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Woo HG, Park JY, Park MS, Song TJ. Association between varicose veins and occurrence of dementia: A nationwide population-based cohort study. PLoS One 2025; 20:e0322892. [PMID: 40305494 PMCID: PMC12043132 DOI: 10.1371/journal.pone.0322892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 03/29/2025] [Indexed: 05/02/2025] Open
Abstract
While varicose vein (VV) and dementia are frequent health problems, research investigating association between these conditions has been limited. We aimed to investigate the relationship between the presence of VV and the development of dementia, as well as to evaluate whether treatment for VV correlates with the occurrence of dementia in a longitudinal study involving the general population. Our study included 430,875 participants based on health screening results conducted from 2005 to 2010 in the South Korean health screening cohort database. Presence of VV was defined with at least two or more claims based on International Classification of Diseases, Tenth Revision (ICD-10) of I830-832, I839, or I868. Propensity score matching at a ratio of 1:5 was employed to categorize the participants into two groups based on the presence and treatment of VV, respectively. Primary outcome was the incidence of all-cause dementia with two or more claims based on ICD-10 code (F00-03, G30, and G31), and secondary outcomes considered occurrence of Alzheimer's disease (AD; F00 or G30) and vascular dementia (VD; F01). Among included participants, presence of VV were noted in 5,096 (1.3%) participants. During a median follow-up of 13.33 (interquartile range 10.4-16.26) years, 55,329 (13.9%) cases of all-cause dementia have occurred. In multivariable analysis, VV group showed increased risk of all-cause dementia compared to non-VV group (hazard ratio [HR]: 1.235, 95% confidence interval [CI]: 1.147-1.329). Contrary to AD, treatment of VV group was significantly associated with decreased risk of VD (HR: 0.566, 95% CI: 0.382-0.841). Our study showed that presence of VV may be associated with an increased risk of future all-cause dementia, and treatment of VV was likely to reduce the incidence risk of VD.
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Affiliation(s)
- Ho Geol Woo
- Department of Neurology, Kyung Hee University College of Medicine, Seoul, Republic of Korea
| | - Ju-young Park
- Department of Statistics, Yeungnam University, Gyeongsan, Gyeongbuk, Republic of Korea
| | - Moo-Seok Park
- Department of Neurology, Seoul Hospital, Ewha Womans University College of Medicine, Seoul, Republic of Korea
| | - Tae-Jin Song
- Department of Neurology, Seoul Hospital, Ewha Womans University College of Medicine, Seoul, Republic of Korea
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Vinjavarapu LA, Yadava S, Dontiboina HR, Chakravarthi G, Kakarla R. Neuroprotective effects of Indole 3-carbinol against Scopolamine-Induced cognitive and memory impairment in rats: modulation of oxidative stress, inflammatory and cholinergic pathways. Metab Brain Dis 2025; 40:154. [PMID: 40100291 DOI: 10.1007/s11011-025-01577-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 03/11/2025] [Indexed: 03/20/2025]
Abstract
Indole 3-carbinol (I3C), a natural compound found in cruciferous vegetables, has demonstrated neuroprotective effects by modulating oxidative stress, inflammation, and cholinergic pathways. This study aimed to evaluate the efficacy of I3C in preventing cognitive impairment induced by scopolamine in rats. Male Wistar rats were assigned to six groups: Control, Scopolamine (1 mg/kg), I3C (25 mg/kg), I3C (50 mg/kg), I3C (100 mg/kg), and Donepezil (5 mg/kg). Memory function was evaluated through behavioral assessments using the Y-maze and Novel Object Recognition (NOR) tests. Biochemical analyses were conducted to assess acetylcholinesterase (AChE) activity and oxidative stress markers, including malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT). ELISA were utilized to quantify oxidative stress regulators (NRF2 and HO-1), inflammatory cytokines (NF-kB, TNF-α, IL-6, and IL-10), and apoptosis-related markers (Cytochrome C, caspase 9, and caspase 3). Additionally, H&E and Nissl staining were performed to evaluate histopathological abnormalities. The findings revealed that I3C administration markedly enhanced cognitive performance in the Y-maze and NOR tests, which were attributed to decreased AChE activity and increased acetylcholine (ACh) levels. Furthermore, I3C significantly alleviated oxidative stress by upregulating antioxidant enzymes, including NRF2 and HO-1. Moreover, I3C mitigated inflammatory responses, as evidenced by elevated levels of IL-10 and reduced levels of NF-kB, TNF-α, and IL-6. These findings indicate that I3C exhibits neuroprotective effects by reducing oxidative stress, suppressing inflammation, and addressing abnormalities in the cholinergic pathway, highlighting its potential as a therapeutic approach for alleviating cognitive deficits.
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Affiliation(s)
- Laksmi Anusha Vinjavarapu
- KL College of Pharmacy, Koneru Lakshmaiah Education Foundation, Vaddeswaram, 522302, India
- SIMS College of Pharmacy, Guntur, Andhra Pradesh, 522001, India
| | - Srikanth Yadava
- KL College of Pharmacy, Koneru Lakshmaiah Education Foundation, Vaddeswaram, 522302, India
| | | | | | - Ramakrishna Kakarla
- KL College of Pharmacy, Koneru Lakshmaiah Education Foundation, Vaddeswaram, 522302, India.
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Sharma G, Badruddeen, Akhtar J, Khan MI, Ahmad M, Sharma PK. "Methyl jasmonate: bridging plant defense mechanisms and human therapeutics". NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-024-03752-x. [PMID: 39847055 DOI: 10.1007/s00210-024-03752-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 12/19/2024] [Indexed: 01/24/2025]
Abstract
A volatile organic substance produced from jasmonic acid, methyl jasmonate (MJ/MeJA), is an important plant hormone involved in stress responses and plant defense. Apart from its role in plants, MJ has garnered significant attention because of its pharmacological effects and possible therapeutic use in human health. This thorough analysis looks into the many biological actions of MJ, such as its antioxidant, anti-inflammatory, and anti-cancer effects. The underlying mechanism of these actions is examined, emphasizing MJ's ability to modulate important signaling pathways, cause cancer cells to undergo apoptosis, and boost immunological responses. Furthermore, MJ's capacity to manage long-term illnesses like cancer and neurological conditions like Parkinson's and Alzheimer's is examined. Preclinical and clinical research are beginning to provide evidence that MJ may be a useful medicinal drug. Nevertheless, more research is needed to fully understand its mode of action, enhance its administration methods, and evaluate its efficacy and safety in humans. This review highlights MJ's therapeutic promise and supports earlier research into its pharmacological capabilities and possible medical applications. This abstract highlights methyl jasmonate's pharmacological effects and therapeutic potential by providing a concise overview of the main topics covered in a thorough review.
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Affiliation(s)
- Garima Sharma
- Faculty of Pharmacy, Integral University, Kursi Road, Lucknow, U.P., 226026, India
| | - Badruddeen
- Faculty of Pharmacy, Integral University, Kursi Road, Lucknow, U.P., 226026, India.
| | - Juber Akhtar
- Faculty of Pharmacy, Integral University, Kursi Road, Lucknow, U.P., 226026, India
| | - Mohammad Irfan Khan
- Faculty of Pharmacy, Integral University, Kursi Road, Lucknow, U.P., 226026, India
| | - Mohammad Ahmad
- Faculty of Pharmacy, Integral University, Kursi Road, Lucknow, U.P., 226026, India
| | - Prakash Kumar Sharma
- Department of Anesthesiology, Hind Institute of Medical Sciences, Safedabad, Lucknow, U.P., 225001, India
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Rinaldi A, Balietti M, Principi E, De Luca M, De Felice E, Narcisi FM, Vilardo L, Rosito M, Piacentini R, D'Alessandro G, D'Agnano I, Maggi L, Conti F, Limatola C, Catalano M. BV2-derived extracellular vesicles modulate microglia inflammatory profile, neuronal plasticity, and behavioural performances in late adult mice. Brain Behav Immun 2024; 122:58-74. [PMID: 39128568 DOI: 10.1016/j.bbi.2024.08.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 07/24/2024] [Accepted: 08/08/2024] [Indexed: 08/13/2024] Open
Abstract
BACKGROUND During aging, both the brain and the immune system undergo a progressive impairment of physiological functions. Microglia, the immunocompetent cells of the central nervous system, shift towards a chronic mild inflammatory state that impacts brain homeostasis. Extracellular vesicles (EVs) released by microglia transport packages of molecular information that mirror the inflammatory status of donor cells and modulate the inflammatory phenotype of recipient microglia and other cell types. RESULTS We demonstrated that intranasal administration of EVs derived from microglial-like BV2 cells to late adult mice (16-20 months of age) shifts microglia toward a "juvenile" morphology affecting their inflammatory profile. Mice treated with BV2-derived EVs have a reduction of anxiety-like behavior and an increased spatial learning, with sex-dependent differences. Further, BV2-derived EVs increased neuronal plasticity both in male and female mice. These findings suggest the involvement of microglial cells in vesicles-mediated anti-aging effect. CONCLUSIONS Our data indicate that BV2-derived EVs could represent a resource to slow down age-dependent inflammation in the mouse brain.
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Affiliation(s)
- Arianna Rinaldi
- Department of Physiology and Pharmacology, Sapienza University, Rome, Italy
| | - Marta Balietti
- IRCCS INRCA, Center for Neurobiology of Aging, Via Birarelli 8, Ancona 60121, Italy
| | - Elisa Principi
- Università Politecnica delle Marche, Department of Experimental and Clinical Medicine, Via Tronto 10/a, Ancona 60126, Italy
| | | | - Eleonora De Felice
- Department of Physiology and Pharmacology, Sapienza University, Rome, Italy
| | | | - Laura Vilardo
- Institute of Biomedical Technologies, CNR, 20054 Segrate, Italy
| | - Maria Rosito
- Department of Physiology and Pharmacology, Sapienza University, Rome, Italy; Center for Life Nanoscience & Neuroscience Istituto Italiano di Tecnologia@Sapienza, Rome, Italy
| | - Roberto Piacentini
- Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy; IRCCS Fondazione Policlinico Universitario A. Gemelli, Largo A. Gemelli 1, Roma, Italy
| | - Giuseppina D'Alessandro
- Department of Physiology and Pharmacology, Sapienza University, Rome, Italy; IRCCS Neuromed, Pozzilli, IS, Italy
| | - Igea D'Agnano
- Institute of Biomedical Technologies, CNR, 20054 Segrate, Italy
| | - Laura Maggi
- Department of Physiology and Pharmacology, Sapienza University, Rome, Italy
| | - Fiorenzo Conti
- Università Politecnica delle Marche, Department of Experimental and Clinical Medicine, Via Tronto 10/a, Ancona 60126, Italy; IRCCS INRCA, Center for Neurobiology of Aging, Via Birarelli 8, Ancona 60121, Italy
| | - Cristina Limatola
- IRCCS Neuromed, Pozzilli, IS, Italy; Department of Physiology and Pharmacology, Sapienza University, Laboratory affiliated to Institute Pasteur Italia, Rome, Italy
| | - Myriam Catalano
- Department of Physiology and Pharmacology, Sapienza University, Rome, Italy.
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Zahoor M, Farhat SM, Khan S, Ahmed T. Daidzin improves neurobehavioral outcome in rat model of traumatic brain injury. Behav Brain Res 2024; 472:115158. [PMID: 39047874 DOI: 10.1016/j.bbr.2024.115158] [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: 02/16/2024] [Revised: 07/13/2024] [Accepted: 07/21/2024] [Indexed: 07/27/2024]
Abstract
Traumatic brain injury (TBI) is associated with the etiology of multiple neurological disorders, including neurodegeneration, leading to various cognitive deficits. Daidzin (obtained from kudzu root and soybean leaves) is known for its neuroprotective effects through multiple mechanisms. This study aimed to investigate the pharmacological effects of Daidzin on sensory, and biochemical parameters, cognitive functions, anxiety, and depressive-like behaviors in the TBI rat model. Rats were divided into four groups (Control, TBI, TBI + Ibuprofen (30 mg/kg), and TBI + Daidzin (5 mg/kg)). Rats were subjected to TBI by dropping a 200 g rod from a height of 26 cm, resulting in an impact force of 0.51 J on the exposed crania. Ibuprofen (30 mg/kg) was used as a positive control reference/standard drug and Daidzin (5 mg/kg) as the test drug. Neurological severity score (NSS) assessment was done to determine the intactness of sensory and motor responses. Brain tissue edema and acetylcholine levels were determined in the cortex and hippocampus. Cognitive functions such as hippocampus-dependent memory, novel object recognition, exploration, depressive and anxiety-like behaviors were measured. Treatment with Daidzin improved NSS, reduced hippocampal and cortical edema, and improved levels of acetylcholine in TBI-induced rats. Furthermore, Daidzin treatment improved hippocampus-dependent memory, exploration behavior, and novel object recognition while reducing depressive and anxiety-like behavior. Our study revealed that Daidzin has a therapeutic potential comparable to Ibuprofen and can offer neuroprotection and enhanced cognitive and behavioral outcomes in rats after TBI.
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Affiliation(s)
- Maryam Zahoor
- Neurobiology Laboratory, Department of Biomedicine, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Sector H-12, Islamabad 44000, Pakistan
| | - Syeda Mehpara Farhat
- Department of Biological Sciences, National University of Medical Sciences, Rawalpindi 46000, Pakistan
| | - Salman Khan
- Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan
| | - Touqeer Ahmed
- Neurobiology Laboratory, Department of Biomedicine, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Sector H-12, Islamabad 44000, Pakistan.
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Ahmad S, Yang W, Orellana A, Frölich L, de Rojas I, Cano A, Boada M, Hernández I, Hausner L, Harms AC, Bakker MHM, Cabrera-Socorro A, Amin N, Ramírez A, Ruiz A, Van Duijn CM, Hankemeier T. Association of oxidative stress and inflammatory metabolites with Alzheimer's disease cerebrospinal fluid biomarkers in mild cognitive impairment. Alzheimers Res Ther 2024; 16:171. [PMID: 39080778 PMCID: PMC11287840 DOI: 10.1186/s13195-024-01542-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 07/22/2024] [Indexed: 08/03/2024]
Abstract
BACKGROUND Isoprostanes and prostaglandins are biomarkers for oxidative stress and inflammation. Their role in Alzheimer's disease (AD) pathophysiology is yet unknown. In the current study, we aim to identify the association of isoprostanes and prostaglandins with the Amyloid, Tau, Neurodegeneration (ATN) biomarkers (Aβ-42, p-tau, and t-tau) of AD pathophysiology in mild cognitive impairment (MCI) subjects. METHODS Targeted metabolomics profiling was performed using liquid chromatography-mass spectrometry (LCMS) in 147 paired plasma-CSF samples from the Ace Alzheimer Center Barcelona and 58 CSF samples of MCI patients from the Mannheim/Heidelberg cohort. Linear regression was used to evaluate the association of metabolites with CSF levels of ATN biomarkers in the overall sample and stratified by Aβ-42 pathology and APOE genotype. We further evaluated the role of metabolites in MCI to AD dementia progression. RESULTS Increased CSF levels of PGF2α, 8,12-iso-iPF2α VI, and 5-iPF2α VI were significantly associated (False discovery rate (FDR) < 0.05) with higher p-tau levels. Additionally, 8,12-iso-iPF2α VI was associated with increased total tau levels in CSF. In MCI due to AD, PGF2α was associated with both p-tau and total tau, whereases 8,12-iso-iPF2α VI was specifically associated with p-tau levels. In APOE stratified analysis, association of PGF2α with p-tau and t-tau was observed in only APOE ε4 carriers while 5-iPF2α VI showed association with both p-tau and t-tau in APOE ε33 carriers. CSF levels of 8,12- iso-iPF2α VI showed association with p-tau and t-tau in APOE ε33/APOE ε4 carriers and with t-tau in APOE ε3 carriers. None of the metabolites showed evidence of association with MCI to AD progression. CONCLUSIONS Oxidative stress (8,12-iso-iPF2α VI) and inflammatory (PGF2α) biomarkers are correlated with biomarkers of AD pathology during the prodromal stage of AD and relation of PGF2α with tau pathology markers may be influenced by APOE genotype.
