, Potenza C. Long term efficacy, safety, and tolerability of tildrakizumab in epileptic patient with psoriasis and eczema. Dermatol Reports 2022; 14:9447. [PMID: 36483227 PMCID: PMC9724640 DOI: 10.4081/dr.2022.9447] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 09/16/2022] [Indexed: 01/21/2023] Open
Abstract
Psoriasis is a chronic inflammatory disease which mostly affects skin. Tildrakizumab is a specific anti-interleukin -23p19 monoclonal antibody approved for the treatment of plaque psoriasis in adults. Herein, we report about a patient who came to our attention for a moderate-to-severe plaque psoriasis, involving primarily upper limbs, elbow, abdomen and knees (PASI 18 - DLQI 22). His medical history was relevant for epilepsy controlled pharmacologically. In addition, an eczematous and edematous appearance of the tibial area was detected; the histologic findings did not contradict the diagnostic hypothesis of subacute spongiotic dermatitis. The patient was treated with Tildrakizumab. After 12 weeks the clinical lesions improved significantly, and the eczematous component disappeared in the tibial area bilaterally. The clinical improvement was maintained even after one year of therapy. Tildrakizumab showed excellent results in the control of psoriasis, with an excellent safety profile. The promising results of clinical trials have been confirmed in a real-life setting. There are no reports about its safety in epileptic patients. In our case, neurological adverse events did not verify and tildrakizumab managed to control both the psoriatic and eczematous components.
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Affiliation(s)
- Nicoletta Bernardini
- Dermatology Unit “Daniele Innocenzi”, “A. Fiorini” Hospital, Via Firenze, 1, 04019, Terracina (LT), Italy. +39.0773.708811.
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22
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Zhou C, Gong S, Xiang S, Liang L, Hu X, Huang R, Liao Z, Ma Y, Xiao Z, Qiu J. Changes and significance of gut microbiota in children with focal epilepsy before and after treatment. Front Cell Infect Microbiol 2022; 12:965471. [PMID: 36405958 PMCID: PMC9671114 DOI: 10.3389/fcimb.2022.965471] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 10/13/2022] [Indexed: 11/06/2022] Open
Abstract
Objective To better understand the alterations in gut microbiota and metabolic pathways in children with focal epilepsy, and to further investigate the changes in the related gut microbiota and metabolic pathways in these children before and after treatment. Methods Ten patients with newly diagnosed focal epilepsy in Hunan Children’s Hospital from April, 2020 to October, 2020 were recruited into the case group. The case group was further divided into a pre-treatment subgroup and a post-treatment subgroup. Additionally, 14 healthy children of the same age were recruited into a control group. The microbial communities were analyzed using 16s rDNA sequencing data. Metastas and LEfSe were used to identify different bacteria between and within groups. The Kyoto Encyclopedia of Genes and Genomes database was used to KEGG enrichment analysis. Results There were significant differences in α diversity among the pre-treatment, post-treatment, and control groups. Besides, the differences in gut microbiota composition in 3 groups were identified by principal co-ordinates analysis (PCoA), which showed a similar composition of the pre-treatment and post-treatment subgroups. At the phyla level, the relative abundance of Actinobacteria in the pre-treatment subgroup was significantly higher than that in the control group, which decreased significantly after 3 months of treatment and showed no significant difference between the control group. In terms of the genus level, Escherichia/Shigella, Streptococcus, Collinsella, and Megamonas were enriched in the pre-treatment subgroup, while Faecalibacterium and Anaerostipes were enriched in the control group. The relative abundance of Escherichia/Shigella, Streptococcus, Collinsella, and Megamonas was reduced significantly after a three-month treatment. Despite some genera remaining significantly different between the post-treatment subgroup and control group, the number of significantly different genera decreased from 9 to 4 through treatment. Notably, we found that the carbohydrate metabolism, especially succinate, was related to focal epilepsy. Conclusion Children with focal epilepsy compared with healthy controls were associated with the statistically significant differences in the gut microbiota and carbohydrate metabolism. The differences were reduced and the carbohydrate metabolism improved after effective treatment. Our research may provide new directions for understanding the role of gut microbiota in the pathogenesis of focal epilepsy and better alternative treatments.
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Affiliation(s)
- Changci Zhou
- Academy of Pediatrics, Hengyang Medical School, University of South China, Hengyang, China
| | - Shuaizheng Gong
- Department of Hematology and Oncology, Hunan Children’s Hospital, Changsha, China
| | - Shiting Xiang
- Pediatrics Research Institute of Hunan Province, Hunan Children’s Hospital, Changsha, China
| | - Lijuan Liang
- Department of Emergency Center, Hunan Children’s Hospital, Changsha, China
| | - Xia Hu
- Department of Emergency Center, Hunan Children’s Hospital, Changsha, China
| | - Ruiwen Huang
- Department of Neonatology, Hunan Children’s Hospital, Changsha, China
| | - Zhenyu Liao
- Department of Neonatology, Hunan Children’s Hospital, Changsha, China
| | - Ye Ma
- Department of Neonatology, Hunan Children’s Hospital, Changsha, China
| | - Zhenghui Xiao
- Department of Emergency Center, Hunan Children’s Hospital, Changsha, China
- *Correspondence: Zhenghui Xiao, ; Jun Qiu,
| | - Jun Qiu
- Pediatrics Research Institute of Hunan Province, Hunan Children’s Hospital, Changsha, China
- *Correspondence: Zhenghui Xiao, ; Jun Qiu,
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Gakharia T, Bakhtadze S, Lim M, Khachapuridze N, Kapanadze N. Alterations of Plasma Pro-Inflammatory Cytokine Levels in Children with Refractory Epilepsies. CHILDREN (BASEL, SWITZERLAND) 2022; 9:children9101506. [PMID: 36291442 PMCID: PMC9600205 DOI: 10.3390/children9101506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 09/22/2022] [Accepted: 09/28/2022] [Indexed: 11/07/2022]
Abstract
Paediatric epilepsy is a multifaceted neurological disorder with various aetiologies. Up to 30% of patients are considered drug-resistant. The background impact of interfering inflammatory and neuronal pathways has been closely linked to paediatric epilepsy. The characteristics of the inflamed state have been described not only in epilepsies, which are considered prototypes of an inflammatory pathophysiology, but also in patients with drug-resistant epilepsy, especially in epileptic encephalopathies. The imbalance of different cytokine levels was confirmed in several epileptic models. Chemokines are new targets for exploring neuroimmune communication in epileptogenesis, which control leukocyte migration and have a possible role in neuromodulation. Additionally, prostaglandin E2 (PGE2) is an important effector molecule for central neural inflammatory responses and may influence drug responsiveness. We measured the serum interictal quantitative levels of chemokines (CCL2, CCL4, CCL11) and PGE2 in correlation with the seizure frequency and severity in controlled and intractable childhood epilepsies. Our refractory seizure group demonstrated significantly increased concentrations of eotaxin (CCL11) compared to the controlled epilepsy group. The higher level of CCL11 was correlated with an increased seizure frequency, while the PGE2 levels were associated with the severity of seizure and epilepsy, supporting the findings that proinflammatory cytokines may contribute to epileptogenesis and possibly have a role in developing seizure resistance.
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Affiliation(s)
- Tatia Gakharia
- Department of Childs Neurology, Tbilisi State Medical University, 0186 Tbilisi, Georgia
- Correspondence: ; Tel.: +995-592933291
| | - Sophia Bakhtadze
- Department of Childs Neurology, Tbilisi State Medical University, 0186 Tbilisi, Georgia
| | - Ming Lim
- Evelina London Children’s Hospital @ Guy’s and St Thomas’ NHS Foundation Trust, London SE1 7EH, UK
- Women’s and Children’s Department, Faculty of Life Sciences and Medicine, Kings College London, London SE1 7EH, UK
| | - Nana Khachapuridze
- Department of Childs Neurology, Tbilisi State Medical University, 0186 Tbilisi, Georgia
| | - Nana Kapanadze
- Department of Childs Neurology, Tbilisi State Medical University, 0186 Tbilisi, Georgia
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Banote RK, Akel S, Zelano J. Blood biomarkers in epilepsy. Acta Neurol Scand 2022; 146:362-368. [PMID: 35411571 PMCID: PMC9790299 DOI: 10.1111/ane.13616] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/04/2022] [Accepted: 03/19/2022] [Indexed: 12/30/2022]
Abstract
Robust and accessible biomarkers are greatly needed in epilepsy. Diagnostic and prognostic precision in the clinic needs to improve, and there is a need for objective quantification of seizure burden. In recent years, there have been advances in the development of accessible and cost-effective blood-based biomarkers in neurology, and these are increasingly studied in epilepsy. However, the field is in its infancy and specificity and sensitivity for most biomarkers in most clinical situations are not known. This review describes advancements regarding human blood biomarkers in epilepsy. Examples of biochemical markers that have been shown to have higher blood concentrations in study subjects with epilepsy include brain proteins like S100B or neuronal specific enolase, and neuroinflammatory proteins like interleukins, and tumor necrosis factor-alpha. Some of the blood biomarkers also seem to reflect seizure duration or frequency, and levels decrease in response to treatment with antiseizure medication. For most biomarkers, the literature contains seemingly conflicting results. This is to be expected in an emerging field and could reflect different study populations, sampling or analysis techniques, and epilepsy classification. More studies are needed with emphasis put on the classification of epilepsy and seizure types. More standardized reporting could perhaps decrease result heterogeneity and increase the potential for data sharing and subgroup analyses.
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Affiliation(s)
- Rakesh Kumar Banote
- Department of NeurologySahlgrenska University HospitalGothenburgSweden,Department of Clinical NeuroscienceSahlgrenska AcademyUniversity of GothenburgGothenburgSweden,Wallenberg Centre for Molecular and Translational MedicineUniversity of GothenburgGothenburgSweden
| | - Sarah Akel
- Department of Clinical NeuroscienceSahlgrenska AcademyUniversity of GothenburgGothenburgSweden
| | - Johan Zelano
- Department of NeurologySahlgrenska University HospitalGothenburgSweden,Department of Clinical NeuroscienceSahlgrenska AcademyUniversity of GothenburgGothenburgSweden,Wallenberg Centre for Molecular and Translational MedicineUniversity of GothenburgGothenburgSweden
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Ketogenic Diet: A Dietary Intervention via Gut Microbiome Modulation for the Treatment of Neurological and Nutritional Disorders (a Narrative Review). Nutrients 2022; 14:nu14173566. [PMID: 36079829 PMCID: PMC9460077 DOI: 10.3390/nu14173566] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 08/24/2022] [Accepted: 08/26/2022] [Indexed: 11/17/2022] Open
Abstract
The ketogenic diet (KD) has been important in treating epilepsy since the 1920s. The benefits of KD further expanded to other neurological diseases, including Alzheimer’s diseases, autism spectrum disorder, and nutritional disorder (obesity). Although the therapeutic efficacy of KD has been generally accepted, there is limited knowledge about its underlying mechanism of action, particularly its effect on our gut microbiome. Gut dysbiosis has been proposed to be involved in those diseases, and KD can promote gut microbiota remodeling that may assist in recovery. This review explores the therapeutic applications of KD, the roles of the gut microbiome in neurological diseases and obesity, as well as the effect of KD on the gut microbiome. The present information suggests that KD has significant roles in altering the gut microbiome to improve disease symptoms, mainly by incrementing Bacteroidetes to Firmicutes (B/F) ratio and reducing Proteobacteria in certain cases. However, current gaps call for continued research to understand better the gut microbiota profile altered by KD.
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An J, Li H, Xia D, Xu B, Wang J, Qiu H, He J. The role of interleukin-17 in epilepsy. Epilepsy Res 2022; 186:107001. [PMID: 35994860 DOI: 10.1016/j.eplepsyres.2022.107001] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 07/26/2022] [Accepted: 08/11/2022] [Indexed: 11/30/2022]
Abstract
Epilepsy is a common neurological disorder that seriously affects human health. It is a chronic central nervous system dysfunction caused by abnormal discharges of neurons. About 50 million patients worldwide are affected by epilepsy. Although epileptic symptoms of most patients are controllable, some patients with refractory epilepsy have no response to antiseizure medications. It is necessary to investigate the pathogenesis of epilepsy and identify new therapeutic targets for refractory epilepsy. Epileptic disorders often accompany cerebral inflammatory reactions. Recently, the role of inflammation in the onset of epilepsy has increasingly attracted attention. The activation of both innate and adaptive immunity plays a significant role in refractory epilepsy. According to several clinical studies, interleukin-17, an essential inflammatory mediator linking innate and adaptive immunity, increased significantly in the body liquid and epileptic focus of patients with epilepsy. Experimental studies also indicated that interleukin-17 participated in epileptogenesis through various mechanisms. This review summarized the current studies about interleukin-17 in epilepsy and aimed at finding new therapeutic targets for refractory epilepsy.
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Affiliation(s)
- Jiayin An
- Emergency Department, Naval Hospital of Eastern Theater, Zhejiang, China.
| | - He Li
- Emergency Department, Naval Hospital of Eastern Theater, Zhejiang, China.
| | - Demeng Xia
- Emergency Department, Naval Hospital of Eastern Theater, Zhejiang, China; Luodian Clinical Drug Research Center, Shanghai Baoshan Luodian Hospital, Shanghai University, Shanghai, China.
| | - Bin Xu
- Emergency Department, Naval Hospital of Eastern Theater, Zhejiang, China.
| | - Jiayan Wang
- Emergency Department, Naval Hospital of Eastern Theater, Zhejiang, China.
| | - Huahui Qiu
- Zhoushan Hospital, Zhejiang University, Zhoushan, Zhejiang, China.
| | - Jiaojiang He
- Department of Neurosurgery, West China Hospital of Sichuan University, Sichuan, China.
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Choi IY, Cho ML, Cho KO. Interleukin-17A Mediates Hippocampal Damage and Aberrant Neurogenesis Contributing to Epilepsy-Associated Anxiety. Front Mol Neurosci 2022; 15:917598. [PMID: 35875667 PMCID: PMC9298510 DOI: 10.3389/fnmol.2022.917598] [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: 04/11/2022] [Accepted: 06/07/2022] [Indexed: 11/23/2022] Open
Abstract
Anxiety disorder is one of the most common comorbidities in temporal lobe epilepsy (TLE), but its neurobiological mechanisms remain unclear. Here we identified a novel target, interleukin-17A (IL-17A), which can contribute to TLE-associated anxiety. Epileptic seizures were induced in 6-week-old IL-17A wild-type (WT) and knockout (KO) mice by pilocarpine injection. To evaluate anxiety level, we subjected mice to open field and elevated plus maze (EPM) tests and measured the time animals spent in center zone or open arms. Epileptic IL-17A WT mice showed thigmotaxis and reluctance to stay in open arms, whereas IL-17A KO mice spent more time in the center area and open arms, suggesting alleviated anxiety in epilepsy. Histological assessments revealed that hippocampal neuronal death as evaluated by Fluoro-Jade B staining was significantly reduced in IL-17A KO mice. Moreover, at 6 weeks after pilocarpine-induced status epilepticus, the number of hilar ectopic granule cells was also markedly decreased by IL-17A deficiency without a difference in the proliferation of neural progenitors or the generation of newborn neurons in the dentate gyrus. Taken together, our data demonstrated that IL-17A deletion mitigates TLE-associated anxiety behavior, possibly via the hippocampal neuroprotection and the reduction of seizure-induced aberrant neurogenesis.
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Affiliation(s)
- In-Young Choi
- Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Mi-La Cho
- Department of Medical Life Science, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Department of Biomedicine and Health Sciences, The Catholic University of Korea, Seoul, South Korea
| | - Kyung-Ok Cho
- Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Department of Biomedicine and Health Sciences, The Catholic University of Korea, Seoul, South Korea.,Catholic Neuroscience Institute, The Catholic University of Korea, Seoul, South Korea.,Institute for Aging and Metabolic Diseases, The Catholic University of Korea, Seoul, South Korea
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Abstract
Infection with SARS-CoV-2, the causative agent of the COVID-19 pandemic, originated in China and quickly spread across the globe. Despite tremendous economic and healthcare devastation, research on this virus has contributed to a better understanding of numerous molecular pathways, including those involving γ-aminobutyric acid (GABA), that will positively impact medical science, including neuropsychiatry, in the post-pandemic era. SARS-CoV-2 primarily enters the host cells through the renin–angiotensin system’s component named angiotensin-converting enzyme-2 (ACE-2). Among its many functions, this protein upregulates GABA, protecting not only the central nervous system but also the endothelia, the pancreas, and the gut microbiota. SARS-CoV-2 binding to ACE-2 usurps the neuronal and non-neuronal GABAergic systems, contributing to the high comorbidity of neuropsychiatric illness with gut dysbiosis and endothelial and metabolic dysfunctions. In this perspective article, we take a closer look at the pathology emerging from the viral hijacking of non-neuronal GABA and summarize potential interventions for restoring these systems.