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Affiliation(s)
- Shahzad Ahmad
- Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands
- Metabolomics and Analytics Center, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands
- Oxford-GSK Institute of Molecular and Computational Medicine (IMCM), Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Wei Yang
- Metabolomics and Analytics Center, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands
| | - Adelina Orellana
- Ace Alzheimer Center Barcelona - Universitat Internacional de Catalunya, Barcelona, Spain
- Networking Research Center On Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
| | - Lutz Frölich
- Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159, Mannheim, Germany
| | - Itziar de Rojas
- Ace Alzheimer Center Barcelona - Universitat Internacional de Catalunya, Barcelona, Spain
- Networking Research Center On Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
| | - Amanda Cano
- Ace Alzheimer Center Barcelona - Universitat Internacional de Catalunya, Barcelona, Spain
- Networking Research Center On Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
| | - Mercè Boada
- Ace Alzheimer Center Barcelona - Universitat Internacional de Catalunya, Barcelona, Spain
- Networking Research Center On Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
| | - Isabel Hernández
- Ace Alzheimer Center Barcelona - Universitat Internacional de Catalunya, Barcelona, Spain
- Networking Research Center On Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
| | - Lucrezia Hausner
- Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159, Mannheim, Germany
| | - Amy C Harms
- Metabolomics and Analytics Center, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands
| | - Margot H M Bakker
- Discovery Research, AbbVie Deutschland GmbH & Co. KG, 67061, KnollstrasseLudwigshafen, Germany
| | | | - Najaf Amin
- Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands
- Nuffield Department of Population Health, University of Oxford, Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Old Road Campus, , Headington-Oxford, OX3 7FZ, UK
| | - Alfredo Ramírez
- Department for Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germany
- Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Medical Faculty, University of Cologne, Cologne, Germany
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
- Excellence Cluster On Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931, Cologne, Germany
- Department of Psychiatry and Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, San Antonio, TX, USA
| | - Agustín Ruiz
- Ace Alzheimer Center Barcelona - Universitat Internacional de Catalunya, Barcelona, Spain
- Networking Research Center On Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
| | - Cornelia M Van Duijn
- Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
- Nuffield Department of Population Health, University of Oxford, Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Old Road Campus, , Headington-Oxford, OX3 7FZ, UK.
| | - Thomas Hankemeier
- Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
- Metabolomics and Analytics Center, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
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de Lima Silva MG, Santos da Silva LY, Torres Pessoa R, de Oliveira MRC, Batista FLA, Alcântara IS, Bezerra Martins AOBP, Ribeiro-Filho J, Coutinho HDM, de Menezes IRA. Antiedematogenic and Analgesic Activities of Abietic Acid in Mice. Chem Biodivers 2023; 20:e202300906. [PMID: 37795905 DOI: 10.1002/cbdv.202300906] [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: 06/20/2023] [Revised: 10/02/2023] [Accepted: 10/05/2023] [Indexed: 10/06/2023]
Abstract
Exacerbated inflammatory responses to harmful stimuli can lead to significant pain, edema, and other complications that require pharmacological intervention. Abietic acid (AA) is a diterpene found as a significant constituent in pine species, and evidence has identified its biological potential. The present study aimed to evaluate abietic acid's antiedematogenic and anti-inflammatory activity in mice. Swiss mice (Mus musculus) weighing 20-30 g were treated with AA at 50, 100, and 200 mg/kg. The central nervous system (CNS) effects were evaluated using open-field and rotarod assays. The antinociceptive and anti-inflammatory screening was assessed by the acetic acid and formalin tests. The antiedematogenic activity was investigated by measuring paw edema induced by carrageenan, dextran, histamine, arachidonic acid, and prostaglandin, in addition to using a granuloma model. The oral administration of abietic acid (200 mg/Kg) showed no evidence of CNS effects. The compound also exhibited significant antiedematogenic and anti-inflammatory activities in the carrageenan and dextran models, mostly related to the inhibition of myeloperoxidase (MOP) activity and histamine action and, to a lesser extent, the inhibition of eicosanoid-dependent pathways. In the granuloma model, abietic acid's effect was less expressive than in the acute models investigated in this study. In conclusion, abietic acid has analgesic and antiedematogenic activities related to anti-inflammatory mechanisms.
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Affiliation(s)
- Maria Gabriely de Lima Silva
- Laboratory of Pharmacology and Molecular Chemistry (LFQM), Department of Biological Chemistry, Regional University of Cariri (URCA), Crato, CE-63105-000, Brazil
| | - Lucas Yure Santos da Silva
- Laboratory of Pharmacology and Molecular Chemistry (LFQM), Department of Biological Chemistry, Regional University of Cariri (URCA), Crato, CE-63105-000, Brazil
| | - Renata Torres Pessoa
- Laboratory of Pharmacology and Molecular Chemistry (LFQM), Department of Biological Chemistry, Regional University of Cariri (URCA), Crato, CE-63105-000, Brazil
| | - Maria Rayane Correia de Oliveira
- Laboratory of Pharmacology and Molecular Chemistry (LFQM), Department of Biological Chemistry, Regional University of Cariri (URCA), Crato, CE-63105-000, Brazil
| | - Francisco Lucas Alves Batista
- Laboratory of Pharmacology and Molecular Chemistry (LFQM), Department of Biological Chemistry, Regional University of Cariri (URCA), Crato, CE-63105-000, Brazil
| | - Isabel Sousa Alcântara
- Laboratory of Pharmacology and Molecular Chemistry (LFQM), Department of Biological Chemistry, Regional University of Cariri (URCA), Crato, CE-63105-000, Brazil
| | | | - Jaime Ribeiro-Filho
- Oswaldo Cruz Foundation (Fiocruz), Fiocruz Ceará, Eusébio, CE-60180-900, Brazil
| | - Henrique Douglas Melo Coutinho
- Laboratory of Microbiology and Molecular Biology, Department of Biological Chemistry, Regional University of Cariri (URCA), Crato, CE-63105-000, Brazil
| | - Irwin Rose Alencar de Menezes
- Laboratory of Pharmacology and Molecular Chemistry (LFQM), Department of Biological Chemistry, Regional University of Cariri (URCA), Crato, CE-63105-000, Brazil
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Fesharaki-Zadeh A. Navigating the Complexities of Traumatic Encephalopathy Syndrome (TES): Current State and Future Challenges. Biomedicines 2023; 11:3158. [PMID: 38137378 PMCID: PMC10740836 DOI: 10.3390/biomedicines11123158] [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: 10/23/2023] [Revised: 11/22/2023] [Accepted: 11/23/2023] [Indexed: 12/24/2023] Open
Abstract
Chronic traumatic encephalopathy (CTE) is a unique neurodegenerative disease that is associated with repetitive head impacts (RHI) in both civilian and military settings. In 2014, the research criteria for the clinical manifestation of CTE, traumatic encephalopathy syndrome (TES), were proposed to improve the clinical identification and understanding of the complex neuropathological phenomena underlying CTE. This review provides a comprehensive overview of the current understanding of the neuropathological and clinical features of CTE, proposed biomarkers of traumatic brain injury (TBI) in both research and clinical settings, and a range of treatments based on previous preclinical and clinical research studies. Due to the heterogeneity of TBI, there is no universally agreed-upon serum, CSF, or neuroimaging marker for its diagnosis. However, as our understanding of this complex disease continues to evolve, it is likely that there will be more robust, early diagnostic methods and effective clinical treatments. This is especially important given the increasing evidence of a correlation between TBI and neurodegenerative conditions, such as Alzheimer's disease and CTE. As public awareness of these conditions grows, it is imperative to prioritize both basic and clinical research, as well as the implementation of necessary safe and preventative measures.
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Affiliation(s)
- Arman Fesharaki-Zadeh
- Department of Neurology and Psychiatry, Yale University School of Medicine, New Haven, CT 06510, USA
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Chen C. Inhibiting degradation of 2-arachidonoylglycerol as a therapeutic strategy for neurodegenerative diseases. Pharmacol Ther 2023; 244:108394. [PMID: 36966972 PMCID: PMC10123871 DOI: 10.1016/j.pharmthera.2023.108394] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 03/17/2023] [Accepted: 03/21/2023] [Indexed: 03/29/2023]
Abstract
Endocannabinoids are endogenous lipid signaling mediators that participate in a variety of physiological and pathological processes. 2-Arachidonoylglycerol (2-AG) is the most abundant endocannabinoid and is a full agonist of G-protein-coupled cannabinoid receptors (CB1R and CB2R), which are targets of Δ9-tetrahydrocannabinol (Δ9-THC), the main psychoactive ingredient in cannabis. While 2-AG has been well recognized as a retrograde messenger modulating synaptic transmission and plasticity at both inhibitory GABAergic and excitatory glutamatergic synapses in the brain, growing evidence suggests that 2-AG also functions as an endogenous terminator of neuroinflammation in response to harmful insults, thus maintaining brain homeostasis. Monoacylglycerol lipase (MAGL) is the key enzyme that degrades 2-AG in the brain. The immediate metabolite of 2-AG is arachidonic acid (AA), a precursor of prostaglandins (PGs) and leukotrienes. Several lines of evidence indicate that pharmacological or genetic inactivation of MAGL, which boosts 2-AG levels and reduces its hydrolytic metabolites, resolves neuroinflammation, mitigates neuropathology, and improves synaptic and cognitive functions in animal models of neurodegenerative diseases, including Alzheimer's disease (AD), multiple sclerosis (MS), Parkinson's disease (PD), and traumatic brain injury (TBI)-induced neurodegenerative disease. Thus, it has been proposed that MAGL is a potential therapeutic target for treatment of neurodegenerative diseases. As the main enzyme hydrolyzing 2-AG, several MAGL inhibitors have been identified and developed. However, our understanding of the mechanisms by which inactivation of MAGL produces neuroprotective effects in neurodegenerative diseases remains limited. A recent finding that inhibition of 2-AG metabolism in astrocytes, but not in neurons, protects the brain from TBI-induced neuropathology might shed some light on this unsolved issue. This review provides an overview of MAGL as a potential therapeutic target for neurodegenerative diseases and discusses possible mechanisms underlying the neuroprotective effects of restraining degradation of 2-AG in the brain.
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Varghese N, Morrison B. Inhibition of cyclooxygenase and EP3 receptor improved long term potentiation in a rat organotypic hippocampal model of repeated blast traumatic brain injury. Neurochem Int 2023; 163:105472. [PMID: 36599378 DOI: 10.1016/j.neuint.2022.105472] [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: 10/21/2022] [Revised: 12/09/2022] [Accepted: 12/30/2022] [Indexed: 01/03/2023]
Abstract
Blast-induced traumatic brain injury (bTBI) is a health concern in military service members who are exposed to multiple blasts throughout their training and deployment. Our group has previously reported decreased long term potentiation (LTP) following repeated bTBI in a rat organotypic hippocampal slice culture (OHSC) model. In this study, we investigated changes in inflammatory markers like cyclooxygenase (COX) and tested the efficacy of COX or prostaglandin EP3 receptor (EP3R) inhibitors in attenuating LTP deficits. Expression of COX-2 was increased 48 h following repeated injury, whereas COX-1 expression was unchanged. EP3R expression was upregulated, and cyclic adenosine monophosphate (cAMP) concentration was decreased after repeated blast exposure. Post-traumatic LTP deficits improved after treatment with a COX-1 specific inhibitor, SC-560, a COX-2 specific inhibitor, rofecoxib, a pan-COX inhibitor, ibuprofen, or an EP3R inhibitor, L-798,106. Delayed treatment with ibuprofen and L-798,106 also prevented LTP deficits. These findings suggest that bTBI induced neuroinflammation may be responsible for some functional deficits that we have observed in injured OHSCs. Additionally, COX and EP3R inhibition may be viable therapeutic strategies to reduce neurophysiological deficits after repeated bTBI.
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Affiliation(s)
- Nevin Varghese
- Department of Biomedical Engineering, Columbia University, 1210 Amsterdam Avenue, New York, NY, 10027, USA.
| | - Barclay Morrison
- Department of Biomedical Engineering, Columbia University, 1210 Amsterdam Avenue, New York, NY, 10027, USA.
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11
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Zhu D, Zhang J, Hashem J, Gao F, Chen C. Inhibition of 2-arachidonoylglycerol degradation enhances glial immunity by single-cell transcriptomic analysis. J Neuroinflammation 2023; 20:17. [PMID: 36717883 PMCID: PMC9885699 DOI: 10.1186/s12974-023-02701-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 01/17/2023] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND 2-Arachidonoylglycerol (2-AG) is the most abundant endogenous cannabinoid. Inhibition of 2-AG metabolism by inactivation of monoacylglycerol lipase (MAGL), the primary enzyme that degrades 2-AG in the brain, produces anti-inflammatory and neuroprotective effects in neurodegenerative diseases. However, the molecular mechanisms underlying these beneficial effects are largely unclear. METHODS Hippocampal and cortical cells were isolated from cell type-specific MAGL knockout (KO) mice. Single-cell RNA sequencing was performed by 10 × Genomics platform. Cell Ranger, Seurat (v3.2) and CellChat (1.1.3) packages were used to carry out data analysis. RESULTS Using single-cell RNA sequencing analysis, we show here that cell type-specific MAGL KO mice display distinct gene expression profiles in the brain. Inactivation of MAGL results in robust changes in expression of immune- and inflammation-related genes in microglia and astrocytes. Remarkably, upregulated expression of chemokines in microglia is more pronounced in mice lacking MAGL in astrocytes. In addition, expression of genes that regulate other cellular functions and Wnt signaling in astrocytes is altered in MAGL KO mice. CONCLUSIONS Our results provide transcriptomic evidence that cell type-specific inactivation of MAGL induces differential expression of immune-related genes and other fundamental cellular pathways in microglia and astrocytes. Upregulation of the immune/inflammatory genes suggests that tonic levels of immune/inflammatory vigilance are enhanced in microglia and astrocytes, particularly in microglia, by inhibition of 2-AG metabolism, which likely contribute to anti-inflammatory and neuroprotective effects produced by inactivation of MAGL in neurodegenerative diseases.
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Affiliation(s)
- Dexiao Zhu
- grid.267309.90000 0001 0629 5880Department of Cellular and Integrative Physiology, Joe R. and Teresa Lozano Long School of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229 USA
| | - Jian Zhang
- grid.267309.90000 0001 0629 5880Department of Cellular and Integrative Physiology, Joe R. and Teresa Lozano Long School of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229 USA
| | - Jack Hashem
- grid.267309.90000 0001 0629 5880Department of Cellular and Integrative Physiology, Joe R. and Teresa Lozano Long School of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229 USA
| | - Fei Gao
- grid.267309.90000 0001 0629 5880Department of Cellular and Integrative Physiology, Joe R. and Teresa Lozano Long School of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229 USA
| | - Chu Chen
- grid.267309.90000 0001 0629 5880Department of Cellular and Integrative Physiology, Joe R. and Teresa Lozano Long School of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229 USA ,grid.267309.90000 0001 0629 5880Center for Biomedical Neuroscience, Joe R. and Teresa Lozano Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229 USA
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12
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Abstract
Microglia and astrocytes are regarded as active participants in the central nervous system under various neuropathological conditions, including Alzheimer's disease (AD). Both microglia and astrocyte activation have been reported to occur with a spatially and temporarily distinct pattern. Acting as a double-edged sword, glia-mediated neuroinflammation may be both detrimental and beneficial to the brain. In a variety of neuropathologies, microglia are activated before astrocytes, which facilitates astrocyte activation. Yet reactive astrocytes can also prevent the activation of adjacent microglia in addition to helping them become activated. Studies describe changes in the genetic profile as well as cellular and molecular responses of these two types of glial cells that contribute to dysfunctional immune crosstalk in AD. In this paper, we construct current knowledge of microglia-astrocyte communication, highlighting the multifaceted functions of microglia and astrocytes and their role in AD. A thorough comprehension of microglia-astrocyte communication could hasten the creation of novel AD treatment approaches.