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Cilberti MG, Santillo A, Polito AN, Messina G, della Malva A, Caroprese M, Sevi A, Albenzio M. Cytokine Pattern of Peripheral Blood Mononuclear Cells Isolated from Children Affected by Generalized Epilepsy Treated with Different Protein Fractions of Meat Sources. Nutrients 2022; 14:nu14112243. [PMID: 35684043 PMCID: PMC9182632 DOI: 10.3390/nu14112243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 05/24/2022] [Accepted: 05/25/2022] [Indexed: 02/01/2023] Open
Abstract
The objective of the present study was the evaluation of cytokine patterns in terms of TNF-α, IL-10, IL-6, and IL-1β secretion in peripheral blood mononuclear cell (PBMC) supernatants isolated from blood of children affected by generalized epilepsy and treated in vitro with myofibrillar, sarcoplasmic, and total protein fractions of meat and fish sources. Children with generalized epilepsy (EC group, n = 16) and children without any clinical signs of disease, representing a control group (CC group n = 16), were recruited at the Complex Structure of Neuropsychiatry Childhood-Adolescence of Policlinico Riuniti (Foggia, Italy). Myofibrillar (MYO), sarcoplasmic (SA), and total (TOT) protein fractions were obtained from longissimus thoracis muscle of beef (BF) and lamb (LA); from pectoralis muscle of chicken (CH); and from dorsal white muscle of sole (Solea solea, SO), European hake (Merluccius merluccius, EH), and sea bass fish (Dicentrarchus labrax, SB), respectively. PBMCs were isolated from peripheral blood of EC and CC groups, and an in vitro stimulation in the presence of 100 μg/mL for each protein fraction from different meat sources was performed. Data were classified according to three different levels of cytokines produced from the EC group relative to the CC group. TNF-α, IL-10, and IL-6 levels were not affected by different meat fractions and meat sources; on the contrary, IL-1β levels were found to be significantly affected by the tested proteins fractions, as well as different meat sources, in high-level cytokine group. On average, the protein fractions obtained from LB, BF, and CH meat sources showed a higher level of IL-1β than the protein fractions obtained from EH and SB fish samples. When all cytokine classes were analyzed, on average, a significant effect was observed for IL-10, IL-1β, and TNF-α. Data obtained in the present study evidence that the nutritional strategy based on protein from fish and meat sources may modulate the immunological cytokine pattern of infants with generalized epilepsy.
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Affiliation(s)
- Maria Giovanna Cilberti
- Department of Agriculture, Food, Natural Resources, and Engineering (DAFNE), University of Foggia, 71122 Foggia, Italy; (M.G.C.); (A.d.M.); (M.C.); (A.S.); (M.A.)
| | - Antonella Santillo
- Department of Agriculture, Food, Natural Resources, and Engineering (DAFNE), University of Foggia, 71122 Foggia, Italy; (M.G.C.); (A.d.M.); (M.C.); (A.S.); (M.A.)
- Correspondence:
| | - Anna N. Polito
- Complex Structure of Neuropsychiatry Childhood-Adolescence of Ospedali Riuniti of Foggia, Viale Pinto, 71122 Foggia, Italy;
| | - Giovanni Messina
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy;
| | - Antonella della Malva
- Department of Agriculture, Food, Natural Resources, and Engineering (DAFNE), University of Foggia, 71122 Foggia, Italy; (M.G.C.); (A.d.M.); (M.C.); (A.S.); (M.A.)
| | - Mariangela Caroprese
- Department of Agriculture, Food, Natural Resources, and Engineering (DAFNE), University of Foggia, 71122 Foggia, Italy; (M.G.C.); (A.d.M.); (M.C.); (A.S.); (M.A.)
| | - Agostino Sevi
- Department of Agriculture, Food, Natural Resources, and Engineering (DAFNE), University of Foggia, 71122 Foggia, Italy; (M.G.C.); (A.d.M.); (M.C.); (A.S.); (M.A.)
| | - Marzia Albenzio
- Department of Agriculture, Food, Natural Resources, and Engineering (DAFNE), University of Foggia, 71122 Foggia, Italy; (M.G.C.); (A.d.M.); (M.C.); (A.S.); (M.A.)
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Liu J, Tian J, Wang Z, Wang L, Huang C, Zhou J, Zeng X, Zhao Y, Zheng W. Secukinumab in the treatment of parenchymal neuro-Behçet's syndrome. Rheumatology (Oxford) 2022; 61:e277-e279. [PMID: 35416940 DOI: 10.1093/rheumatology/keac222] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/19/2022] [Accepted: 03/25/2022] [Indexed: 11/14/2022] Open
Affiliation(s)
- Jinjing Liu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Rheumatology, Ministry of Education, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Beijing, China
| | - Jimei Tian
- Department of Rheumatology, Heping Hospital Affiliated to Changzhi Medical College
| | - Zhimian Wang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Rheumatology, Ministry of Education, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Beijing, China
| | - Li Wang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Rheumatology, Ministry of Education, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Beijing, China
| | - Can Huang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Rheumatology, Ministry of Education, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Beijing, China
| | - Jiaxin Zhou
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Rheumatology, Ministry of Education, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Beijing, China
| | - Xiaofeng Zeng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Rheumatology, Ministry of Education, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Beijing, China
| | - Yan Zhao
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Rheumatology, Ministry of Education, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Beijing, China
| | - Wenjie Zheng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Rheumatology, Ministry of Education, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Beijing, China
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龚 帅, 仇 君, 吴 丽, 谭 李. Change in intestinal flora after treatment in children with focal epilepsy. ZHONGGUO DANG DAI ER KE ZA ZHI = CHINESE JOURNAL OF CONTEMPORARY PEDIATRICS 2022; 24:290-296. [PMID: 35351260 PMCID: PMC8974657 DOI: 10.7499/j.issn.1008-8830.2109134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 01/18/2022] [Indexed: 06/14/2023]
Abstract
OBJECTIVES To study the difference in intestinal flora between children with focal epilepsy and healthy children and the change in intestinal flora after treatment in children with epilepsy. METHODS A total of 10 children with newly diagnosed focal epilepsy were recruited as the case group and were all treated with oxcarbazepine alone. Their clinical data were recorded. Fecal specimens before treatment and after 3 months of treatment were collected. Fourteen aged-matched healthy children were recruited as the control group. Total bacterial DNA was extracted from the fecal specimens for 16S rDNA sequencing and bioinformatics analysis. RESULTS After 3 months of carbamazepine treatment, the seizure frequency was reduced by >50% in the case group. At the phylum level, the abundance of Actinobacteria in the case group before treatment was significantly higher than that in the control group (P<0.05), and it was reduced after treatment (P<0.05). At the genus level, the abundances of Escherichia/Shigella, Streptococcus, Collinsella, and Megamonas in the case group before treatment were significantly higher than those in the control group (P<0.05), and the abundances of these bacteria decreased significantly after treatment (P<0.05). CONCLUSIONS There is a significant difference in intestinal flora between children with focal epilepsy and healthy children. Oxcarbazepine can significantly improve the symptoms and intestinal flora in children with epilepsy.
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Affiliation(s)
| | - 君 仇
- 湖南省儿童医院《临床小儿外科杂志》 编辑部，湖南长沙410007
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Soltani Khaboushan A, Yazdanpanah N, Rezaei N. Neuroinflammation and Proinflammatory Cytokines in Epileptogenesis. Mol Neurobiol 2022; 59:1724-1743. [PMID: 35015252 DOI: 10.1007/s12035-022-02725-6] [Citation(s) in RCA: 111] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 12/30/2021] [Indexed: 02/06/2023]
Abstract
Increasing evidence corroborates the fundamental role of neuroinflammation in the development of epilepsy. Proinflammatory cytokines (PICs) are crucial contributors to the inflammatory reactions in the brain. It is evidenced that epileptic seizures are associated with elevated levels of PICs, particularly interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α), which underscores the impact of neuroinflammation and PICs on hyperexcitability of the brain and epileptogenesis. Since the pathophysiology of epilepsy is unknown, determining the possible roles of PICs in epileptogenesis could facilitate unraveling the pathophysiology of epilepsy. About one-third of epileptic patients are drug-resistant, and existing treatments only resolve symptoms and do not inhibit epileptogenesis; thus, treatment of epilepsy is still challenging. Accordingly, understanding the function of PICs in epilepsy could provide us with promising targets for the treatment of epilepsy, especially drug-resistant type. In this review, we outline the role of neuroinflammation and its primary mediators, including IL-1β, IL-1α, IL-6, IL-17, IL-18, TNF-α, and interferon-γ (IFN-γ) in the pathophysiology of epilepsy. Furthermore, we discuss the potential therapeutic targeting of PICs and cytokine receptors in the treatment of epilepsy.
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Affiliation(s)
- Alireza Soltani Khaboushan
- Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Niloufar Yazdanpanah
- Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
- Children's Medical Center Hospital, Dr. Qarib St, Keshavarz Blvd, 14194, Tehran, Iran.