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Affiliation(s)
- Yingying Wu
- Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences (GELIFES), University of Groningen, Groningen, The Netherlands
- Department of Neurology, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China
| | - Ulrich L.M. Eisel
- Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences (GELIFES), University of Groningen, Groningen, The Netherlands
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13
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Yanai S, Tago T, Toyohara J, Arasaki T, Endo S. Reversal of spatial memory impairment by phosphodiesterase 3 inhibitor cilostazol is associated with reduced neuroinflammation and increased cerebral glucose uptake in aged male mice. Front Pharmacol 2022; 13:1031637. [PMID: 36618932 PMCID: PMC9810637 DOI: 10.3389/fphar.2022.1031637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 11/30/2022] [Indexed: 12/24/2022] Open
Abstract
The nucleotide second messenger 3', 5'-cyclic adenosine monophosphate (cAMP) and 3', 5'-cyclic guanosine monophosphate (cGMP) mediate fundamental functions of the brain, including learning and memory. Phosphodiesterase 3 (PDE3) can hydrolyze both cAMP and cGMP and appears to be involved in the regulation of their contents in cells. We previously demonstrated that long-term administration of cilostazol, a PDE3 inhibitor, maintained good memory performance in aging mice. Here, we report on studies aimed at determining whether cilostazol also reverses already-impaired memory in aged male mice. One month of oral 1.5% cilostazol administration in 22-month-old mice reversed age-related declines in hippocampus-dependent memory tasks, including the object recognition and the Morris water maze. Furthermore, cilostazol reduced neuroinflammation, as evidenced by immunohistochemical staining, and increased glucose uptake in the brain, as evidence by positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG). These results suggest that already-expressed memory impairment in aged male mice that depend on cyclic nucleotide signaling can be reversed by inhibition of PDE3. The reversal of age-related memory impairments may occur in the central nervous system, either through cilostazol-enhanced recall or strengthening of weak memories that otherwise may be resistant to recall.
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Affiliation(s)
- Shuichi Yanai
- Aging Neuroscience Research Team, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
| | - Tetsuro Tago
- Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
| | - Jun Toyohara
- Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
| | - Tomoko Arasaki
- Aging Neuroscience Research Team, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
| | - Shogo Endo
- Aging Neuroscience Research Team, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan,*Correspondence: Shogo Endo,
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14
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Micheli L, Toti A, Lucarini E, Ferrara V, Ciampi C, Olivero G, Pittaluga A, Mattoli L, Pelucchini C, Burico M, Lucci J, Carrino D, Pacini A, Pallanti S, Di Cesare Mannelli L, Ghelardini C. Efficacy of a vegetal mixture composed of Zingiber officinale, Echinacea purpurea, and Centella asiatica in a mouse model of neuroinflammation: In vivo and ex vivo analysis. Front Nutr 2022; 9:887378. [PMID: 36118773 PMCID: PMC9472218 DOI: 10.3389/fnut.2022.887378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 07/25/2022] [Indexed: 12/04/2022] Open
Abstract
Experimental evidence suggests that neuroinflammation is a key pathological event of many diseases affecting the nervous system. It has been well recognized that these devastating illnesses (e.g., Alzheimer’s, Parkinson’s, depression, and chronic pain) are multifactorial, involving many pathogenic mechanisms, reason why pharmacological treatments are unsatisfactory. The purpose of this study was to evaluate the efficacy of a vegetal mixture capable of offering a multiple approach required to manage the multifactoriality of neuroinflammation. A mixture composed of Zingiber officinale (150 mg kg−1), Echinacea purpurea (20 mg kg−1), and Centella asiatica (200 mg kg−1) was tested in a mouse model of systemic neuroinflammation induced by lipopolysaccharide (LPS, 1 mg kg−1). Repeated treatment with the vegetal mixture was able to completely counteract thermal and mechanical allodynia as reported by the Cold plate and von Frey tests, respectively, and to reduce the motor impairments as demonstrated by the Rota rod test. Moreover, the mixture was capable of neutralizing the memory loss in the Passive avoidance test and reducing depressive-like behavior in the Porsolt test, while no efficacy was shown in decreasing anhedonia as demonstrated by the Sucrose preference test. Finally, LPS stimulation caused a significant increase in the activation of glial cells, of the central complement proteins and of inflammatory cytokines in selected regions of the central nervous system (CNS), which were rebalanced in animals treated with the vegetal mixture. In conclusion, the vegetal mixture tested thwarted the plethora of symptoms evoked by LPS, thus being a potential candidate for future investigations in the context of neuroinflammation.
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Affiliation(s)
- Laura Micheli
- Neurofarba—Pharmacology and Toxicology Section, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy
- *Correspondence: Laura Micheli,
| | - Alessandra Toti
- Neurofarba—Pharmacology and Toxicology Section, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy
| | - Elena Lucarini
- Neurofarba—Pharmacology and Toxicology Section, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy
| | - Valentina Ferrara
- Neurofarba—Pharmacology and Toxicology Section, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy
| | - Clara Ciampi
- Neurofarba—Pharmacology and Toxicology Section, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy
| | - Guendalina Olivero
- Department of Pharmacy, School of Medical and Pharmaceutical Sciences, University of Genoa, Genoa, Italy
- Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
| | - Anna Pittaluga
- Department of Pharmacy, School of Medical and Pharmaceutical Sciences, University of Genoa, Genoa, Italy
- Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
| | - Luisa Mattoli
- Innovation and Medical Science Division, Aboca SpA Società Agricola, Sansepolcro, Italy
| | - Caroline Pelucchini
- Innovation and Medical Science Division, Aboca SpA Società Agricola, Sansepolcro, Italy
| | - Michela Burico
- Innovation and Medical Science Division, Aboca SpA Società Agricola, Sansepolcro, Italy
| | - Jacopo Lucci
- Innovation and Medical Science Division, Aboca SpA Società Agricola, Sansepolcro, Italy
| | - Donatello Carrino
- Anatomy and Histology Section, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Alessandra Pacini
- Anatomy and Histology Section, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Stefano Pallanti
- Psychiatry Section, Department of Neurofarba, University of Florence, Florence, Italy
- Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, New York, NY, United States
- Institute of Neuroscience, Florence, Italy
| | - Lorenzo Di Cesare Mannelli
- Neurofarba—Pharmacology and Toxicology Section, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy
| | - Carla Ghelardini
- Neurofarba—Pharmacology and Toxicology Section, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy
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15
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Li Y, Zhu H, Cheng D, Zhao Z. Inhibition of Γδ T Cells Alleviates Brain Ischemic Injury in Cardiopulmonary-Cerebral Resuscitation Mice. Transplant Proc 2022; 54:1984-1991. [PMID: 35931471 DOI: 10.1016/j.transproceed.2022.05.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 05/26/2022] [Accepted: 05/31/2022] [Indexed: 10/16/2022]
Abstract
BACKGROUND A half-million people in the United States suffer from cardiac arrest (CA) requiring cardiopulmonary resuscitation (CPR). An inflammatory mechanism is associated with neuronal injury in the presence of cerebral ischemia. T lymphocytes are identified as crucial regulators of inflammation. Therefore, we investigated the relationship between CA/CPR-induced ischemia injury and T lymphocytes. METHODS C57BL/6 mice were subjected to CA through injection of KCl (30 μL of 0.5 mol/L) and cessation of mechanical ventilation followed by CPR. The survival rate and neurologic deficit scores were assessed. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining was carried out to detect neuronal death. Histologic changes were observed by hematoxylin-eosin staining. The levels of Trgv4, Trgv5 and Trgv7 were quantified by RT-qPCR. Inflammatory responses were identified by measurement of IL-1β, IL-6 and IL-17. RESULTS Downregulated γδ T cells improved survival and neurologic outcomes and inhibits neuronal apoptosis. γδ T inhibition protected brains from CA/CPR-mediated tissue damage. UC7-13D5 treatment inhibited the levels of γδ T markers. Knockdown of γδ T cells ameliorated neuroinflammation. CONCLUSIONS Inhibition of γδ T cells ameliorates ischemic injury in mice with CA/CPR by attenuating inflammation and neuronal apoptosis.
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Affiliation(s)
- Yeqiu Li
- Department of Anesthesiology, People's Hospital of Dongxihu District, Wuhan, China
| | - Hongfei Zhu
- Department of Anesthesiology, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China; Department of Anesthesiology, The Affiliated Hospital of Hubei Traditional Chinese Medicine University, Wuhan, China; Hubei Province Academy of Traditional Chinese Medicine, Wuhan, China.
| | - Dong Cheng
- Department of Anesthesiology, People's Hospital of Dongxihu District, Wuhan, China
| | - Zhenglan Zhao
- Department of Anesthesiology, People's Hospital of Dongxihu District, Wuhan, China
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16
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Needham H, Torpey G, Flores CC, Davis CJ, Vanderheyden WM, Gerstner JR. A Dichotomous Role for FABP7 in Sleep and Alzheimer's Disease Pathogenesis: A Hypothesis. Front Neurosci 2022; 16:798994. [PMID: 35844236 PMCID: PMC9280343 DOI: 10.3389/fnins.2022.798994] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 05/10/2022] [Indexed: 11/15/2022] Open
Abstract
Fatty acid binding proteins (FABPs) are a family of intracellular lipid chaperone proteins known to play critical roles in the regulation of fatty acid uptake and transport as well as gene expression. Brain-type fatty acid binding protein (FABP7) is enriched in astrocytes and has been implicated in sleep/wake regulation and neurodegenerative diseases; however, the precise mechanisms underlying the role of FABP7 in these biological processes remain unclear. FABP7 binds to both arachidonic acid (AA) and docosahexaenoic acid (DHA), resulting in discrete physiological responses. Here, we propose a dichotomous role for FABP7 in which ligand type determines the subcellular translocation of fatty acids, either promoting wakefulness aligned with Alzheimer's pathogenesis or promoting sleep with concomitant activation of anti-inflammatory pathways and neuroprotection. We hypothesize that FABP7-mediated translocation of AA to the endoplasmic reticulum of astrocytes increases astrogliosis, impedes glutamatergic uptake, and enhances wakefulness and inflammatory pathways via COX-2 dependent generation of pro-inflammatory prostaglandins. Conversely, we propose that FABP7-mediated translocation of DHA to the nucleus stabilizes astrocyte-neuron lactate shuttle dynamics, preserves glutamatergic uptake, and promotes sleep by activating anti-inflammatory pathways through the peroxisome proliferator-activated receptor-γ transcriptional cascade. Importantly, this model generates several testable hypotheses applicable to other neurodegenerative diseases, including amyotrophic lateral sclerosis and Parkinson's disease.
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Affiliation(s)
- Hope Needham
- Department of Biology, Gonzaga University, Spokane, WA, United States
| | - Grace Torpey
- Department of Biology, Gonzaga University, Spokane, WA, United States
| | - Carlos C. Flores
- Department of Translational Medicine and Physiology, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, United States
| | - Christopher J. Davis
- Department of Translational Medicine and Physiology, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, United States
- Sleep and Performance Research Center, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, United States
| | - William M. Vanderheyden
- Department of Translational Medicine and Physiology, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, United States
- Sleep and Performance Research Center, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, United States
| | - Jason R. Gerstner
- Department of Translational Medicine and Physiology, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, United States
- Sleep and Performance Research Center, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, United States
- Steve Gleason Institute for Neuroscience, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, United States
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17
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Rahimian R, Belliveau C, Chen R, Mechawar N. Microglial Inflammatory-Metabolic Pathways and Their Potential Therapeutic Implication in Major Depressive Disorder. Front Psychiatry 2022; 13:871997. [PMID: 35782423 PMCID: PMC9245023 DOI: 10.3389/fpsyt.2022.871997] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 05/23/2022] [Indexed: 12/19/2022] Open
Abstract
Increasing evidence supports the notion that neuroinflammation plays a critical role in the etiology of major depressive disorder (MDD), at least in a subset of patients. By virtue of their capacity to transform into reactive states in response to inflammatory insults, microglia, the brain's resident immune cells, play a pivotal role in the induction of neuroinflammation. Experimental studies have demonstrated the ability of microglia to recognize pathogens or damaged cells, leading to the activation of a cytotoxic response that exacerbates damage to brain cells. However, microglia display a wide range of responses to injury and may also promote resolution stages of inflammation and tissue regeneration. MDD has been associated with chronic priming of microglia. Recent studies suggest that altered microglial morphology and function, caused either by intense inflammatory activation or by senescence, may contribute to depression and associated impairments in neuroplasticity. In this context, modifying microglia phenotype by tuning inflammatory pathways might have important translational relevance to harness neuroinflammation in MDD. Interestingly, it was recently shown that different microglial phenotypes are associated with distinct metabolic pathways and analysis of the underlying molecular mechanisms points to an instrumental role for energy metabolism in shaping microglial functions. Here, we review various canonical pro-inflammatory, anti-inflammatory and metabolic pathways in microglia that may provide new therapeutic opportunities to control neuroinflammation in brain disorders, with a strong focus on MDD.
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Affiliation(s)
- Reza Rahimian
- Douglas Mental Health University Institute, McGill Group for Suicide Studies, Verdun, QC, Canada
| | - Claudia Belliveau
- Douglas Mental Health University Institute, McGill Group for Suicide Studies, Verdun, QC, Canada
- Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada
| | - Rebecca Chen
- Douglas Mental Health University Institute, McGill Group for Suicide Studies, Verdun, QC, Canada
- Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada
| | - Naguib Mechawar
- Douglas Mental Health University Institute, McGill Group for Suicide Studies, Verdun, QC, Canada
- Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada
- Department of Psychiatry, McGill University, Montreal, QC, Canada
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18
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Saeedi M, Mehranfar F. Challenges and approaches of drugs such as Memantine, Donepezil, Rivastigmine and Aducanumab in the treatment, control and management of Alzheimer's disease. Recent Pat Biotechnol 2022; 16:102-121. [PMID: 35236274 DOI: 10.2174/1872208316666220302115901] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 10/20/2021] [Accepted: 12/28/2021] [Indexed: 11/22/2022]
Abstract
Alzheimer's disease (AD) is a kinds of neuropsychiatric illnesses that affect the central nervous system. In this disease, the accumulation of amyloid-beta increases, and phosphorylated tau (P-tau) protein, one of the ways to treat this disease is to reduce the accumulation of amyloid-beta. Various studies have demonstrated that pharmacological approaches have considerable effects in the treatment of AD, despite the side effects and challenges. Cholinesterase inhibitors and the NMDA receptor antagonist memantine are presently authorized therapies for AD. Memantine and Donepezil are the most common drugs for the prevention and therapy of AD with mechanisms such as lessened β-amyloid plaque, effect on N-Methyl-D-aspartate (NMDA) receptors. Diminution glutamate and elevated acetylcholine are some of the influences of medications administrated to treat AD, and drugs can also play a role in slowing the progression of cognitive and memory impairment. A new pharmacological approach and strategy is required to control the future of AD. This review appraises the effects of memantine, donepezil, rivastigmine, and aducanumab in clinical trials, in vitro and animal model studies that have explored how these drugs versus AD development and also discuss possible mechanisms of influence on the brain. Research in clinical trials has substantial findings that support the role of these medications in AD treatment and ameliorate the safety and efficacy of AD therapy, although more clinical trials are required to prove their effectiveness.
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Affiliation(s)
- Mohammad Saeedi
- Department of Laboratory Science, Faculty of medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Fatemeh Mehranfar
- Department of Laboratory Science, Faculty of medicine, Semnan University of Medical Sciences, Semnan, Iran
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19
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You M, Wang K, Pan Y, Tao L, Ma Q, Zhang G, Hu F. Combined royal jelly 10-hydroxydecanoic acid and aspirin has a synergistic effect against memory deficit and neuroinflammation. Food Funct 2022; 13:2336-2353. [PMID: 35142767 DOI: 10.1039/d1fo02397g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Alzheimer's disease (AD), the most common form of neurodegenerative dementia among the older population, is associated with acute or chronic inflammation. As a nonsteroidal anti-inflammatory drug, aspirin has recently been widely studied in the prevention and treatment of neurodegenerative diseases. However, there is a controversy about the efficacy as well as the adverse effects of aspirin. 10-Hydroxydecanoic acid (10-HDAA) is a characteristic fatty acid found in the honey bee product royal jelly. In this study, we found that 10-HDAA attenuated the activation of the NF-κB pathway, then targeted Ptgs-1/2, the well-known target of aspirin. Hence, combined therapy of 10-HDAA and aspirin was conducted. In vitro assays suggested that this combinatory group alleviated LPS-induced inflammation in BV-2 cells, as assessed by the downregulation of nitric oxide, COX-2, and IL-6 compared to 10-HDAA or aspirin treatment alone. In vivo assays showed that the combined treatment synergistically inhibited the overactivation of glial cells and decreased the levels of pro-inflammatory mediators. Moreover, 10-HDAA alleviated the adverse effects of aspirin on gastrointestinal injuries and microbiota dysbiosis. The Morris water maze test indicated that neither 10-HDAA nor aspirin effectively improved LPS-induced memory dysfunction, but the combined therapy showed synergistic effects. Altogether, our findings support 10-HDAA and aspirin combinatory therapy as the basis for future therapeutics for AD and other neuroinflammation-related diseases with minimal adverse effects.
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Affiliation(s)
- Mengmeng You
- College of Animal Sciences, Zhejiang University, Hangzhou, China. .,School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.,College of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Kangli Wang
- College of Animal Sciences, Zhejiang University, Hangzhou, China.
| | - Yongming Pan
- Experimental Animal Research Center, Zhejiang Chinese Medical University, Hangzhou, China
| | - Lingchen Tao
- College of Animal Sciences, Zhejiang University, Hangzhou, China.
| | - Quanxin Ma
- College of Animal Sciences, Zhejiang University, Hangzhou, China.
| | - Guozhi Zhang
- College of Animal Sciences, Zhejiang University, Hangzhou, China.
| | - Fuliang Hu
- College of Animal Sciences, Zhejiang University, Hangzhou, China.
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20
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Yau SY, Yip YSL, Formolo DA, He S, Lee THY, Wen C, Hryciw DH. Chronic consumption of a high linoleic acid diet during pregnancy, lactation and post-weaning period increases depression-like behavior in male, but not female offspring. Behav Brain Res 2022; 416:113538. [PMID: 34418475 DOI: 10.1016/j.bbr.2021.113538] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 07/28/2021] [Accepted: 08/13/2021] [Indexed: 12/16/2022]
Abstract
Polyunsaturated fatty acids (PUFAs) play an essential role in brain development. Emerging data have suggested a possible link between an imbalance in PUFAs and cognitive behavioral deficits in offspring. A diet rich in high linoleic acid (HLA), typically from preconception to lactation, leads to an increase in the ratio of omega-6 (n-6) to omega-3 (n-3) fatty acids in the fetus. Arising research has suggested that a deficiency in omega-3 fatty acids is a potential risk factor for inducing autism spectrum disorder (ASD)-like behavioral deficits. However, the impact of a high n- diet during preconception, pregnancy, lactation, and post-weaning on the brain development of adolescent offspring are yet to be determined. This study examined whether consumption of an HLA diet during pregnancy, lactation, and post-weaning induced social and cognitive impairments in female and male offspring rats that resemble autistic phenotypes in humans. Female Wistar Kyoto rats were fed with either HLA or low linoleic acid (LLA) control diet for 10 weeks before mating, then continued with the same diet throughout the pregnancy and lactation period. Female and male offspring at 5 weeks old were subjected to behavioral tests to assess social interaction behavior and depression-/anxiety-like behavior. Our result showed that chronic consumption of an HLA diet did not affect sociability and social recognition memory, but induced depression-like behavior in male but not in female offspring.
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Affiliation(s)
- Suk-Yu Yau
- Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hong Kong; Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia.
| | - Yvette Siu Ling Yip
- Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hong Kong; Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia
| | - Douglas A Formolo
- Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hong Kong; Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia
| | - Siyuen He
- Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hong Kong; Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia
| | - Thomas Ho Yin Lee
- Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hong Kong; Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia
| | - Chunyi Wen
- Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hong Kong; Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia
| | - Deanne H Hryciw
- Centre for Planetary Health and Food Security, Griffith University, Nathan, Queensland, Australia; School of Environment and Science, Griffith University, Nathan, QLD, Australia; Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia
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21
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Vitaliti G, Falsaperla R. Chorioamnionitis, Inflammation and Neonatal Apnea: Effects on Preterm Neonatal Brainstem and on Peripheral Airways: Chorioamnionitis and Neonatal Respiratory Functions. CHILDREN (BASEL, SWITZERLAND) 2021; 8:917. [PMID: 34682182 PMCID: PMC8534519 DOI: 10.3390/children8100917] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/01/2021] [Accepted: 10/13/2021] [Indexed: 11/16/2022]
Abstract
Background: The present manuscript aims to be a narrative review evaluating the association between inflammation in chorioamnionitis and damage on respiratory centers, peripheral airways, and lungs, explaining the pathways responsible for apnea in preterm babies born by delivery after chorioamnionitis. Methods: A combination of keywords and MESH words was used, including: "inflammation", "chorioamnionitis", "brainstem", "cytokines storm", "preterm birth", "neonatal apnea", and "apnea physiopathology". All identified papers were screened for title and abstracts by the two authors to verify whether they met the proper criteria to write the topic. Results: Chorioamnionitis is usually associated with Fetal Inflammatory Response Syndrome (FIRS), resulting in injury of brain and lungs. Literature data have shown that infections causing chorioamnionitis are mostly associated with inflammation and consequent hypoxia-mediated brain injury. Moreover, inflammation and infection induce apneic episodes in neonates, as well as in animal samples. Chorioamnionitis-induced inflammation favors the systemic secretion of pro-inflammatory cytokines that are involved in abnormal development of the respiratory centers in the brainstem and in alterations of peripheral airways and lungs. Conclusions: Preterm birth shows a suboptimal development of the brainstem and abnormalities and altered development of peripheral airways and lungs. These alterations are responsible for reduced respiratory control and apnea. To date, mostly animal studies have been published. Therefore, more clinical studies on the role of chorioamninitis-induced inflammation on prematurity and neonatal apnea are necessary.
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Affiliation(s)
- Giovanna Vitaliti
- Unit of Pediatrics, Department of Medical Sciences, Section of Pediatrics, University of Ferrara, 44121 Ferrara, Italy
| | - Raffaele Falsaperla
- Pediatrics and Pediatric Emergency Operative Unit, Azienda Ospedaliero Universitaria Policlinico G.Rodolico-San Marco, San Marco Hospital, University of Catania, 95124 Catania, Italy;
- Neonatal Intensive Care Unit, Azienda Ospedaliero Universitaria Policlinico G.Rodolico-San Marco, San Marco Hospital, San Marco Hospital, University of Catania, 95124 Catania, Italy
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22
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Hu H, Wang J, Ren J, Li X, Zhang B, Lv Z, Dai F. Hydrophilic polymer driven crystallization self-assembly: an inflammatory multi-drug combination nanosystem against Alzheimer's disease. J Mater Chem B 2021; 9:8272-8288. [PMID: 34505608 DOI: 10.1039/d1tb00762a] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The hydrophobic polymer driven crystallization of self-assembled micelles is usually sufficient for their purposes in materials chemistry studies. However, with the state of smart drug delivery research, micelles alone are not enough. The principles of the self assembly driven by hydrophilic dextran brushes together with charged poly(3-acrylamidophenyl boronic acid) (PPBA) are uncovered in this study. A series of poly(ε-caprolactone)-block-poly(3-acrylamidophenyl boronic acid)-dextran (PCL-b-PPBA-Dex) micelles and vesicles are investigated as potential Alzheimer's disease (AD) treatments. Three inflammatory microenvironment responsive micelles, including celecoxib drug-loaded micelles (CEL), ibuprofen drug-loaded micelles (IBU) and telmisartan drug-loaded micelles (TEL), are developed. In vivo, CEL/IBU (mixture of CEL and IBU) and CEL/TEL (mixture of CEL and TEL) suppress the activation of glia and reduce the levels of inflammatory mediators through eliminating cyclooxygenase 2 (COX-2) signals. The CEL/TEL combination nanosystem is better at correcting neuroinflammation and improving the spatial memory ability of a senescence-accelerated mouse prone 8 model (SAMP8). We consider that the inflammation responsive combination nanosystem provides a new potential treatment for AD clinical patients.
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Affiliation(s)
- Haodong Hu
- State Key Laboratory of Separation Membranes and Membrane Processes/National Center for International Joint Research on Separation Membranes, School of Material Science and Engineering, Tiangong University, Tianjin, 300387, P. R. China.
| | - Jinna Wang
- State Key Laboratory of Separation Membranes and Membrane Processes/National Center for International Joint Research on Separation Membranes, School of Material Science and Engineering, Tiangong University, Tianjin, 300387, P. R. China.
| | - Jian Ren
- State Key Laboratory of Separation Membranes and Membrane Processes/National Center for International Joint Research on Separation Membranes, School of Material Science and Engineering, Tiangong University, Tianjin, 300387, P. R. China.
| | - Xinpo Li
- State Key Laboratory of Separation Membranes and Membrane Processes/National Center for International Joint Research on Separation Membranes, School of Material Science and Engineering, Tiangong University, Tianjin, 300387, P. R. China.
| | - Bo Zhang
- State Key Laboratory of Separation Membranes and Membrane Processes/National Center for International Joint Research on Separation Membranes, School of Material Science and Engineering, Tiangong University, Tianjin, 300387, P. R. China.
| | - Zhengang Lv
- State Key Laboratory of Coal Conversion, Institute of Coal Chemistry, Chinese Academy of Sciences and Synfuels China Co., Ltd, Beijing, P. R. China.
| | - Fengying Dai
- State Key Laboratory of Separation Membranes and Membrane Processes/National Center for International Joint Research on Separation Membranes, School of Material Science and Engineering, Tiangong University, Tianjin, 300387, P. R. China.
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23
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Sluter MN, Hou R, Li L, Yasmen N, Yu Y, Liu J, Jiang J. EP2 Antagonists (2011-2021): A Decade's Journey from Discovery to Therapeutics. J Med Chem 2021; 64:11816-11836. [PMID: 34352171 PMCID: PMC8455147 DOI: 10.1021/acs.jmedchem.1c00816] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
In the wake of health disasters associated with the chronic use of cyclooxygenase-2 (COX-2) inhibitor drugs, it has been widely proposed that modulation of downstream prostanoid synthases or receptors might provide more specificity than simply shutting down the entire COX cascade for anti-inflammatory benefits. The pathogenic actions of COX-2 have long been thought attributable to the prostaglandin E2 (PGE2) signaling through its Gαs-coupled EP2 receptor subtype; however, the truly selective EP2 antagonists did not emerge until 2011. These small molecules provide game-changing tools to better understand the EP2 receptor in inflammation-associated conditions. Their applications in preclinical models also reshape our knowledge of PGE2/EP2 signaling as a node of inflammation in health and disease. As we celebrate the 10-year anniversary of this breakthrough, the exploration of their potential as drug candidates for next-generation anti-inflammatory therapies has just begun. The first decade of EP2 antagonists passes, while their future looks brighter than ever.
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Affiliation(s)
- Madison N Sluter
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
| | - Ruida Hou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
| | - Lexiao Li
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
| | - Nelufar Yasmen
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
| | - Ying Yu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
| | - Jiawang Liu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
- Medicinal Chemistry Core, Office of Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
| | - Jianxiong Jiang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
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24
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Aluko OM, Iroegbu JD, Ijomone OM, Umukoro S. Methyl Jasmonate: Behavioral and Molecular Implications in Neurological Disorders. CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2021; 19:220-232. [PMID: 33888651 PMCID: PMC8077066 DOI: 10.9758/cpn.2021.19.2.220] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 10/27/2020] [Accepted: 10/28/2020] [Indexed: 01/04/2023]
Abstract
Methyl jasmonate (MJ) is a derivative of the jasmonate family which is found in most tropical regions of the world and present in many fruits and vegetables such as grapevines, tomato, rice, and sugarcane. MJ is a cyclopentanone phytohormone that plays a vital role in defense against stress and pathogens in plants. This has led to its isolation from plants for studies in animals. Many of these studies have been carried out to evaluate its therapeutic effects on behavioral and neurochemical functions. It has however been proposed to have beneficial potential over a wide range of neurological disorders. Hence, this review aims to provide an overview of the neuroprotective properties of MJ and its probable mechanisms of ameliorating neurological disorders. The information used for this review was sourced from research articles and scientific databases using 'methyl jasmonate', 'behavior', 'neuroprotection', 'neurodegenerative diseases', and 'mechanisms' as search words. The review highlights its influences on behavioral patterns of anxiety, aggression, depression, memory, psychotic, and stress. The molecular mechanisms such as modulation of the antioxidant defense, inflammatory biomarkers, neurotransmitter regulation, and neuronal regeneration, underlying its actions in managing neurodegenerative diseases like Alzheimer's and Parkinson's diseases are also discussed. This review, therefore, provides a detailed evaluation of methyl jasmonate as a potential neuroprotective compound with the ability to modify behavioral and molecular biomarkers underlying neurological disorders. Hence, MJ could be modeled as a guided treatment for the management of brain diseases.
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Affiliation(s)
- Oritoke Modupe Aluko
- Department of Physiology, School of Health and Health Technology, Federal University of Technology, Akure, Nigeria.,The Neuro-Lab, School of Health and Health Technology, Federal University of Technology, Akure, Nigeria.,Department of Pharmacology and Therapeutics, University of Ibadan, Ibadan, Nigeria
| | - Joy Dubem Iroegbu
- The Neuro-Lab, School of Health and Health Technology, Federal University of Technology, Akure, Nigeria
| | - Omamuyovwi Meashack Ijomone
- The Neuro-Lab, School of Health and Health Technology, Federal University of Technology, Akure, Nigeria.,Department of Human Anatomy, School of Health and Health Technology, Federal University of Technology, Akure, Nigeria
| | - Solomon Umukoro
- Department of Pharmacology and Therapeutics, University of Ibadan, Ibadan, Nigeria
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25
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Yang S, Yang Y, Chen C, Wang H, Ai Q, Lin M, Zeng Q, Zhang Y, Gao Y, Li X, Chen N. The Anti-Neuroinflammatory Effect of Fuzi and Ganjiang Extraction on LPS-Induced BV2 Microglia and Its Intervention Function on Depression-Like Behavior of Cancer-Related Fatigue Model Mice. Front Pharmacol 2021; 12:670586. [PMID: 34122094 PMCID: PMC8193093 DOI: 10.3389/fphar.2021.670586] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 05/04/2021] [Indexed: 11/17/2022] Open
Abstract
The Chinese herb couple Fuzi and Ganjiang (FG) has been a classic combination of traditional Chinese medicine that is commonly used clinically in China for nearly 2000 years. Traditional Chinese medicine suggests that FG can treat various ailments, including heart failure, fatigue, gastrointestinal upset, and depression. Neuroinflammation is one of the main pathogenesis of many neurodegenerative diseases in which microglia cells play a critical role in the occurrence and development of neuroinflammation. FG has been clinically proven to have an efficient therapeutic effect on depression and other neurological disorders, but its mechanism remains unknown. Cancer-related fatigue (CRF) is a serious threat to the quality of life of cancer patients and is characterized by both physical and psychological fatigue. Recent studies have found that neuroinflammation is a key inducement leading to the occurrence and development of CRF. Traditional Chinese medicine theory believes that extreme fatigue and depressive symptoms of CRF are related to Yang deficiency, and the application of Yang tonic drugs such as Fuzi and Ganjiang can relieve CRF symptoms, but the underlying mechanisms remain unknown. In order to define whether FG can inhibit CRF depression-like behavior by suppressing neuroinflammation, we conducted a series of experimental studies in vitro and in vivo. According to the UPLC-Q-TOF/MSE results, we speculated that there were 49 compounds in the FG extraction, among which 30 compounds were derived from Fuzi and 19 compounds were derived from Ganjiang. Our research data showed that FG can effectively reduce the production of pro-inflammatory mediators IL-6, TNF-α, ROS, NO, and PGE2 and suppress the expression of iNOS and COX2, which were related to the inhibition of NF-κB/activation of Nrf2/HO-1 signaling pathways. In addition, our research results revealed that FG can improve the depression-like behavior performance of CRF model mice in the tail suspension test, open field test, elevated plus maze test, and forced swimming test, which were associated with the inhibition of the expression of inflammatory mediators iNOS and COX2 in the prefrontal cortex and hippocampus of CRF model mice. Those research results suggested that FG has a satisfactory effect on depression-like behavior of CRF, which was related to the inhibition of neuroinflammation.