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Yue Q, Cai M, Xiao B, Zhan Q, Zeng C. The Microbiota-Gut-Brain Axis and Epilepsy. Cell Mol Neurobiol 2022; 42:439-453. [PMID: 34279746 PMCID: PMC11441249 DOI: 10.1007/s10571-021-01130-2] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 07/14/2021] [Indexed: 12/15/2022]
Abstract
Honoured as the second genome in humans, the gut microbiota is involved in a constellation of physiological and pathological processes, including those related to the central nervous system. The communication between the gut microbiota and the brain is realized by a complex bidirectional connection, known as the "microbiota-gut-brain axis", via neuroendocrine, immunological, and direct neural mechanisms. Recent studies indicate that gut dysfunction/dysbiosis is presumably involved in the pathogenesis of and susceptibility to epilepsy. In addition, the reconstruction of the intestinal microbiome through, for example, faecal microbiota transplantation, probiotic intervention, and a ketogenic diet, has exhibited beneficial effects on drug-resistant epilepsy. The purposes of this review are to provide a brief overview of the microbiota-gut-brain axis and to synthesize what is known about the involvement of the gut microbiota in the pathogenesis and treatment of epilepsy, to bring new insight into the pathophysiology of epilepsy and to present a preliminary discussion of novel therapeutic options for epilepsy based on the gut microbiota.
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Affiliation(s)
- Qiang Yue
- Department of Neurology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, China
| | - Mingfei Cai
- Department of Neurology, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, 410011, China
| | - Bo Xiao
- Department of Neurology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, China
| | - Qiong Zhan
- Department of Neurology, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, 410011, China.
| | - Chang Zeng
- Health Management Center, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, China.
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Mu X, Zhang X, Gao H, Gao L, Li Q, Zhao C. Crosstalk between peripheral and the brain-resident immune components in epilepsy. J Integr Neurosci 2022; 21:9. [PMID: 35164445 DOI: 10.31083/j.jin2101009] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 03/30/2021] [Accepted: 05/31/2021] [Indexed: 01/05/2025] Open
Abstract
Epilepsy is one of the most common neurology diseases. It is characterized by recurrent, spontaneous seizures and accompanied by various comorbidities which can significantly affect a person's life. Accumulating evidence indicates an essential pathophysiological role for neuroinflammation in epilepsy, which involves activation of microglia and astrocytes, recruitment of peripheral leukocytes into the central nervous system, and release of some inflammatory mediators, including pro-inflammatory factors and anti-inflammatory cytokines. There is complex crosstalk between the central nervous system and peripheral immune responses associated with the progression of epilepsy. This review provides an update of current knowledge about the contribution of this crosstalk associated with epilepsy. Additionally, how gut microbiota is involved in epilepsy and its possible influence on crosstalk is also discussed. Such recent advances in understanding suggest innovative methods for targeting the molecules correlated with the crosstalk and may provide a better prognosis for patients diagnosed with epilepsy.
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Affiliation(s)
- Xiaopeng Mu
- Neurology, The First Hospital of China Medical University, 110001 Shenyang, Liaoning, China
- Neurology, The Fourth Hospital of China Medical University, 110032 Shenyang, Liaoning, China
| | - Xiuchun Zhang
- Neurology, The First Hospital of China Medical University, 110001 Shenyang, Liaoning, China
| | - Honghua Gao
- Neurology, The Fourth Hospital of China Medical University, 110032 Shenyang, Liaoning, China
| | - Lianbo Gao
- Neurology, The Fourth Hospital of China Medical University, 110032 Shenyang, Liaoning, China
| | - Qingchang Li
- Department of Pathology, The First Hospital of China Medical University, 110001 Shenyang, Liaoning, China
| | - Chuansheng Zhao
- Neurology, The First Hospital of China Medical University, 110001 Shenyang, Liaoning, China
- Stroke Center, The First Hospital of China Medical University, 110001 Shenyang, Liaoning, China
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Th17 cell-mediated immune response in a subpopulation of dogs with idiopathic epilepsy. PLoS One 2022; 17:e0262285. [PMID: 35025939 PMCID: PMC8757915 DOI: 10.1371/journal.pone.0262285] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 12/21/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Canine idiopathic epilepsy (IE) is a common neurological disease with severe impact on the owner´s and the dog's quality of life. A subpopulation of dogs with IE does not respond to antiseizure drugs (non-responder). Th17 cells (T helper cells) and their proinflammatory Interleukin-17 (IL-17) are part of the immune system and previous studies showed their involvement in the pathogenesis of several autoimmune diseases. Non-responder might have an abnormal immune response against structures of the central nervous system. To discover a new aetiology of canine IE and thereby optimising the therapy of intractable IE, this prospective study aimed to investigate Th17 cells and IL-17 in dogs with IE. The underlying hypothesis was that in some dogs with IE a Th17 cell-mediated immune response could be detectable. METHODS 57 dogs with IE and 10 healthy dogs (control group, C) were enrolled in the study. EDTA blood was taken to measure Th17 cells by flow cytometry. IL-17 was measured in 35 cerebrospinal fluid (CSF) and 33 serum samples using an enzyme-linked immunosorbent assay (ELISA). It was investigated whether there was a significant increase of stimulated Th17 cells in blood samples or of IL-17 in serum and CSF samples of dogs with IE in comparison to C. Correlations between the amount of Th17 cells/μL or IL-17 and different clinical parameters e.g. seizure frequency, seizure type, seizure severity or treatment response were evaluated. Additionally, Th17 cells/μL were randomly controlled of 17 dogs with IE and were examined for changes over time and in relation to treatment response. RESULTS Ten dogs with IE had strongly elevated stimulated Th17 cells/μL within the blood (>100 Th17 cells/μL). A slight positive correlation between stimulated Th17 cells/μL and seizure severity (p = 0.046; rSpear = 0.27) was proven in these dogs. In addition, 4/10 dogs with elevated Th17 levels experienced cluster seizures and status epilepticus in comparison to 9% of the dogs with non-elevated Th17 levels (<100 Th17 cells/μL). Dogs with IE had significantly higher IL-17 values in CSF and serum samples compared to C (p<0.001; p<0.002; respectively). CONCLUSION In single dogs with IE, strongly increased amounts of Th17 cells were detectable and dogs with elevated Th17 cells seemed to have a greater risk for experiencing a combination of cluster seizures and status epilepticus. Therefore, an underlying Th17-cell mediated immune response was suspected and hence anti-inflammatory drugs could be indicated in these single cases with intractable epilepsy.
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de Oliveira MCVA, Viana DCF, Silva AA, Pereira MC, Duarte FS, Pitta MGR, Pitta IR, Pitta MGR. Synthesis of novel thiazolidinic-phthalimide derivatives evaluated as new multi-target antiepileptic agents. Bioorg Chem 2021; 119:105548. [PMID: 34959174 DOI: 10.1016/j.bioorg.2021.105548] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 11/19/2021] [Accepted: 12/05/2021] [Indexed: 12/25/2022]
Abstract
Epilepsy is a disease that affects millions of people around the globe and has a multifactorial cause. Inflammation is a process that can be involved in the development of seizures. Thus, the present study proposed the design and synthesis of new candidates for antiepileptic drugs that would also control the inflammatory process. Nine new derivatives of the substituted thiazophthalimide hybrid core were obtained with satisfactory purity ≥99% and yields between 27% and 87%. All compounds showed cell viability values greater than 90% in the culture of PBMC cells from healthy volunteers and, therefore, were not considered cytotoxic. These compounds modulated proinflammatory cytokines IFN-y and IL-17A and can mitigate inflammation. Acute toxicity studies of compound 7i in an animal model indicated that the compound has low toxicity and an LD50 greater than 2 g/kg in healthy adult rats. The same compound did not show positive results for anticonvulsant activity through the PTZ test. However, 7i demonstrates the interaction with the target GABA-A receptor in silico, indicating a possible activity as an agonist of that receptor. Thus, further studies are needed to investigate the anticonvulsant activity, in particular, using models in which the inflammatory process triggers epileptic seizures.