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Affiliation(s)
- Songwei Yang
- Hunan University of Chinese Medicine and Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, Changsha, China
| | - Yantao Yang
- Hunan University of Chinese Medicine and Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, Changsha, China
| | - Cong Chen
- Hunan University of Chinese Medicine and Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, Changsha, China
| | - Huiqin Wang
- Hunan University of Chinese Medicine and Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, Changsha, China.,State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia and Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qidi Ai
- Hunan University of Chinese Medicine and Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, Changsha, China
| | - Meiyu Lin
- Hunan University of Chinese Medicine and Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, Changsha, China
| | - Qi Zeng
- Hunan University of Chinese Medicine and Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, Changsha, China
| | - Yi Zhang
- Hunan University of Chinese Medicine and Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, Changsha, China
| | - Yan Gao
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia and Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xun Li
- Hunan University of Chinese Medicine and Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, Changsha, China
| | - Naihong Chen
- Hunan University of Chinese Medicine and Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, Changsha, China.,State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia and Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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26
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Inhibition of 2-Arachidonoylglycerol Metabolism Alleviates Neuropathology and Improves Cognitive Function in a Tau Mouse Model of Alzheimer's Disease. Mol Neurobiol 2021; 58:4122-4133. [PMID: 33939165 DOI: 10.1007/s12035-021-02400-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 04/21/2021] [Indexed: 10/21/2022]
Abstract
Alzheimer's disease (AD) is the most common cause of dementia, which affects more than 5 million individuals in the USA. Unfortunately, no effective therapies are currently available to prevent development of AD or to halt progression of the disease. It has been proposed that monoacylglycerol lipase (MAGL), the key enzyme degrading the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, is a therapeutic target for AD based on the studies using the APP transgenic models of AD. While inhibition of 2-AG metabolism mitigates β-amyloid (Aβ) neuropathology, it is still not clear whether inactivation of MAGL alleviates tauopathies as accumulation and deposition of intracellular hyperphosphorylated tau protein are the neuropathological hallmark of AD. Here we show that JZL184, a potent MAGL inhibitor, significantly reduced proinflammatory cytokines, astrogliosis, phosphorylated GSK3β and tau, cleaved caspase-3, and phosphorylated NF-kB while it elevated PPARγ in P301S/PS19 mice, a tau mouse model of AD. Importantly, tau transgenic mice treated with JZL184 displayed improvements in spatial learning and memory retention. In addition, inactivation of MAGL ameliorates deteriorations in expression of synaptic proteins in P301S/PS19 mice. Our results provide further evidence that MAGL is a promising therapeutic target for AD.
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27
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Sharma S, Tiarks G, Haight J, Bassuk AG. Neuropathophysiological Mechanisms and Treatment Strategies for Post-traumatic Epilepsy. Front Mol Neurosci 2021; 14:612073. [PMID: 33708071 PMCID: PMC7940684 DOI: 10.3389/fnmol.2021.612073] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 01/26/2021] [Indexed: 12/11/2022] Open
Abstract
Traumatic brain injury (TBI) is a leading cause of death in young adults and a risk factor for acquired epilepsy. Severe TBI, after a period of time, causes numerous neuropsychiatric and neurodegenerative problems with varying comorbidities; and brain homeostasis may never be restored. As a consequence of disrupted equilibrium, neuropathological changes such as circuit remodeling, reorganization of neural networks, changes in structural and functional plasticity, predisposition to synchronized activity, and post-translational modification of synaptic proteins may begin to dominate the brain. These pathological changes, over the course of time, contribute to conditions like Alzheimer disease, dementia, anxiety disorders, and post-traumatic epilepsy (PTE). PTE is one of the most common, devastating complications of TBI; and of those affected by a severe TBI, more than 50% develop PTE. The etiopathology and mechanisms of PTE are either unknown or poorly understood, which makes treatment challenging. Although anti-epileptic drugs (AEDs) are used as preventive strategies to manage TBI, control acute seizures and prevent development of PTE, their efficacy in PTE remains controversial. In this review, we discuss novel mechanisms and risk factors underlying PTE. We also discuss dysfunctions of neurovascular unit, cell-specific neuroinflammatory mediators and immune response factors that are vital for epileptogenesis after TBI. Finally, we describe current and novel treatments and management strategies for preventing PTE.
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Affiliation(s)
- Shaunik Sharma
- Medical Laboratories, Department of Pediatrics, University of Iowa, Iowa City, IA, United States
| | - Grant Tiarks
- Medical Laboratories, Department of Pediatrics, University of Iowa, Iowa City, IA, United States
| | - Joseph Haight
- Medical Laboratories, Department of Pediatrics, University of Iowa, Iowa City, IA, United States
| | - Alexander G Bassuk
- Medical Laboratories, Department of Pediatrics, University of Iowa, Iowa City, IA, United States
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28
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Figus FA, Piga M, Azzolin I, McConnell R, Iagnocco A. Rheumatoid arthritis: Extra-articular manifestations and comorbidities. Autoimmun Rev 2021; 20:102776. [PMID: 33609792 DOI: 10.1016/j.autrev.2021.102776] [Citation(s) in RCA: 247] [Impact Index Per Article: 61.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 12/27/2020] [Indexed: 12/20/2022]
Abstract
Although synovitis is the pathological hallmark of rheumatoid arthritis (RA), many extra-articular manifestations (EMs) and comorbidities likely occur due to the complex, chronic, inflammatory, and autoimmune features of RA. Cardiovascular (CV) disease is the most common cause of death in patients with RA. Compared to the general population, patients with RA have twice the risk of myocardial infarction and up to 50% increased CV mortality risk. Severe and prolonged disease activity, genetics, and inflammation (e.g. CRP, ACPA, cytokines, matrix-degrading enzymes) play important roles in CV disease and atheroscleroticdamage. The second major cause of death in patients with RA is respiratory disease, which occurs in 30-40% of patients. RA may affect the lung interstitium, airways, and pleurae, while pulmonary vascular involvement is less frequent. Central and peripheral nervous system involvement is usually due to small vessel vasculitis, joint damage, or drug toxicity. There is also evidence that microvascular cerebral damage caused by systemic inflammation is associated with the development of Alzheimer's disease and vascular dementia. Some observational studies have hinted how Disease Modified Anti-Rheumatic Drugs and biologics could reduce the incidence of dementia. Primary gastrointestinal and renal involvements are rare and often relate to drug therapy. To minimize morbidity and mortality, physicians must manage RA disease activity (treat-to-target) and monitor risk factors and concomitant conditions (e.g. smoking cessation; weight regulation; monitoring blood pressure, lipids, thyroid hormone, folic acid and homocysteine; screening for depression, anxiety, atlantoaxial instability, and atherosclerosis). This article aims to provide an overview of the most prevalent and important EMs and comorbidities associated with RA.
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Affiliation(s)
- Fabiana Assunta Figus
- Academic Rheumatology Centre, MFRU and Dipartimento Scienze Cliniche e Biologiche, Università degli Studi di Torino, Torino, Italy
| | - Matteo Piga
- Rheumatology Unit, University Clinic and AOU of Cagliari, Monserrato, Italy
| | - Irene Azzolin
- Academic Rheumatology Centre, MFRU and Dipartimento Scienze Cliniche e Biologiche, Università degli Studi di Torino, Torino, Italy
| | | | - Annamaria Iagnocco
- Academic Rheumatology Centre, MFRU and Dipartimento Scienze Cliniche e Biologiche, Università degli Studi di Torino, Torino, Italy.
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29
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Scheinman SB, Zaldua S, Dada A, Krochmaliuk K, Dye K, Marottoli FM, Thatcher GRJ, Tai LM. Systemic Candesartan Treatment Modulates Behavior, Synaptic Protein Levels, and Neuroinflammation in Female Mice That Express Human APOE4. Front Neurosci 2021; 15:628403. [PMID: 33642985 PMCID: PMC7902885 DOI: 10.3389/fnins.2021.628403] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 01/20/2021] [Indexed: 11/26/2022] Open
Abstract
Evidence suggests that angiotensin receptor blockers (ARBs) could be beneficial for Alzheimer’s disease (AD) patients independent of any effects on hypertension. However, studies in rodent models directly testing the activity of ARB treatment on behavior and AD-relevent pathology including neuroinflammation, Aβ levels, and cerebrovascular function, have produced mixed results. APOE4 is a major genetic risk factor for AD and has been linked to many of the same functions as those purported to be modulated by ARB treatment. Therefore, evaluating the effects of ARB treatment on behavior and AD-relevant pathology in mice that express human APOE4 could provide important information on whether to further develop ARBs for AD therapy. In this study, we treated female and male mice that express the human APOE4 gene in the absence (E4FAD−) or presence (E4FAD+) of high Aβ levels with the ARB prodrug candesartan cilexetil for a duration of 4 months. Compared to vehicle, candesartan treatment resulted in greater memory-relevant behavior and higher hippocampal presynaptic protein levels in female, but not male, E4FAD− and E4FAD+ mice. The beneficial effects of candesartan in female E4FAD− and E4FAD+ mice occurred in tandem with lower GFAP and Iba1 levels in the hippocampus, whereas there were no effects on markers of cerebrovascular function and Aβ levels. Collectively, these data imply that the effects of ARBs on AD-relevant pathology may be modulated in part by the interaction between APOE genotype and biological sex. Thus, the further development of ARBs could provide therapeutic options for targeting neuroinflammation in female APOE4 carriers.
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Affiliation(s)
- Sarah B Scheinman
- Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, United States
| | - Steve Zaldua
- Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, United States
| | - Adedoyin Dada
- Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, United States
| | - Kateryna Krochmaliuk
- Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, United States
| | - Katherine Dye
- UICentre, University of Illinois at Chicago, Chicago, IL, United States
| | - Felecia M Marottoli
- Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, United States
| | - Gregory R J Thatcher
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, United States
| | - Leon M Tai
- Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, United States
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30
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Casaril AM, Domingues M, Lourenço DDA, Vieira B, Begnini K, Corcini CD, França RT, Varela Junior AS, Seixas FK, Collares T, Lenardão EJ, Savegnago L. 3-[(4-chlorophenyl)selanyl]-1-methyl-1H-indole ameliorates long-lasting depression- and anxiogenic-like behaviors and cognitive impairment in post-septic mice: Involvement of neuroimmune and oxidative hallmarks. Chem Biol Interact 2020; 331:109278. [PMID: 33038329 DOI: 10.1016/j.cbi.2020.109278] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 08/26/2020] [Accepted: 09/28/2020] [Indexed: 11/30/2022]
Abstract
Only in the last decade the long-term consequences of sepsis started to be studied and even less attention has been given to the treatment of psychological symptoms of sepsis survivors. It is estimated that 60% of sepsis survivors have psychological disturbances, including depression, anxiety, and cognitive impairment. Although the causative factors remain largely poorly understood, blood-brain barrier (BBB) disturbances, neuroinflammation, and oxidative stress have been investigated. Therefore, we sought to explore if the immunomodulatory and antioxidant selenocompound 3-[(4-chlorophenyl)selanyl]-1-methyl-1H-indole (CMI) would be able to ameliorate long-term behavioral and biochemical alterations in sepsis survivors male Swiss mice. CMI treatment (1 mg/kg, given orally for seven consecutive days) attenuated depression- and anxiogenic-like behaviors and cognitive impairment present one month after the induction of sepsis (lipopolysaccharide, 5 mg/kg intraperitoneally). Meantime, CMI treatment modulated the number of neutrophils and levels of reactive species in neutrophils, lymphocytes, and monocytes. In addition, peripheral markers of liver and kidneys dysfunction (AST, ALT, urea, and creatinine) were reduced after CMI treatment in post-septic mice. Notably, CMI treatment to non-septic mice did not alter AST, ALT, urea, and creatinine levels, indicating the absence of acute hepatotoxicity and nephrotoxicity following CMI treatment. Noteworthy, CMI ameliorated BBB dysfunction induced by sepsis, modulating the expression of inflammation-associated genes (NFκB, IL-1β, TNF-α, IDO, COX-2, iNOS, and BDNF) and markers of oxidative stress (reactive species, nitric oxide, and lipid peroxidation levels) in the prefrontal cortices and hippocampi of mice. In conclusion, we unraveled crucial molecular pathways that are impaired in post-septic mice and we present CMI as a promising therapeutic candidate aimed to manage the long-lasting behavioral alterations of sepsis survivors to improve their quality of life.
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Affiliation(s)
- Angela Maria Casaril
- Technological Development Center, Division of Biotechnology, Neurobiotechology Research Group, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Micaela Domingues
- Technological Development Center, Division of Biotechnology, Neurobiotechology Research Group, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Darling de Andrade Lourenço
- Technological Development Center, Division of Biotechnology, Neurobiotechology Research Group, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Beatriz Vieira
- Center of Chemical, Pharmaceutical and Food Sciences, Laboratory of Clean Organic Synthesis, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Karine Begnini
- Technological Development Center, Division of Biotechnology, Cancer Biotechnology Laboratory, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Carine Dahl Corcini
- Center for Animal Reproduction, Faculty of Veterinary Medicine, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Raqueli Teresinha França
- Center for Animal Reproduction, Faculty of Veterinary Medicine, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Antônio Sergio Varela Junior
- Center for Animal Reproduction, Faculty of Veterinary Medicine, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Fabiana Kӧmmling Seixas
- Technological Development Center, Division of Biotechnology, Cancer Biotechnology Laboratory, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Tiago Collares
- Technological Development Center, Division of Biotechnology, Cancer Biotechnology Laboratory, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Eder João Lenardão
- Center of Chemical, Pharmaceutical and Food Sciences, Laboratory of Clean Organic Synthesis, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Lucielli Savegnago
- Technological Development Center, Division of Biotechnology, Neurobiotechology Research Group, Federal University of Pelotas, Pelotas, RS, Brazil.