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Affiliation(s)
- Maria Cecilia V A de Oliveira
- Laboratory of Design and Drug Synthesis (LPSF), Nucleus of Research in Therapeutical Innovation Suely Galdino (NUPIT SG), Biosciences Center, Federal University of Pernambuco, Recife, Brazil
| | - Douglas C F Viana
- Laboratory of Design and Drug Synthesis (LPSF), Nucleus of Research in Therapeutical Innovation Suely Galdino (NUPIT SG), Biosciences Center, Federal University of Pernambuco, Recife, Brazil
| | - Anderson A Silva
- Laboratory of Experimental Neuropharmacology, Department of Physiology and Pharmacology, Biosciences Center, Federal University of Pernambuco, Recife, Brazil
| | - Michelly C Pereira
- Laboratory of Immunomodulation and New Therapeutic Approaches (LINAT), Nucleus of Research in Therapeutical Innovation Suely Galdino (NUPIT SG), Biosciences Center, Federal University of Pernambuco, Recife, Brazil
| | - Filipe S Duarte
- Laboratory of Experimental Neuropharmacology, Department of Physiology and Pharmacology, Biosciences Center, Federal University of Pernambuco, Recife, Brazil
| | - Maira G R Pitta
- Laboratory of Immunomodulation and New Therapeutic Approaches (LINAT), Nucleus of Research in Therapeutical Innovation Suely Galdino (NUPIT SG), Biosciences Center, Federal University of Pernambuco, Recife, Brazil
| | - Ivan R Pitta
- Laboratory of Design and Drug Synthesis (LPSF), Nucleus of Research in Therapeutical Innovation Suely Galdino (NUPIT SG), Biosciences Center, Federal University of Pernambuco, Recife, Brazil; Laboratory of Immunomodulation and New Therapeutic Approaches (LINAT), Nucleus of Research in Therapeutical Innovation Suely Galdino (NUPIT SG), Biosciences Center, Federal University of Pernambuco, Recife, Brazil
| | - Marina G R Pitta
- Laboratory of Design and Drug Synthesis (LPSF), Nucleus of Research in Therapeutical Innovation Suely Galdino (NUPIT SG), Biosciences Center, Federal University of Pernambuco, Recife, Brazil.
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Ding M, Lang Y, Shu H, Shao J, Cui L. Microbiota-Gut-Brain Axis and Epilepsy: A Review on Mechanisms and Potential Therapeutics. Front Immunol 2021; 12:742449. [PMID: 34707612 PMCID: PMC8542678 DOI: 10.3389/fimmu.2021.742449] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 09/17/2021] [Indexed: 12/16/2022] Open
Abstract
The gut-brain axis refers to the bidirectional communication between the gut and brain, and regulates intestinal homeostasis and the central nervous system via neural networks and neuroendocrine, immune, and inflammatory pathways. The development of sequencing technology has evidenced the key regulatory role of the gut microbiota in several neurological disorders, including Parkinson's disease, Alzheimer's disease, and multiple sclerosis. Epilepsy is a complex disease with multiple risk factors that affect more than 50 million people worldwide; nearly 30% of patients with epilepsy cannot be controlled with drugs. Interestingly, patients with inflammatory bowel disease are more susceptible to epilepsy, and a ketogenic diet is an effective treatment for patients with intractable epilepsy. Based on these clinical facts, the role of the microbiome and the gut-brain axis in epilepsy cannot be ignored. In this review, we discuss the relationship between the gut microbiota and epilepsy, summarize the possible pathogenic mechanisms of epilepsy from the perspective of the microbiota gut-brain axis, and discuss novel therapies targeting the gut microbiota. A better understanding of the role of the microbiota in the gut-brain axis, especially the intestinal one, would help investigate the mechanism, diagnosis, prognosis evaluation, and treatment of intractable epilepsy.
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Affiliation(s)
| | | | | | | | - Li Cui
- Department of Neurology, First Hospital of Jilin University, Changchun, China
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Abd El-Hameed AM, Abuelsaad ASA, Khalil A. Bee venom acupuncture therapy ameliorates neuroinflammatory alterations in a pilocarpine-induced epilepticus model. Metab Brain Dis 2021; 36:2047-2058. [PMID: 34138441 DOI: 10.1007/s11011-021-00766-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 06/06/2021] [Indexed: 11/25/2022]
Abstract
Bee venom (BV) is applied in different traditional medicinal therapies and is used worldwide to prevent and treat many acute and chronic diseases. Epilepsy has various neurological effects, e.g., epileptogenic insults; thus, it is considered a life-threatening condition. Seizures and their effects add to the burden of epilepsy because they can have health effects including residual disability and even premature mortality. The use of antiinflammatory drugs to treat epilepsy is controversial; therefore, the alternative nonchemical apitherapy benefits of BV were evaluated in the present study by assessing neuroinflammatory changes in a pilocarpine-induced epilepticus model. Levels of electrolytes, neurotransmitters, and mRNA expression for some gate channels were determined. Moreover, ELISA assays were conducted to detect pro- and anti-inflammatory cytokines, whereas RT-PCR was performed to assess mRNA expression of Foxp3 and CTLA-4. BV ameliorated the interruption in electrolytes and ions through voltage- and ligand-gated ion channels, and it limited neuronal excitability via rapid repolarization of action potentials. In addition, BV inhibited the high expression of proinflammatory cytokines. Acupuncture with BV was effective in preventing some of the deleterious consequences of epileptogenesis associated with high levels of glutamate and DOPA in the hippocampus. BV ameliorates changes in the expression of voltage-gated channels, rebalances blood electrolytes and neurotransmitters, and modulates the levels of pro- and anti-inflammatory cytokines. Thus, BV could reduce the progression of epileptogenesis as a cotherapy with other antiepileptic drugs.
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Affiliation(s)
| | - Abdelaziz S A Abuelsaad
- Immunology Division, Department of Zoology, Faculty of Science, Beni-Suef University, 62511, Beni-Suef, Egypt.
| | - Abdelwahab Khalil
- Medical Entomology Division, Department of Zoology, Faculty of Science, Beni-Suef University, Beni-Suef, 62521, Egypt
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Kilinc E, Ankarali S, Ayhan D, Ankarali H, Torun IE, Cetinkaya A. Protective effects of long-term probiotic mixture supplementation against pentylenetetrazole-induced seizures, inflammation and oxidative stress in rats. J Nutr Biochem 2021; 98:108830. [PMID: 34333116 DOI: 10.1016/j.jnutbio.2021.108830] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 06/13/2021] [Accepted: 07/24/2021] [Indexed: 02/06/2023]
Abstract
Emerging evidence indicates that dysbiosis of gut microbiota plays an important role in epilepsy, although the underlying mechanisms remain unclear due to the complex nature of both microbial composition and pathophysiology of epilepsy. We investigated effects of long-term probiotics supplementation on epileptic seizures, and inflammatory and oxidant/antioxidant biomarkers in a pentylenetetrazole(PTZ)-induced seizure model in rats. Male Wistar weaner-rats were divided into four groups. The first two groups received 1 ml/day saline solution, while the other groups received 0.05 mg/1ml/day vehicle or 109cfu/1ml/day probiotic-mixture, respectively, for 60 days by gavage. Seizure was induced by a single convulsive dose of PTZ. Seizures were evaluated using Racine's scale. Concentrations of pro-inflammatory cytokines in plasma and brain tissue were determined using ELISA, while oxidant/antioxidant biomarkers were measured using an automated-colorimetric method. Probiotics supplementation exhibited anticonvulsant effects against PTZ-induced seizures by retarding onset-times of both myoclonic-jerk and generalized tonic-clonic seizure, and by shortening duration of generalized tonic-clonic seizure. Additionally, it alleviated PTZ-induced increases in levels of pro-inflammatory cytokines IL-1β, IL-6, and IL-17A, but not of IFNγ, in plasma and brain tissue. Moreover, it restored PTZinduced fluctuations in levels of oxidants TOS and disulfide, and of antioxidants native thiol and total thiol. Our findings suggest that long-term probiotics supplementation exhibits protective effects against epileptic seizures, and alleviates (neuro)inflammation and oxidative stress related to pathophysiology of epilepsy. A probiotic-rich diet provided from childhood may provide prophylaxis against epileptic seizures, especially in susceptible individuals, as the neonate diet represents a fundamental extrinsic factor in establishing gut microbiota.
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Affiliation(s)
- Erkan Kilinc
- Department of Physiology, Bolu Abant Izzet Baysal University, Bolu, Turkey.