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Zhang RY, Tu JB, Ran RT, Zhang WX, Tan Q, Tang P, Kuang T, Cheng SQ, Chen CZ, Jiang XJ, Chen C, Han TL, Zhang T, Cao XQ, Peng B, Zhang H, Xia YY. Using the Metabolome to Understand the Mechanisms Linking Chronic Arsenic Exposure to Microglia Activation, and Learning and Memory Impairment. Neurotox Res 2020; 39:720-739. [PMID: 32955723 DOI: 10.1007/s12640-020-00286-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 08/28/2020] [Accepted: 09/07/2020] [Indexed: 12/19/2022]
Abstract
The activation of microglia is a hallmark of neuroinflammation and contributes to various neurodegenerative diseases. Chronic inorganic arsenic exposure is associated with impaired cognitive ability and increased risk of neurodegeneration. The present study aimed to investigate whether chronic inorganic arsenic-induced learning and memory impairment was associated with microglial activation, and how organic (DMAV 600 μM, MMAV 0.1 μM) and inorganic arsenic (NaAsO2 0.6 μM) affect the microglia. Male C57BL/6J mice were divided into two groups: a control group and a group exposed to arsenic in their drinking water (50 mg/L NaAsO2 for 24 weeks). The Morris water maze was performed to analyze neuro-behavior and transmission electron microscopy was used to assess alterations in cellular ultra-structures. Hematoxylin-eosin and Nissl staining were used to observe pathological changes in the cerebral cortex and hippocampus. Flow cytometry was used to reveal the polarization of the arsenic-treated microglia phenotype and GC-MS was used to assess metabolomic differences in the in vitro microglia BV-2 cell line model derived from mice. The results showed learning and memory impairments and activation of microglia in the cerebral cortex and dentate gyrus (DG) zone of the hippocampus, in mice chronically exposed to arsenic. Flow cytometry demonstrated that BV-2 cells were activated with the treatment of different arsenic species. The GC-MS data showed three important metabolites to be at different levels according to the different arsenic species used to treat the microglia. These included tyrosine, arachidonic acid, and citric acid. Metabolite pathway analysis showed that a metabolic pathways associated with tyrosine metabolism, the dopaminergic synapse, Parkinson's disease, and the citrate cycle were differentially affected when comparing exposure to organic arsenic and inorganic arsenic. Organic arsenic MMAV was predominantly pro-inflammatory, and inorganic arsenic exposure contributed to energy metabolism disruptions in BV-2 microglia. Our findings provide novel insight into understanding the neurotoxicity mechanisms of chronic arsenic exposure and reveal the changes of the metabolome in response to exposure to different arsenic species in the microglia.
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Affiliation(s)
- Rui-Yuan Zhang
- Department of Occupational and Environmental Hygiene, School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, People's Republic of China
| | - Jie-Bai Tu
- Department of Occupational and Environmental Hygiene, School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, People's Republic of China
| | - Rui-Tu Ran
- Department of Urinary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Wen-Xuan Zhang
- Department of Occupational and Environmental Hygiene, School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, People's Republic of China
| | - Qiang Tan
- Department of Occupational and Environmental Hygiene, School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, People's Republic of China
| | - Ping Tang
- Department of Occupational and Environmental Hygiene, School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, People's Republic of China
| | - Tao Kuang
- Department of Occupational and Environmental Hygiene, School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, People's Republic of China
| | - Shu-Qun Cheng
- Department of Occupational and Environmental Hygiene, School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, People's Republic of China
| | - Cheng-Zhi Chen
- Department of Occupational and Environmental Hygiene, School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, People's Republic of China
| | - Xue-Jun Jiang
- Department of Occupational and Environmental Hygiene, School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, People's Republic of China
| | - Chang Chen
- Institute of Life Sciences, Chongqing Medical University, Chongqing, People's Republic of China
| | - Ting-Li Han
- Institute of Life Sciences, Chongqing Medical University, Chongqing, People's Republic of China.,State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing Medical University, Chongqing, People's Republic of China
| | - Ting Zhang
- State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing Medical University, Chongqing, People's Republic of China
| | - Xian-Qing Cao
- Department of Occupational and Environmental Hygiene, School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, People's Republic of China
| | - Bin Peng
- Department of Statistics, School of Public Health and Management, Chongqing Medical University, Chongqing, People's Republic of China
| | - Hua Zhang
- Institute of Life Sciences, Chongqing Medical University, Chongqing, People's Republic of China.,Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Yin-Yin Xia
- Department of Occupational and Environmental Hygiene, School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, People's Republic of China.
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Ardeshiri MR, Beheshti SA, Beheshti F, Hosseini M, Akbari E. Curcumin modulates long term potentiation in lipopolysaccharide-treated rats. PHARMANUTRITION 2020; 13:100195. [DOI: 10.1016/j.phanu.2020.100195] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Ajayi AM, Chidebe EO, Ben-Azu B, Umukoro S. Chrysophyllum albidum (African star apple) fruit-supplemented diet enhances cognitive functions and attenuates lipopolysaccharide-induced memory impairment, oxidative stress, and release of proinflammatory cytokines. NUTRIRE : REVISTA DE SOCIEDADE BRASILEIRA DE ALIMENTACAO E NUTRICAO = JOURNAL OF THE BRAZILIAN SOCIETY OF FOOD AND NUTRITION 2020; 45:20. [PMID: 38624427 PMCID: PMC7448960 DOI: 10.1186/s41110-020-00123-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Accepted: 08/16/2020] [Indexed: 12/19/2022]
Abstract
Purpose Fruit-based supplement has an important role in protecting the brain against oxido-inflammatory stress. Chrysophyllum albidum fruit contained several phytonutrients that possess antioxidants and anti-inflammatory properties. Hence, this study investigated the effect of C. albidum fruit supplemented diet (CAFD) on cognitive functions and lipopolysaccharide (LPS)-induced memory impairment and oxido-inflammatory response in mice. Methods Mice were randomized into two experiments. Experiment 1 with naïve mice contained four groups (n = 6) while experiment 2 with LPS contains five groups (n = 6). Mice in experiments 1 and 2 were fed on CAFD (5%, 10%, and 20%) in naïve (6 weeks) and LPS (250 μg/kg, i.p.) in the 7th week, respectively. Cognitive performance was tested using Y-maze test (YMT) and novel object recognition test (NORT) in the naïve and LPS mice. Brain samples were obtained for determination of oxido-inflammatory parameters and acetylcholinesterase activity. Results The CAFD significantly enhanced cognitive performance in the YMT and NORT in naïve and LPS mice, as evidenced by increased % alternation and discrimination index, respectively. CAFD supplementation significantly reduced acetylcholinesterase enzyme activity while it attenuated depletion of reduced glutathione and catalase activities in brains of naive and LPS-treated animals. The CAFD significantly reduced LPS-induced increased malondialdehyde levels in mice brains. CAFD supplementation significantly attenuated LPS-induced pro-inflammatory cytokines (IL-6, TNF-α) in mice brains. Conclusion Chrysophyllum albidum fruit supplementation in diet enhances memory function and prevents cognitive deficits induced by LPS via mechanisms associated with inhibition of oxidative stress-related processes, acetylcholinesterase activity, and pro-inflammatory mediators.
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Affiliation(s)
- Abayomi Mayowa Ajayi
- Neuropharmacology Unit, Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, University of Ibadan, Ibadan, Oyo State Nigeria
| | - Emmanuel Oyinyechukwu Chidebe
- Neuropharmacology Unit, Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, University of Ibadan, Ibadan, Oyo State Nigeria
| | - Benneth Ben-Azu
- Neuropharmacology Unit, Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, University of Ibadan, Ibadan, Oyo State Nigeria
- Department of Pharmacology, Faculty of Basic Medical Sciences, PAMO University of Medical Sciences, Port Harcourt, Rivers State Nigeria
| | - Solomon Umukoro
- Neuropharmacology Unit, Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, University of Ibadan, Ibadan, Oyo State Nigeria
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Moyano P, Sanjuan J, García JM, Anadon MJ, Naval MV, Sola E, García J, Frejo MT, Pino JD. Dysregulation of prostaglandine E2 and BDNF signaling mediated by estrogenic dysfunction induces primary hippocampal neuronal cell death after single and repeated paraquat treatment. Food Chem Toxicol 2020; 144:111611. [PMID: 32738378 DOI: 10.1016/j.fct.2020.111611] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 07/05/2020] [Accepted: 07/13/2020] [Indexed: 01/01/2023]
Abstract
Paraquat (PQ) produces hippocampal neuronal cell death and cognitive dysfunctions after unique and continued exposure, but the mechanisms are not understood. Primary hippocampal wildtype or βAPP-Tau silenced cells were co-treated with PQ with or without E2, N-acetylcysteine (NAC), NS-398 (cyclooxygenase-2 inhibitor), MF63 (PGES-1 inhibitor) and/or recombinant brain-derived neurotrophic factor (BDNF) during one- and fourteen-days to studied PQ effect on prostaglandin E2 (PGE2) and BDNF signaling and their involvement in hyperphosphorylated Tau (pTau) and amyloid-beta (Aβ) protein formation, and oxidative stress generation, that lead to neuronal cell loss through estrogenic disruption, as a possible mechanism of cognitive dysfunctions produced by PQ. Our results indicate that PQ overexpressed cyclooxygenase-2 that leads to an increase of PGE2 and alters the expression of EP1-3 receptor subtypes. PQ induced also a decrease of proBDNF and mature BDNF levels and altered P75NTR and tropomyosin receptor kinase B (TrkB) expression. PQ induced PGE2 and BDNF signaling dysfunction, mediated through estrogenic disruption, leading to Aβ and pTau proteins synthesis, oxidative stress generation and finally to cell death. Our research provides relevant information to explain PQ hippocampal neurotoxic effects, indicating a probable explanation of the cognitive dysfunction observed and suggests new therapeutic strategies to protect against PQ toxic effects.
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Affiliation(s)
- Paula Moyano
- Department of Pharmacology and Toxicology, Veterinary School, Complutense University of Madrid, 28040, Madrid, Spain
| | - Javier Sanjuan
- Department of Pharmacology and Toxicology, Veterinary School, Complutense University of Madrid, 28040, Madrid, Spain
| | - José Manuel García
- Department of Pharmacology and Toxicology, Veterinary School, Complutense University of Madrid, 28040, Madrid, Spain
| | - María José Anadon
- Department of Legal Medicine, Psychiatry and Pathology, Medical School, Complutense University of Madrid, 28041, Madrid, Spain
| | - Maria Victoria Naval
- Department of Pharmacology, Pharmacognosy and Botany, Pharmacy School, Complutense University of Madrid, 28041, Madrid, Spain
| | - Emma Sola
- Department of Legal Medicine, Psychiatry and Pathology, Medical School, Complutense University of Madrid, 28041, Madrid, Spain
| | - Jimena García
- Department of Pharmacology, Health Sciences School, Alfonso X University, 28691, Madrid, Spain
| | - María Teresa Frejo
- Department of Pharmacology and Toxicology, Veterinary School, Complutense University of Madrid, 28040, Madrid, Spain
| | - Javier Del Pino
- Department of Pharmacology and Toxicology, Veterinary School, Complutense University of Madrid, 28040, Madrid, Spain.
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Rodríguez-Gómez JA, Kavanagh E, Engskog-Vlachos P, Engskog MK, Herrera AJ, Espinosa-Oliva AM, Joseph B, Hajji N, Venero JL, Burguillos MA. Microglia: Agents of the CNS Pro-Inflammatory Response. Cells 2020; 9:E1717. [PMID: 32709045 PMCID: PMC7407646 DOI: 10.3390/cells9071717] [Citation(s) in RCA: 216] [Impact Index Per Article: 43.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 07/14/2020] [Accepted: 07/15/2020] [Indexed: 12/21/2022] Open
Abstract
The pro-inflammatory immune response driven by microglia is a key contributor to the pathogenesis of several neurodegenerative diseases. Though the research of microglia spans over a century, the last two decades have increased our understanding exponentially. Here, we discuss the phenotypic transformation from homeostatic microglia towards reactive microglia, initiated by specific ligand binding to pattern recognition receptors including toll-like receptor-4 (TLR4) or triggering receptors expressed on myeloid cells-2 (TREM2), as well as pro-inflammatory signaling pathways triggered such as the caspase-mediated immune response. Additionally, new research disciplines such as epigenetics and immunometabolism have provided us with a more holistic view of how changes in DNA methylation, microRNAs, and the metabolome may influence the pro-inflammatory response. This review aimed to discuss our current knowledge of pro-inflammatory microglia from different angles, including recent research highlights such as the role of exosomes in spreading neuroinflammation and emerging techniques in microglia research including positron emission tomography (PET) scanning and the use of human microglia generated from induced pluripotent stem cells (iPSCs). Finally, we also discuss current thoughts on the impact of pro-inflammatory microglia in neurodegenerative diseases.
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Affiliation(s)
- José A. Rodríguez-Gómez
- Institute of Biomedicine of Seville (IBIS)-Hospital Universitario Virgen del Rocío/CSIC/University of Seville, 41012 Seville, Spain; (J.A.R.-G.); (A.J.H.); (A.M.E.-O.); (J.L.V.)
- Department of Medical Physiology and Biophysics, Faculty of Medicine, University of Seville, 41009 Sevilla, Spain
| | - Edel Kavanagh
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain;
| | - Pinelopi Engskog-Vlachos
- Institute of Environmental Medicine, Toxicology Unit, Karolinska Institute, 17177 Stockholm, Sweden; (P.E.-V.); (B.J.)
| | - Mikael K.R. Engskog
- Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry, Uppsala University, 751 23 Uppsala, Sweden;
| | - Antonio J. Herrera
- Institute of Biomedicine of Seville (IBIS)-Hospital Universitario Virgen del Rocío/CSIC/University of Seville, 41012 Seville, Spain; (J.A.R.-G.); (A.J.H.); (A.M.E.-O.); (J.L.V.)
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain;
| | - Ana M. Espinosa-Oliva
- Institute of Biomedicine of Seville (IBIS)-Hospital Universitario Virgen del Rocío/CSIC/University of Seville, 41012 Seville, Spain; (J.A.R.-G.); (A.J.H.); (A.M.E.-O.); (J.L.V.)
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain;
| | - Bertrand Joseph
- Institute of Environmental Medicine, Toxicology Unit, Karolinska Institute, 17177 Stockholm, Sweden; (P.E.-V.); (B.J.)
| | - Nabil Hajji
- Division of Brain Sciences, The John Fulcher Molecular Neuro-Oncology Laboratory, Imperial College London, London W12 ONN, UK;
| | - José L. Venero
- Institute of Biomedicine of Seville (IBIS)-Hospital Universitario Virgen del Rocío/CSIC/University of Seville, 41012 Seville, Spain; (J.A.R.-G.); (A.J.H.); (A.M.E.-O.); (J.L.V.)
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain;
| | - Miguel A. Burguillos
- Institute of Biomedicine of Seville (IBIS)-Hospital Universitario Virgen del Rocío/CSIC/University of Seville, 41012 Seville, Spain; (J.A.R.-G.); (A.J.H.); (A.M.E.-O.); (J.L.V.)