| | - Seyit Ankarali
- Department of Physiology, Istanbul Medeniyet University, Istanbul, Turkey
| | - Didem Ayhan
- Department of Physiology, Bolu Abant Izzet Baysal University, Bolu, Turkey
| | - Handan Ankarali
- Department of Biostatistics and Medical Informatics, Istanbul Medeniyet University, Istanbul, Turkey
| | | | - Ayhan Cetinkaya
- Department of Physiology, Bolu Abant Izzet Baysal University, Bolu, Turkey
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Alvim MKM, Morita-Sherman ME, Yasuda CL, Rocha NP, Vieira ÉL, Pimentel-Silva LR, Henrique Nogueira M, Barbosa R, Watanabe N, Coan AC, Lopes-Cendes I, Teixeira AL, Cendes F. Inflammatory and neurotrophic factor plasma levels are related to epilepsy independently of etiology. Epilepsia 2021; 62:2385-2394. [PMID: 34331458 DOI: 10.1111/epi.17023] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 06/30/2021] [Accepted: 07/15/2021] [Indexed: 12/31/2022]
Abstract
OBJECTIVE Inflammation plays an essential role in epilepsy. Studies indicate that cytokines and neurotrophic factors can act in neuroexcitability and epileptogenesis. We aimed to investigate the association between plasma inflammatory and neurotrophic markers, seizure frequency, and chronic epilepsy subtypes. METHODS We studied 446 patients with epilepsy and 166 healthy controls. We classified patients according to etiology and seizure frequency. We measured plasma levels of interleukin-1 (IL-1), IL-2, IL-4, IL-6, IL-10, IL-17, interferon-γ (IFNγ), tumor necrosis factor α (TNFα), soluble TNF receptor 1 (sTNFr1), sTNFr2, brain-derived neurotrophic factor (BDNF), neurotrophic factor 3 (NT3), NT4/5, ciliary neurotrophic factor (CNTF), nerve growth factor (NGF), and glial cell line-derived neurotrophic factor (GDNF) by enzyme-linked immunosorbent assay or cytometric bead array. RESULTS The plasma levels of BDNF, NT3, NGF, and sTNFr2 were higher, whereas IL-2, IL-4, IL-6, IL-10, IL-17, IFNγ, TNFα, CNTF, and sTNFr1 were lower in patients than controls. IL1, GDNF, and NT4/5 were similar between groups. These markers did not correlate with age, sex, and epilepsy duration. The molecule sTNFr2 was the best marker to discriminate patients from controls (area under the curve = .857), also differing between patients with frequent and infrequent seizures. SIGNIFICANCE This large cohort confirmed that patients with epilepsy have abnormal levels of plasma inflammatory and neurotrophic markers independent of the underlying etiology. Plasma level of sTNFr2 was related to seizure frequency and discriminated people with or without epilepsy with good accuracy, making it a potential biomarker for epilepsy and seizure burden.
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Affiliation(s)
| | | | | | - Natália P Rocha
- School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Érica L Vieira
- School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | | | | | | | | | | | | | - Antonio L Teixeira
- School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil
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Librizzi L, Vila Verde D, Colciaghi F, Deleo F, Regondi MC, Costanza M, Cipelletti B, de Curtis M. Peripheral blood mononuclear cell activation sustains seizure activity. Epilepsia 2021; 62:1715-1728. [PMID: 34061984 DOI: 10.1111/epi.16935] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 05/07/2021] [Accepted: 05/07/2021] [Indexed: 12/25/2022]
Abstract
OBJECTIVE The influx of immune cells and serum proteins from the periphery into the brain due to a dysfunctional blood-brain barrier (BBB) has been proposed to contribute to the pathogenesis of seizures in various forms of epilepsy and encephalitis. We evaluated the pathophysiological impact of activated peripheral blood mononuclear cells (PBMCs) and serum albumin on neuronal excitability in an in vitro brain preparation. METHODS A condition of mild endothelial activation induced by arterial perfusion of lipopolysaccharide (LPS) was induced in the whole brain preparation of guinea pigs maintained in vitro by arterial perfusion. We analyzed the effects of co-perfusion of human recombinant serum albumin with human PBMCs activated with concanavalin A on neuronal excitability, BBB permeability (measured by FITC-albumin extravasation), and microglial activation. RESULTS Bioplex analysis in supernatants of concanavalin A-stimulated PBMCs revealed increased levels of several inflammatory mediators, in particular interleukin (IL)-1β, tumor necrosis factor (TNF)-α, interferon (INF)-γ, IL-6, IL-10, IL-17A, and MIP3α. LPS and human albumin arterially co-perfused with either concanavalin A-activated PBMCs or the cytokine-enriched supernatant of activated PBMCs (1) modulated calcium-calmodulin-dependent protein kinase II at excitatory synapses, (2) enhanced BBB permeability, (3) induced microglial activation, and (4) promoted seizure-like events. Separate perfusions of either nonactivated PBMCs or concanavalin A-activated PBMCs without LPS/human albumin (hALB) failed to induce inflammatory and excitability changes. SIGNIFICANCE Activated peripheral immune cells, such as PBMCs, and the extravasation of serum proteins in a condition of BBB impairment contribute to seizure generation.
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Affiliation(s)
- Laura Librizzi
- Epilepsy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
| | - Diogo Vila Verde
- Epilepsy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
| | - Francesca Colciaghi
- Epilepsy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
| | - Francesco Deleo
- Epilepsy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
| | | | - Massimo Costanza
- Molecular Neuro-Oncology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
| | - Barbara Cipelletti
- Epilepsy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
| | - Marco de Curtis
- Epilepsy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
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Abstract
AbstractHuman herpes virus 6 (HHV-6) is a ubiquitous and most common pathogen that affects humans. Human herpes virus 6B (HHV-6B) is a wide spread human herpesvirus that infects most people when they are children, establishes latent infections in the central nervous system (CNS), especially in the hippocampus and amygdala, and induces neurologic diseases. HHV-6 can establish a latent infection and be reactivated by various stimuli. Recently, viral genomic DNA of HHV-6B has been detected in surgically removed brain tissues of intractable epilepsy patients, suggesting the involvement of HHV-6B in the pathogenesis of epilepsy. Temporal lobe epilepsy (TLE) has been shown to be closely related with HHV-6B. TLE patients with HHV-6B in their brains suffer from reiterative attacks of febrile seizures and hippocampal sclerosis. However, the mechanisms underlying the contribution of this virus to the development of TLE remains unknown. The direct damage and immune activation caused by the virus are involved in the process of neuron damage, abnormal neural circuit formation and glial cell proliferation. In addition, some cytokines like interleukin-17A (IL-17A), nuclear factor-kappa B (NF-κb), transforming growth factor-β (TGF-β), mitogen-activated protein kinase (MAPK) and phospholipase A2 are up-regulated and involved in the pathological process of TLE. More studies are needed to clarify the mechanisms underlying the link between HHV-6B and epilepsy, and identify biomarkers to recognize different patient groups for anti-inflammatory or immunomodulatory therapies.
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Orsini A, Foiadelli T, Costagliola G, Michev A, Consolini R, Vinci F, Peroni D, Striano P, Savasta S. The role of inflammatory mediators in epilepsy: Focus on developmental and epileptic encephalopathies and therapeutic implications. Epilepsy Res 2021; 172:106588. [PMID: 33721708 DOI: 10.1016/j.eplepsyres.2021.106588] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/28/2021] [Accepted: 02/16/2021] [Indexed: 02/06/2023]
Abstract
In recent years, there has been an increasing interest in the potential involvement of neuroinflammation in the pathogenesis of epilepsy. Specifically, the role of innate immunity (that includes cytokines and chemokines) has been extensively investigated either in animal models of epilepsy and in clinical settings. Developmental and epileptic encephalopathies (DEE) are a heterogeneous group of epileptic disorders, in which uncontrolled epileptic activity results in cognitive, motor and behavioral impairment. By definition, epilepsy in DEE is poorly controlled by common antiepileptic drugs but may respond to alternative treatments, including steroids and immunomodulatory drugs. In this review, we will focus on how cytokines and chemokines play a role in the pathogenesis of DEE and why expanding our knowledge about the role of neuroinflammation in DEE may be crucial to develop new and effective targeted therapeutic strategies to prevent seizure recurrence and developmental regression.
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Affiliation(s)
- Alessandro Orsini
- Department of Clinical and Experimental Medicine, Section of Pediatrics, University of Pisa, Via Roma 67, 56126 Pisa, Italy
| | - Thomas Foiadelli
- Pediatric Clinic, IRCCS Policlinico San Matteo Foundation, University of Pavia, Viale Golgi 19, 27100 Pavia, Italy.
| | - Giorgio Costagliola
- Department of Clinical and Experimental Medicine, Section of Pediatrics, University of Pisa, Via Roma 67, 56126 Pisa, Italy
| | - Alexandre Michev
- Pediatric Clinic, IRCCS Policlinico San Matteo Foundation, University of Pavia, Viale Golgi 19, 27100 Pavia, Italy
| | - Rita Consolini
- Department of Clinical and Experimental Medicine, Section of Pediatrics, University of Pisa, Via Roma 67, 56126 Pisa, Italy
| | - Federica Vinci
- Pediatric Clinic, IRCCS Policlinico San Matteo Foundation, University of Pavia, Viale Golgi 19, 27100 Pavia, Italy
| | - Diego Peroni
- Department of Clinical and Experimental Medicine, Section of Pediatrics, University of Pisa, Via Roma 67, 56126 Pisa, Italy
| | - Pasquale Striano
- Paediatric Neurology and Muscular Diseases Unit, "G. Gaslini" Institute, Via Gaslini 5, 16147 Genova, Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Via Gaslini 5, 16147 Genova, Italy
| | - Salvatore Savasta
- Pediatric Clinic, IRCCS Policlinico San Matteo Foundation, University of Pavia, Viale Golgi 19, 27100 Pavia, Italy
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Suleymanova EM. Behavioral comorbidities of epilepsy and neuroinflammation: Evidence from experimental and clinical studies. Epilepsy Behav 2021; 117:107869. [PMID: 33684786 DOI: 10.1016/j.yebeh.2021.107869] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 02/14/2021] [Accepted: 02/14/2021] [Indexed: 12/24/2022]
Abstract
Currently, a significant amount of data is accumulated showing that neuroinflammation is one of the key processes in the development of brain pathology in trauma, neurodegenerative diseases, and epilepsy. Various brain insults, such as prolonged seizure activity, trigger the activation of microglia and astrocytes in the brain. These cells, in turn, begin to synthesize pro-inflammatory cytokines. The inflammatory response to the insult causes a cascade of processes leading to a wide range of pathological effects, including changes in neuronal excitability, long-term plastic changes, astrocyte dysfunction, impaired blood-brain barrier (BBB) permeability, and neurodegeneration. These effects may ultimately contribute to the development of chronic spontaneous seizures. On the other hand, neuroinflammation contributes to the pathogenesis of a number of neuropsychiatric disorders. Therefore, neuroinflammation can be a link between epilepsy and its comorbidities, such as mood and anxiety disorders and memory impairment. The mechanisms behind these behavioral and cognitive impairments remain not fully understood. In this paper, clinical evidence of an important role of neuroinflammation in epilepsy and potentially comorbid neurological disorders is reviewed, as well as possible mechanisms of its involvement in the pathogenesis of these conditions obtained from experimental data.