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain;
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Correa J, Ronchetti S, Labombarda F, De Nicola AF, Pietranera L. Activation of the G Protein-Coupled Estrogen Receptor (GPER) Increases Neurogenesis and Ameliorates Neuroinflammation in the Hippocampus of Male Spontaneously Hypertensive Rats. Cell Mol Neurobiol 2020; 40:711-723. [PMID: 31784921 PMCID: PMC11448800 DOI: 10.1007/s10571-019-00766-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 11/22/2019] [Indexed: 01/20/2023]
Abstract
It is known that spontaneously hypertensive rats (SHR) present a marked encephalopathy, targeting vulnerable regions such as the hippocampus. Abnormalities of the hippocampus of SHR include decreased neurogenesis in the dentate gyrus (DG), partial loss of neurons in the hilus of the DG, micro and astrogliosis and inflammation. It is also known that 17β-estradiol (E2) exert neuroprotective effects and prevent hippocampal abnormalities of SHR. The effects of E2 may involve a variety of mechanisms, including intracellular receptors of the ERα and ERβ subtypes or membrane-located receptors, such as the G protein-coupled estradiol receptor (GPER). We have now investigated the protective role of GPER in SHR employing its synthetic agonist G1. To accomplish this objective, 5 month-old male SHR received 150 μg/day of G1 during 2 weeks. At the end of this period, we analyzed neuronal progenitors by staining for doublecortin (DCX), and counted the number of glial fibrillary acidic protein (GFAP)-labeled astrocytes and Iba1-stained microglial cells by computerized image analysis. We found that G1 activation of GPER increased DCX+ cells in the DG and reduced GFAP+ astrogliosis and Iba1+ microgliosis in the CA1 region of hippocampus. We also found that the high expression of proinflammatory makers IL1β and cyclooxygenase 2 (COX2) of SHR was decreased after G1 treatment, which correlated with a change of microglia phenotype from the activated to a resting morphology. Additionally, G1 treatment increased the anti-inflammatory factor TGFβ in SHR hippocampus. Altogether, our results suggest that activation of GPER plays a neuroprotective role on the encephalopathy of SHR, an outcome resembling E2 effects but avoiding secondary effects of the natural hormone.
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Affiliation(s)
- Julieta Correa
- Laboratory of Neuroendocrine Biochemistry, Instituto de Biología y Medicina Experimental, Vuelta de Obligado 2490, 1428, Buenos Aires, Argentina
| | - Santiago Ronchetti
- Laboratory of Neuroendocrine Biochemistry, Instituto de Biología y Medicina Experimental, Vuelta de Obligado 2490, 1428, Buenos Aires, Argentina
| | - Florencia Labombarda
- Laboratory of Neuroendocrine Biochemistry, Instituto de Biología y Medicina Experimental, Vuelta de Obligado 2490, 1428, Buenos Aires, Argentina
- Department of Human Biochemistry, Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina
| | - Alejandro F De Nicola
- Laboratory of Neuroendocrine Biochemistry, Instituto de Biología y Medicina Experimental, Vuelta de Obligado 2490, 1428, Buenos Aires, Argentina
- Department of Human Biochemistry, Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina
| | - Luciana Pietranera
- Laboratory of Neuroendocrine Biochemistry, Instituto de Biología y Medicina Experimental, Vuelta de Obligado 2490, 1428, Buenos Aires, Argentina.
- Department of Human Biochemistry, Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina.
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Ling QL, Akasaka H, Chen C, Haile CN, Winoske K, Ruan KH. The Protective Effects of Up-Regulating Prostacyclin Biosynthesis on Neuron Survival in Hippocampus. J Neuroimmune Pharmacol 2020; 15:292-308. [PMID: 31897976 DOI: 10.1007/s11481-019-09896-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 11/22/2019] [Indexed: 01/09/2023]
Abstract
Cellular arachidonic acid (AA), an unsaturated fatty acid found ubiquitously in plasma membranes, is metabolized to different prostanoids, such as prostacyclin (PGI2) and prostaglandin E2 (PGE2), by the three-step reactions coupling the upstream cyclooxygenase (COX) isoforms (COX-1 and COX-2) with the corresponding individual downstream synthases. While the vascular actions of these prostanoids are well-characterized, their specific roles in the hippocampus, a major brain area for memory, are poorly understood. The major obstacle for its understanding in the brain was to mimic the biosynthesis of each prostanoid. To solve the problem, we utilized Single-Chain Hybrid Enzyme Complexes (SCHECs), which could successfully control cellular AA metabolites to the desired PGI2 or PGE2. Our in vitro studies suggested that neurons with higher PGI2 content and lower PGE2 content exhibited survival protection and resistance to Amyloid-β-induced neurotoxicity. Further extending to an in vivo model, the hybrid of PGI2-producing transgenic mice and Alzheimer's disease (AD) mice showed restored long-term memory. These findings suggested that the vascular prostanoids, PGI2 and PGE2, exerted significant regulatory influences on neuronal protection (by PGI2), or damage (by PGE2) in the hippocampus, and raised a concern that the wide uses of aspirin in cardiovascular diseases may exert negative impacts on neurodegenerative protection. Graphic Abstract Our study intended to understand the crosstalk of prostanoids in the hippocampus, a major brain area impacted in AD, by using hybrid enzymes to redirect the synthesis of prostanoids to PGE2 and PGI2, respectively. Our data indicated that during inflammation, the vascular mediators, PGI2 and PGE2, exerted significant regulatory influences on neuronal protection (by PGI2), or damage (by PGE2) in the hippocampus. These findings also raised a concern that the widely uses of non-steroidal anti-inflammatory drugs in cardiovascular diseases may exert negative impacts on neurodegenerative protection.
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Affiliation(s)
- Qing-Lan Ling
- The Center for Experimental Therapeutics and Pharmacoinformatics, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Health and Biomedical Sciences Building 2, 4849 Calhoun Road, Room 3044, Houston, TX, 77204-5037, USA
| | - Hironari Akasaka
- The Center for Experimental Therapeutics and Pharmacoinformatics, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Health and Biomedical Sciences Building 2, 4849 Calhoun Road, Room 3044, Houston, TX, 77204-5037, USA
| | - Chang Chen
- The Center for Experimental Therapeutics and Pharmacoinformatics, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Health and Biomedical Sciences Building 2, 4849 Calhoun Road, Room 3044, Houston, TX, 77204-5037, USA
- Department of Anesthesia, Zhongnan Hospital of Wuhan University, Wuhan, 430071, People's Republic of China
| | - Colin N Haile
- University of Houston Animal Behavior Core Facility, Texas Institute for Measurement, Evaluation and Statistics (TIMES), Department of Psychology, University of Houston, Houston, TX, 77204, USA
| | - Kevin Winoske
- University of Houston Animal Behavior Core Facility, Texas Institute for Measurement, Evaluation and Statistics (TIMES), Department of Psychology, University of Houston, Houston, TX, 77204, USA
| | - Ke-He Ruan
- The Center for Experimental Therapeutics and Pharmacoinformatics, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Health and Biomedical Sciences Building 2, 4849 Calhoun Road, Room 3044, Houston, TX, 77204-5037, USA.
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Ramos AGB, de Menezes IRA, da Silva MSA, Torres Pessoa R, de Lacerda Neto LJ, Rocha Santos Passos F, Melo Coutinho HD, Iriti M, Quintans-Júnior LJ. Antiedematogenic and Anti-Inflammatory Activity of the Monoterpene Isopulegol and Its β-Cyclodextrin (β-CD) Inclusion Complex in Animal Inflammation Models. Foods 2020; 9:E630. [PMID: 32423148 PMCID: PMC7278878 DOI: 10.3390/foods9050630] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 05/06/2020] [Accepted: 05/08/2020] [Indexed: 01/15/2023] Open
Abstract
Isopulegol (ISO) is an alcoholic monoterpene widely found in different plant species, such as Melissa officinalis, and has already been reported to have a number of pharmacological properties. Like other terpenes, ISO is a highly volatile compound that is slightly soluble in water, so its inclusion into cyclodextrins (CDs) is an interesting approach to increase its solubility and bioavailability. Thus, our aim was to evaluate the antiedematogenic and anti-inflammatory activity of isopulegol and a β-cyclodextrin-isopulegol inclusion complex (ISO/β-CD) in rodent models. For the anti-inflammatory activity evaluation, antiedematogenic plethysmometry and acute (peritonitis and pleurisy), as well as chronic (cotton pellet-induced granuloma) anti-inflammatory models, were used. The docking procedure is used to evaluate, analyze, and predict their binding mode of interaction with H1 and Cox-2 receptors. The animals (n = 6) were divided into groups: ISO and ISO/β-CD, negative control (saline), and positive control (indomethacin and promethazine). ISO and ISO/β-CD were able to reduce acute inflammatory activity by decreasing albumin extravasation, leukocyte migration, and MPO concentration, and reducing exudate levels of IL-1β and TNF-α. ISO and ISO/β-CD significantly inhibited edematogenic activity in carrageenan- and dextran-induced paw edema. Moreover, both significantly reduced chronic inflammatory processes, given the lower weight and protein concentration of granulomas in the foreign body granulomatous inflammation model. The results suggest that the inclusion of ISO in β-cyclodextrins improves its pharmacological properties, with the histamine and prostaglandin pathways as probable mechanisms of inhibition, and also reinforces the anti-inflammatory profile of this terpene.
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Affiliation(s)
- Andreza Guedes Barbosa Ramos
- Department of Biological Chemistry, Regional University of Cariri, Crato 63105-000, Brazil; (A.G.B.R.); (I.R.A.d.M.); (M.S.A.d.S.); (R.T.P.); (L.J.d.L.N.); (H.D.M.C.)
| | - Irwin Rose Alencar de Menezes
- Department of Biological Chemistry, Regional University of Cariri, Crato 63105-000, Brazil; (A.G.B.R.); (I.R.A.d.M.); (M.S.A.d.S.); (R.T.P.); (L.J.d.L.N.); (H.D.M.C.)
| | - Maria Sanádia Alexandre da Silva
- Department of Biological Chemistry, Regional University of Cariri, Crato 63105-000, Brazil; (A.G.B.R.); (I.R.A.d.M.); (M.S.A.d.S.); (R.T.P.); (L.J.d.L.N.); (H.D.M.C.)
| | - Renata Torres Pessoa
- Department of Biological Chemistry, Regional University of Cariri, Crato 63105-000, Brazil; (A.G.B.R.); (I.R.A.d.M.); (M.S.A.d.S.); (R.T.P.); (L.J.d.L.N.); (H.D.M.C.)
| | - Luiz Jardelino de Lacerda Neto
- Department of Biological Chemistry, Regional University of Cariri, Crato 63105-000, Brazil; (A.G.B.R.); (I.R.A.d.M.); (M.S.A.d.S.); (R.T.P.); (L.J.d.L.N.); (H.D.M.C.)
| | - Fabíola Rocha Santos Passos
- Department of Physiology, Federal University of Sergipe, São Cristóvão, Aracaju - SE 49100-000, Brazil; (F.R.S.P.); (L.J.Q.-J.)
| | - Henrique Douglas Melo Coutinho
- Department of Biological Chemistry, Regional University of Cariri, Crato 63105-000, Brazil; (A.G.B.R.); (I.R.A.d.M.); (M.S.A.d.S.); (R.T.P.); (L.J.d.L.N.); (H.D.M.C.)
| | - Marcello Iriti
- Department of Agricultural and Environmental Sciences, Milan State University, via G. Celoria 2, 20133 Milan, Italy
| | - Lucindo José Quintans-Júnior
- Department of Physiology, Federal University of Sergipe, São Cristóvão, Aracaju - SE 49100-000, Brazil; (F.R.S.P.); (L.J.Q.-J.)
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Uddin MS, Kabir MT, Mamun AA, Barreto GE, Rashid M, Perveen A, Ashraf GM. Pharmacological approaches to mitigate neuroinflammation in Alzheimer's disease. Int Immunopharmacol 2020; 84:106479. [PMID: 32353686 DOI: 10.1016/j.intimp.2020.106479] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 03/13/2020] [Accepted: 04/02/2020] [Indexed: 12/12/2022]
Abstract
Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases characterized by the formation of extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). Growing evidence suggested that there is an association between neuronal dysfunction and neuroinflammation (NI) in AD, coordinated by the chronic activation of astrocytes and microglial cells along with the subsequent excessive generation of the proinflammatory molecule. Therefore, a better understanding of the relationship between the nervous and immune systems is important in order to delay or avert the neurodegenerative events of AD. The inflammatory/immune pathways and the mechanisms to control these pathways may provide a novel arena to develop new drugs in order to target NI in AD. In this review, we represent the influence of cellular mediators which are involved in the NI process, with regards to the progression of AD. We also discuss the processes and the current status of multiple anti-inflammatory agents which are used in AD and have gone through or going through clinical trials. Moreover, new prospects for targeting NI in the development of AD drugs have also been highlighted.
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Affiliation(s)
- Md Sahab Uddin
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh; Pharmakon Neuroscience Research Network, Dhaka, Bangladesh.
| | | | - Abdullah Al Mamun
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh; Pharmakon Neuroscience Research Network, Dhaka, Bangladesh
| | - George E Barreto
- Department of Biological Sciences, University of Limerick, Limerick, Ireland; Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile
| | - Mamunur Rashid
- Department of Pharmacy, University of Rajshahi, Rajshahi, Bangladesh
| | - Asma Perveen
- School of Life Sciences, The Glocal University, Saharanpur, Uttar Pradesh 247121, India
| | - Ghulam Md Ashraf
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
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40
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Downregulation of peripheral PTGS2/COX-2 in response to valproate treatment in patients with epilepsy. Sci Rep 2020; 10:2546. [PMID: 32054883 PMCID: PMC7018850 DOI: 10.1038/s41598-020-59259-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 01/22/2020] [Indexed: 12/18/2022] Open
Abstract
Antiepileptic drug therapy has significant inter-patient variability in response towards it. The current study aims to understand this variability at the molecular level using microarray-based analysis of peripheral blood gene expression profiles of patients receiving valproate (VA) monotherapy. Only 10 unique genes were found to be differentially expressed in VA responders (n = 15) and 6 genes in the non-responders (n = 8) (fold-change >2, p < 0.05). PTGS2 which encodes cyclooxygenase-2, COX-2, showed downregulation in the responders compared to the non-responders. PTGS2/COX-2 mRNA profiles in the two groups corresponded to their plasma profiles of the COX-2 product, prostaglandin E2 (PGE2). Since COX-2 is believed to regulate P-glycoprotein (P-gp), a multidrug efflux transporter over-expressed at the blood-brain barrier (BBB) in drug-resistant epilepsy, the pathway connecting COX-2 and P-gp was further explored in vitro. Investigation of the effect of VA upon the brain endothelial cells (hCMEC/D3) in hyperexcitatory conditions confirmed suppression of COX-2-dependent P-gp upregulation by VA. Our findings suggest that COX-2 downregulation by VA may suppress seizure-mediated P-gp upregulation at the BBB leading to enhanced drug delivery to the brain in the responders. Our work provides insight into the association of peripheral PTGS2/COX-2 expression with VA efficacy and the role of COX-2 as a potential therapeutic target for developing efficacious antiepileptic treatment.
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Casaril AM, Domingues M, Bampi SR, Lourenço DDA, Smaniotto TÂ, Segatto N, Vieira B, Seixas FK, Collares T, Lenardão EJ, Savegnago L. The antioxidant and immunomodulatory compound 3-[(4-chlorophenyl)selanyl]-1-methyl-1H-indole attenuates depression-like behavior and cognitive impairment developed in a mouse model of breast tumor. Brain Behav Immun 2020; 84:229-241. [PMID: 31837417 DOI: 10.1016/j.bbi.2019.12.005] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 11/20/2019] [Accepted: 12/09/2019] [Indexed: 12/15/2022] Open
Abstract
Psychiatric alterations are often found in patients with breast cancer even before the initiation of adjuvant therapy, resulting in a poor quality of life. It has become accepted that neuroinflammation and oxidative stress are involved in the pathophysiology of depression and cognitive impairment. Herein, we tested the hypothesis that treatment with the antioxidant and immunomodulatory selenium-containing compound 3-[(4-chlorophenyl)selanyl]-1-methyl-1H-indole (CMI)could attenuate behavioral and neurochemical alterations in a mammary (4T1) tumor model. Female BALB/c mice were subcutaneously inoculated with 4T1 cancer cells (1 × 105 cells/mice) or PBS. From days 14 to 20, mice received daily gavage with canola oil or CMI. On day 21, mice were submitted to behavioral tests followed by euthanasia. We found that CMI did not alter tumor growth, body weight, and body temperature in tumor-bearing mice. Importantly, treatment with CMI abrogated tumor-induced depression-like behavior and cognitive impairment. By the time CMI improved the behavioral alterations, it had reduced tumor-induced neuroinflammation (altered expression of NFκB, IL-1β, TNF-α, IL-10, IDO, and COX-2) and oxidative stress (altered expression of iNOS and Nrf2, and levels of reactive species, nitric oxide, lipid peroxidation, and superoxide dismutase activity) in the prefrontal cortices and hippocampi of mice. A molecular docking approach suggested the ability of CMI to inhibit the activity of iNOS and COX-2. Together, our results indicate that CMI treatment may attenuate depression and cognitive impairment in 4T1 tumor-bearing mice, and be a groundbreaking strategy for the treatment of cancer-related psychiatric symptoms to improve the quality of life of cancer patients.