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Affiliation(s)
- Elena M Suleymanova
- Institute of Higher Nervous Activity and Neurophysiology of RAS, 117485 Butlerova 5A, Moscow, Russia.
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Ouédraogo O, Rébillard RM, Jamann H, Mamane VH, Clénet ML, Daigneault A, Lahav B, Uphaus T, Steffen F, Bittner S, Zipp F, Bérubé A, Lapalme-Remis S, Cossette P, Nguyen DK, Arbour N, Keezer MR, Larochelle C. Increased frequency of proinflammatory CD4 T cells and pathological levels of serum neurofilament light chain in adult drug-resistant epilepsy. Epilepsia 2021; 62:176-189. [PMID: 33140401 DOI: 10.1111/epi.16742] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 10/02/2020] [Accepted: 10/07/2020] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Adult drug-resistant epilepsy (DRE) is associated with significant morbidity. Infiltration of immune cells is observed in DRE epileptic foci; however, the relation between DRE and the peripheral immune cell compartment remains only partially understood. We aimed to investigate differences in immune cell populations, cytokines, and neurodegenerative biomarkers in the peripheral blood of subjects with epilepsy versus healthy controls, and in DRE compared to well-controlled epilepsy (WCE). METHODS Peripheral blood mononuclear cells and serum from >120 age- and sex-matched adults suffering from focal onset epilepsy and controls were analyzed by multipanel flow cytometry, multiplex immunoassays, and ultrasensitive single molecule array. RESULTS Using a data-driven analytical approach, we identified that CD4 T cells in the peripheral blood are present in a higher proportion in DRE patients. Moreover, we observed that the frequency of CD4 T cells expressing proinflammatory cytokines interleukin (IL)-17A, IL-22, tumor necrosis factor, interferon-γ, and granulocyte-macrophage colony-stimulating factor, but not anti-inflammatory cytokines IL-10 and IL-4, is elevated in the peripheral blood of DRE subjects compared to WCE. In parallel, we found that Th17-related circulating proinflammatory cytokines are elevated, but Th2-related cytokine IL-4 is reduced, in the serum of epilepsy and DRE subjects. As Th17 cells can exert neurotoxicity, we measured levels of serum neurofilament light chain (sNfL), a marker of neuronal injury. We found significantly elevated levels of sNfL in DRE compared to controls, especially among older individuals. SIGNIFICANCE Our data support that DRE is associated with an expansion of the CD4 Tcell subset in the peripheral blood and with a shift toward a proinflammatory Th17/Th1 CD4 Tcell immune profile. Our results further show that pathological levels of sNfL are more frequent in DRE, supporting a potential neurodegenerative component in adult DRE. With this work, we provide evidence for novel potential inflammatory and degenerative biomarkers in DRE.
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Affiliation(s)
- Oumarou Ouédraogo
- Research Center of the University of Montreal Hospital Center, Montreal, QC, Canada
- Department of Microbiology, Immunology, and Infectiology, University of Montreal, Montreal, QC, Canada
| | - Rose-Marie Rébillard
- Research Center of the University of Montreal Hospital Center, Montreal, QC, Canada
- Department of Neurosciences, University of Montreal, Montreal, QC, Canada
| | - Hélène Jamann
- Research Center of the University of Montreal Hospital Center, Montreal, QC, Canada
- Department of Neurosciences, University of Montreal, Montreal, QC, Canada
| | - Victoria Hannah Mamane
- Research Center of the University of Montreal Hospital Center, Montreal, QC, Canada
- Department of Neurosciences, University of Montreal, Montreal, QC, Canada
| | - Marie-Laure Clénet
- Research Center of the University of Montreal Hospital Center, Montreal, QC, Canada
- Department of Microbiology, Immunology, and Infectiology, University of Montreal, Montreal, QC, Canada
| | - Audrey Daigneault
- Research Center of the University of Montreal Hospital Center, Montreal, QC, Canada
| | - Boaz Lahav
- University of Montreal Hospital Center, Montreal, QC, Canada
| | - Timo Uphaus
- Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Falk Steffen
- Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Stefan Bittner
- Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Frauke Zipp
- Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Arline Bérubé
- Department of Neurosciences, University of Montreal, Montreal, QC, Canada
- University of Montreal Hospital Center, Montreal, QC, Canada
| | - Samuel Lapalme-Remis
- Department of Neurosciences, University of Montreal, Montreal, QC, Canada
- University of Montreal Hospital Center, Montreal, QC, Canada
| | - Patrick Cossette
- Research Center of the University of Montreal Hospital Center, Montreal, QC, Canada
- Department of Neurosciences, University of Montreal, Montreal, QC, Canada
- University of Montreal Hospital Center, Montreal, QC, Canada
| | - Dang Khoa Nguyen
- Research Center of the University of Montreal Hospital Center, Montreal, QC, Canada
- Department of Neurosciences, University of Montreal, Montreal, QC, Canada
- University of Montreal Hospital Center, Montreal, QC, Canada
| | - Nathalie Arbour
- Research Center of the University of Montreal Hospital Center, Montreal, QC, Canada
- Department of Neurosciences, University of Montreal, Montreal, QC, Canada
| | - Mark R Keezer
- Research Center of the University of Montreal Hospital Center, Montreal, QC, Canada
- Department of Neurosciences, University of Montreal, Montreal, QC, Canada
- University of Montreal Hospital Center, Montreal, QC, Canada
- Department of Social and Preventive Medicine, School of Public Health, University of Montreal, Montreal, QC, Canada
| | - Catherine Larochelle
- Research Center of the University of Montreal Hospital Center, Montreal, QC, Canada
- Department of Neurosciences, University of Montreal, Montreal, QC, Canada
- University of Montreal Hospital Center, Montreal, QC, Canada
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Bergantin LB. Common Issues Among Asthma, Epilepsy, and Schizophrenia: From Inflammation to Ca 2+/cAMP Signalling. Antiinflamm Antiallergy Agents Med Chem 2021; 20:229-232. [PMID: 33176668 DOI: 10.2174/1871523019999201110192029] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 09/29/2020] [Accepted: 10/11/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND A large amount of evidence has described that asthma may be associated with a high epilepsy risk, and epilepsy may be linked with high asthma risk, especially among children and individuals in their 30s. Curiously, asthma has also been associated with an increased risk for schizophrenia. Most interestingly, a bidirectional link between schizophrenia and epilepsy has also been established and has been of interest for many years. OBJECTIVE Bearing in mind the experience of our group in the field of Ca2+/cAMP signalling pathways, this article discussed, beyond inflammation, the role of these signalling pathways in this link among epilepsy, asthma, and schizophrenia. METHODS Publications involving these signalling pathways, asthma, epilepsy, and schizophrenia (alone or combined) were collected by searching PubMed and EMBASE. RESULTS AND CONCLUSION There is a clear relationship between Ca2+ signalling, e.g. increased Ca2+ signals and inflammatory responses. In addition to Ca2+, cAMP regulates pro- and anti-inflammatory responses. Then, beyond inflammation, the comprehension of the link among epilepsy, asthma, and schizophrenia could improve the drug therapy.
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Affiliation(s)
- Leandro Bueno Bergantin
- Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, Rua Pedro de Toledo, 669-Vila Clementino, São Paulo-SP, 04039-032, Brazil
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Chmielewska N, Maciejak P, Osuch B, Kursa MB, Szyndler J. Pro-inflammatory cytokines, but not brain- and extracellular matrix-derived proteins, are increased in the plasma following electrically induced kindling of seizures. Pharmacol Rep 2020; 73:506-515. [PMID: 33377994 PMCID: PMC7994222 DOI: 10.1007/s43440-020-00208-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 11/13/2020] [Accepted: 12/07/2020] [Indexed: 12/16/2022]
Abstract
Background The aim of the study was to evaluate the brain-derived proteins, extracellular matrix-derived protein and cytokines as potential peripheral biomarkers of different susceptibility to seizure development in an animal model of epilepsy evoked by chronic focal electrical stimulation of the brain. Methods The plasma levels of IL-1β (interleukin 1β), IL-6 (interleukin 6), UCH-L1 (ubiquitin C-terminal hydrolase 1), MMP-9 (matrix metalloproteinase 9), and GFAP (glial fibrillary acidic protein) were assessed. The peripheral concentrations of the selected proteins were analyzed according to the status of kindling and seizure severity parameters. In our study, increased concentrations of plasma IL-1β and IL-6 were observed in rats subjected to hippocampal kindling compared to sham-operated rats. Results Animals that developed tonic–clonic seizures after the last stimulation had higher plasma concentrations of IL-1β and IL-6 than sham-operated rats and rats that did not develop seizure. Elevated levels of IL-1β and IL-6 were observed in rats that presented more severe seizures after the last five stimulations compared to sham-operated animals. A correlation between plasma IL-1β and IL-6 concentrations was also found. On the other hand, the plasma levels of the brain-derived proteins UCH-L1, MMP-9, and GFAP were unaffected by kindling status and seizure severity parameters. Conclusions The plasma concentrations of IL-1β and IL-6 may have potential utility as peripheral biomarkers of immune system activation in the course of epilepsy and translational potential for future clinical use. Surprisingly, markers of cell and nerve ending damage (GFAP, UCH-L1 and MMP-9) may have limited utility.
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Affiliation(s)
- Natalia Chmielewska
- Department of Neurochemistry, Institute of Psychiatry and Neurology, Sobieskiego Street 9, 02-957, Warsaw, Poland.
| | - Piotr Maciejak
- Department of Neurochemistry, Institute of Psychiatry and Neurology, Sobieskiego Street 9, 02-957, Warsaw, Poland
| | - Bartosz Osuch
- Department of Neurochemistry, Institute of Psychiatry and Neurology, Sobieskiego Street 9, 02-957, Warsaw, Poland
| | - Miron B Kursa
- Interdisciplinary Centre for Mathematical and Computational Modelling, University of Warsaw, Pawinskiego Street 5A, 02-106, Warsaw, Poland
| | - Janusz Szyndler
- Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology CePT, Medical University of Warsaw, Banacha Street 1B, 02-097, Warsaw, Poland
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Meng F, Yao L. The role of inflammation in epileptogenesis. ACTA EPILEPTOLOGICA 2020; 2:15. [DOI: 10.1186/s42494-020-00024-y] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 08/13/2020] [Indexed: 12/14/2022] Open
Abstract
AbstractEpilepsy is a chronic neurological disorder that has an extensive impact on a patient’s life. Accumulating evidence has suggested that inflammation participates in the progression of spontaneous and recurrent seizures. Pro-convulsant incidences can stimulate immune cells, augment the release of pro-inflammatory cytokines, elicit neuronal excitation as well as blood-brain barrier (BBB) dysfunction, and finally trigger the generation or recurrence of seizures. Understanding the pathogenic roles of inflammatory mediators, including inflammatory cytokines, cells, and BBB, in epileptogenesis will be beneficial for the treatment of epilepsy. In this systematic review, we performed a literature search on the PubMed database using the following keywords: “epilepsy” or “seizures” or “epileptogenesis”, and “immunity” or “inflammation” or “neuroinflammation” or “damage-associated molecular patterns” or “cytokines” or “chemokines” or “adhesion molecules” or “microglia” or “astrocyte” or “blood-brain barrier”. We summarized the classic inflammatory mediators and their pathogenic effects in the pathogenesis of epilepsy, based on the most recent findings from both human and animal model studies.
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Herrmann I, Kradischnig C, Skor O, Pakozdy A, Panakova L. Higher prevalence of seizure activity in a small population of atopic dogs: a retrospective breed- and age-matched study. Vet Dermatol 2020; 32:126-e27. [PMID: 33245178 DOI: 10.1111/vde.12913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 07/14/2020] [Accepted: 08/14/2020] [Indexed: 11/29/2022]
Abstract
BACKGROUND Atopic dermatitis (AD) is considered to be a systemic disease in people shown to have an association with epilepsy. However, so far, no data about the association of epilepsy and atopy have been reported in dogs. OBJECTIVES Given the homology between human and canine AD, and the increased incidence of epilepsy in atopic people, we investigated the association between AD and seizure-associated activity in a small canine population. ANIMALS We included 34 atopic dogs and 34 breed- and age range-matched nonatopic dogs. METHODS AND MATERIALS We investigated the association between canine AD and signs of seizures in a retrospective, breed- and age range-matched, case-controlled study. Dog owners were interviewed using a standardized questionnaire. The presence or absence of signs of seizure activity and possible comorbidities were questioned. RESULTS Seven of the 34 atopic dogs also suffered from seizure activity. By contrast, only one dog affected with seizure signs could be identified among the 34 nonatopic dogs. Atopic dermatitis was associated with a higher frequency of seizure activity (McNemar test, P = 0.035; one-sided) and atopic dogs had a higher odds ratio to develop seizures [(95% CI) 7 (0.9-56.9)] compared to the age- and breed-matched nonatopic control group. No other comorbidities were detected. CONCLUSION AND CLINICAL IMPORTANCE In our small retrospective study, we observed an increased prevalence of seizure activity in the atopic dog population. Further larger and prospective studies are needed to confirm these results.
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Affiliation(s)
- Ina Herrmann
- Comparative Medicine, The Interuniversity Messerli Research Institute, University of Veterinary Medicine Vienna, Medical University Vienna and University Vienna, Veterinärplatz 1, Vienna, 1210, Austria.,Department for Companion Animals and Horses, University of Veterinary Medicine Vienna, Veterinärplatz 1, Vienna, 1210, Austria
| | - Clarissa Kradischnig
- Department for Companion Animals and Horses, University of Veterinary Medicine Vienna, Veterinärplatz 1, Vienna, 1210, Austria
| | - Ondrej Skor
- Department for Companion Animals and Horses, University of Veterinary Medicine Vienna, Veterinärplatz 1, Vienna, 1210, Austria
| | - Akos Pakozdy
- Department for Companion Animals and Horses, University of Veterinary Medicine Vienna, Veterinärplatz 1, Vienna, 1210, Austria
| | - Lucia Panakova
- Department for Companion Animals and Horses, University of Veterinary Medicine Vienna, Veterinärplatz 1, Vienna, 1210, Austria
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Alekseeva LA, Zheleznikova GF, Gorelik EY, Sckripchenko NV, Zhirkov AA. Cytokines and neuro-specific proteins in viral encephalitis and convulsive syndrome in children. II. Convulsive syndrome. RUSSIAN JOURNAL OF INFECTION AND IMMUNITY 2020; 11:433-446. [DOI: 10.15789/2220-7619-can-1449] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Abstract
In this Section we provide new data on the pathogenetic factors in pediatric convulsive syndrome, including a prominent role of viral infection in developing seizures and epilepsy (EPL) in children, as evidenced by clinical and experimental studies. Various forms of convulsive syndrome associated with viral infection include febrile convulsions and febrile epileptic status, encephalitis-related acute symptomatic seizures, and postencephalitic epilepsy. The human herpesvirus-6 isolated in temporal lobe epilepsy is a frequent causative agent of febrile seizures and febrile epileptic status. Febrile seizures and, especially, febrile epileptic status are associated with further developing epilepsy. Of special note is the febrile infection-related epileptic syndrome (FIRES) more often affecting school-aged children and characterized by extremely severe course and unfavorable outcome. Convulsive syndrome is associated with systemic inflammation and overproduced pro-inflammatory cytokines that increase permeability of the blood-brain barrier and functional activity of brain-resident cells, which are involved in eliciting seizures and maintaining epileptogenesis. Taking into consideration the key role of inflammation underlying convulsive syndrome, in recent decades cytokines and chemokines have been widely studied as possible prognostic criteria for epileptogenesis. Neuron-specific proteins are examined as markers of brain cell damage in various inflammatory diseases of the central nervous system. The first Section of the review presented current understanding on systemic and local cytokine/chemokine response in viral encephalitis. Here we present clinical trials published within the last 5—7 years assessing cytokines/chemokines and neuron-specific proteins in children with various forms of convulsive syndrome, including epilepsy. Association between biomarker level and disease clinical parameters as well as potential for their use to diagnose and predict its further course are discussed.
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