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Affiliation(s)
- Angela Maria Casaril
- Technological Development Center, Division of Biotechnology, Neurobiotechology Research Group, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Micaela Domingues
- Technological Development Center, Division of Biotechnology, Neurobiotechology Research Group, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Suely Ribeiro Bampi
- Technological Development Center, Division of Biotechnology, Neurobiotechology Research Group, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Darling de Andrade Lourenço
- Technological Development Center, Division of Biotechnology, Neurobiotechology Research Group, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Thiago Ângelo Smaniotto
- Technological Development Center, Division of Biotechnology, Neurobiotechology Research Group, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Natália Segatto
- Technological Development Center, Division of Biotechnology, Molecular and Cellular Oncology Research Group and Functional Genomics Laboratory, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Beatriz Vieira
- Center of Chemical, Pharmaceutical and Food Sciences, Laboratory of Clean Organic Synthesis, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Fabiana K Seixas
- Technological Development Center, Division of Biotechnology, Molecular and Cellular Oncology Research Group and Functional Genomics Laboratory, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Tiago Collares
- Technological Development Center, Division of Biotechnology, Molecular and Cellular Oncology Research Group and Functional Genomics Laboratory, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Eder João Lenardão
- Center of Chemical, Pharmaceutical and Food Sciences, Laboratory of Clean Organic Synthesis, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Lucielli Savegnago
- Technological Development Center, Division of Biotechnology, Neurobiotechology Research Group, Federal University of Pelotas, Pelotas, RS, Brazil.
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42
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Ji NN, Wu L, Shao BM, Meng QX, Xu JN, Zhu HW, Zhang YM. CTL-Derived Granzyme B Participates in Hippocampal Neuronal Apoptosis Induced by Cardiac Arrest and Resuscitation in Rats. Front Neurol 2019; 10:1306. [PMID: 31920929 PMCID: PMC6920252 DOI: 10.3389/fneur.2019.01306] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2019] [Accepted: 11/26/2019] [Indexed: 12/13/2022] Open
Abstract
Hippocampal neuronal apoptosis is a devastating consequence of cardiac arrest (CA) and subsequent cardiopulmonary resuscitation (CPR). In this study, we assessed the contribution of cytotoxic T lymphocyte (CTL)-derived toxic mediator granzyme B (Gra-b) to the hippocampal neuronal apoptosis following CA/CPR in rats. Rats that experienced CA/CPA presented with cytosomal shrinkage, dense cytoplasm, and intensive eosinophilic staining in the CA1 region of dorsal hippocampus. CA/CPR rats also exhibited inability in spatial navigation and a local infiltration of peripheral CD8+ T cells into the hippocampus. The protein levels of Gra-b, cleaved Caspase-3, and cleaved PARP1 were significantly elevated in rats undergoing CA/CPR. Pretreatment with Gra-b inhibitor suppressed Gra-b release, attenuated hippocampal neuronal apoptosis, as well as improved cognitive impairment. Together, this study indicates that CTL-derived Gra-b is involved in the CA/CPR-induced neuronal apoptosis, and pharmacological manipulation of Gra-b may represent a novel avenue for the treatment of brain injury following CA/CPR.
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Affiliation(s)
- Ning-Ning Ji
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China
| | - Liang Wu
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China.,Anesthesiology Department of the First People's Hospital of Xuzhou, Xuzhou, China
| | - Bo-Ming Shao
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China
| | - Qing-Xiang Meng
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China
| | - Jin-Nan Xu
- School of Anesthesiology, Xuzhou Medical University, Xuzhou, China
| | - Hao-Wen Zhu
- School of Anesthesiology, Xuzhou Medical University, Xuzhou, China
| | - Yong-Mei Zhang
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China.,School of Anesthesiology, Xuzhou Medical University, Xuzhou, China
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Seeger DR, Golovko SA, Golovko MY. Blood-Brain Barrier Is the Major Site for a Rapid and Dramatic Prostanoid Increase upon Brain Global Ischemia. Lipids 2019; 55:79-85. [PMID: 31814137 DOI: 10.1002/lipd.12205] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 11/12/2019] [Accepted: 11/15/2019] [Indexed: 12/17/2022]
Abstract
We and others have demonstrated a rapid and dramatic increase in brain prostanoids upon decapitation-induced brain global ischemia and injury. However, the mechanism for this induction, including the cell types involved, are unknown. In the present study, we have validated and applied a pharmacological approach to inhibit prostanoid synthesis in the blood-brain barrier including endothelial cells. Our results indicate that a nonspecific cyclooxygenase (COX) inhibitor, ketorolac, does not pass the blood-brain barrier and does not enter red blood cells but penetrates endothelial cells. Ketorolac treatment did not affect basal prostanoid levels but completely prevented prostanoid induction upon global ischemia. These data indicate that basal prostanoids are synthesized in brain parenchyma cells, while inducible prostanoids are synthesized in the blood-brain barrier, most likely in endothelial cells. However, future studies with cell and COX isoform-specific gene ablation are needed to further validate this conclusion. These findings identify endothelial cells as a possible target for the development of pharmacological approaches to selectively attenuate inducible prostanoid pools without affecting basal levels under brain ischemia, trauma, surgery, and other related conditions.
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Affiliation(s)
- Drew R Seeger
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, 1301 N. Columbia Rd., Grand Forks, ND, 58202-9037, USA
| | - Svetlana A Golovko
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, 1301 N. Columbia Rd., Grand Forks, ND, 58202-9037, USA
| | - Mikhail Y Golovko
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, 1301 N. Columbia Rd., Grand Forks, ND, 58202-9037, USA
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44
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Some Biogenetic Considerations Regarding the Marine Natural Product (-)-Mucosin. Molecules 2019; 24:molecules24224147. [PMID: 31731797 PMCID: PMC6891381 DOI: 10.3390/molecules24224147] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 11/13/2019] [Accepted: 11/14/2019] [Indexed: 02/06/2023] Open
Abstract
Recently, the identity of the marine hydrindane natural product (−)-mucosin was revised to the trans-fused structure 6, thereby providing a biogenetic puzzle that remains to be solved. We are now disseminating some of our insights with regard to the possible machinery delivering the established architecture. Aspects with regard to various modes of cyclization in terms of concerted versus stepwise processes are held up against the enzymatic apparatus known to be working on arachidonic acid (8). To provide a contrast to the tentative polyunsaturated fatty acid biogenesis, the structural pattern featured in (−)-mucosin (6) is compared to some marine hydrinane natural products of professed polyketide descent. Our appraisal points to a different origin and strengthens the hypothesis of a polyunsaturated fatty acids (PUFA) as the progenitor of (−)-mucosin (6).
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45
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Grimsey NL, Savinainen JR, Attili B, Ahamed M. Regulating membrane lipid levels at the synapse by small-molecule inhibitors of monoacylglycerol lipase: new developments in therapeutic and PET imaging applications. Drug Discov Today 2019; 25:330-343. [PMID: 31622747 DOI: 10.1016/j.drudis.2019.10.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 09/17/2019] [Accepted: 10/09/2019] [Indexed: 12/14/2022]
Abstract
Monoacylglycerol lipase (MAGL) is a major endocannabinoid hydrolyzing enzyme and can be regulated to control endogenous lipid levels in the brain. This review highlights the pharmacological roles and in vivo PET imaging of MAGL in brain.
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Affiliation(s)
- Natasha L Grimsey
- Department of Pharmacology and Clinical Pharmacology, and Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, New Zealand
| | - Juha R Savinainen
- Institute of Biomedicine, Faculty of Health Sciences, The University of Eastern Finland, Finland
| | - Bala Attili
- Department of Radiology, The University of Cambridge, UK
| | - Muneer Ahamed
- ARC Centre for Innovation in Biomedical Imaging Technology, Centre for Advanced Imaging, The University of Queensland, Australia.
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46
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Golia MT, Poggini S, Alboni S, Garofalo S, Ciano Albanese N, Viglione A, Ajmone-Cat MA, St-Pierre A, Brunello N, Limatola C, Branchi I, Maggi L. Interplay between inflammation and neural plasticity: Both immune activation and suppression impair LTP and BDNF expression. Brain Behav Immun 2019; 81:484-494. [PMID: 31279682 DOI: 10.1016/j.bbi.2019.07.003] [Citation(s) in RCA: 94] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Revised: 06/29/2019] [Accepted: 07/03/2019] [Indexed: 01/11/2023] Open
Abstract
An increasing number of studies show that both inflammation and neural plasticity act as key players in the vulnerability and recovery from psychiatric disorders and neurodegenerative diseases. However, the interplay between these two players has been limitedly explored. In fact, while a few studies reported an immune activation, others conveyed an immune suppression, associated with an impairment in neural plasticity. Therefore, we hypothesized that deviations in inflammatory levels in both directions may impair neural plasticity. We tested this hypothesis experimentally, by acute treatment of C57BL/6 adult male mice with different doses of two inflammatory modulators: lipopolysaccharide (LPS), an endotoxin, and ibuprofen (IBU), a nonselective cyclooxygenase inhibitor, which are respectively a pro- and an anti-inflammatory agent. The results showed that LPS and IBU have different effects on behavior and inflammatory response. LPS treatment induced a reduction of body temperature, a decrease of body weight and a reduced food and liquid intake. In addition, it led to increased levels of inflammatory markers expression, both in the total hippocampus and in isolated microglia cells, including Interleukin (IL)-1β, and enhanced the concentration of prostaglandin E2 (PGE2). On the other hand, IBU increased the level of anti-inflammatory markers, decreased tryptophan 2,3-dioxygenase (TDO2), the first step in the kynurenine pathway known to be activated during inflammatory conditions, and PGE2 levels. Though LPS and IBU administration differently affected mediators related with pro- or anti-inflammatory responses, they produced overlapping effects on neural plasticity. Indeed, higher doses of both LPS and IBU induced a statistically significant decrease in the amplitude of long-term potentiation (LTP), in Brain-Derived Neurotrophic Factor (BDNF) expression levels and in the phosphorylation of the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor subunit GluR1, compared to the control group. Such effect appears to be dose-dependent since only the higher, but not the lower, dose of both compounds led to a plasticity impairment. Overall, the present findings indicate that acute treatment with pro- and anti-inflammatory agents impair neural plasticity in a dose dependent manner.
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Affiliation(s)
- Maria Teresa Golia
- Department of Physiology and Pharmacology, Laboratory Affiliated to Istituto Pasteur-Italy, Sapienza University of Rome, Italy
| | - Silvia Poggini
- Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy
| | - Silvia Alboni
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Stefano Garofalo
- Department of Physiology and Pharmacology, Laboratory Affiliated to Istituto Pasteur-Italy, Sapienza University of Rome, Italy
| | - Naomi Ciano Albanese
- Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy
| | - Aurelia Viglione
- Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy; PhD Program in Neuroscience, Scuola Superiore di Pisa, Pisa, Italy
| | | | - Abygaël St-Pierre
- Axe Neurosciences, Centre de recherche du CHU de Québec, Québec, Canada
| | - Nicoletta Brunello
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Cristina Limatola
- Department of Physiology and Pharmacology, Laboratory Affiliated to Istituto Pasteur-Italy, Sapienza University of Rome, Italy; IRCCS Neuromed, Pozzilli, Isernia, Italy
| | - Igor Branchi
- Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy
| | - Laura Maggi
- Department of Physiology and Pharmacology, Laboratory Affiliated to Istituto Pasteur-Italy, Sapienza University of Rome, Italy.
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Min C, Bang WJ, Kim M, Oh DJ, Choi HG. Rheumatoid arthritis and neurodegenerative dementia: a nested case-control study and a follow-up study using a national sample cohort. Clin Rheumatol 2019; 39:159-166. [PMID: 31523786 DOI: 10.1007/s10067-019-04769-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Revised: 08/28/2019] [Accepted: 09/03/2019] [Indexed: 12/29/2022]
Abstract
OBJECTIVES The present study evaluated the associations between rheumatoid arthritis (RA) and neurodegenerative dementia using a Korean national sample cohort. METHODS We designed two studies using the Korean National Health Insurance Service-National Sample Cohort from 2002 to 2013. Study I included participants with dementia matched 1:4 with controls and analyzed the participants' history of RA. Study II included participants with RA matched 1:4 with controls and analyzed the occurrence of dementia. RA was defined by the presence of relevant ICD-10 codes (M05 or M06) and medication histories. Neurodegenerative dementia was defined using ICD-10 codes (G30 or F00). Crude and adjusted odds ratios (ORs) were analyzed using conditional logistic regression analyses. Crude and adjusted hazard ratios (HRs) were analyzed using the stratified Cox proportional hazard model. Subgroup analyses were performed on groups stratified by age and sex. RESULTS The adjusted ORs for RA were 0.96 (95% CI = 0.78-1.16, P = 0.644) in the dementia group in study I. The adjusted HRs for dementia were 0.91 (95% CI = 0.76-1.10, P = 0.319) in the RA group in study II. No subgroup analysis reached the statistical significance level. CONCLUSION We could not identify any significant relationship between RA and dementia.Key Points• Two studies were conducted to identify the relationship between rheumatoid arthritis and dementia using national cohort data.• Neither study showed any association between rheumatoid arthritis and dementia.
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Affiliation(s)
- Chanyang Min
- Hallym Data Science Laboratory, Hallym University College of Medicine, Anyang, South Korea.,Department of Otorhinolaryngology-Head & Neck Surgery, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, 22, Gwanpyeong-ro 170beon-gil, Dongan-gu, Anyang-si, Gyeonggi-do, 14068, Republic of Korea.,Graduate School of Public Health, Seoul National University, Seoul, South Korea
| | - Woo Jin Bang
- Department of Urology, Hallym University Sacred Heart Hospital, Anyang, South Korea
| | - Miyoung Kim
- Department of Laboratory Medicine, Hallym University College of Medicine, Anyang, South Korea
| | - Dong Jun Oh
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Hyo Geun Choi
- Hallym Data Science Laboratory, Hallym University College of Medicine, Anyang, South Korea. .,Department of Otorhinolaryngology-Head & Neck Surgery, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, 22, Gwanpyeong-ro 170beon-gil, Dongan-gu, Anyang-si, Gyeonggi-do, 14068, Republic of Korea.
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48
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Fu WY, Wang X, Ip NY. Targeting Neuroinflammation as a Therapeutic Strategy for Alzheimer's Disease: Mechanisms, Drug Candidates, and New Opportunities. ACS Chem Neurosci 2019; 10:872-879. [PMID: 30221933 DOI: 10.1021/acschemneuro.8b00402] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Alzheimer's disease is a progressive neurodegenerative disease, and its incidence is expected to increase owing to the aging population worldwide. Current therapies merely provide symptomatic relief. Therefore, interventions for AD that delay the disease onset or progression are urgently required. Recent genomics and functional studies suggest that immune/inflammatory pathways are involved in the pathogenesis of AD. Although many anti-inflammatory drug candidates have undergone clinical trials, most have failed. This might be because of our limited understanding of the pathological mechanisms of neuroinflammation in AD. However, recent advances in the understanding of immune/inflammatory pathways in AD and their regulatory mechanisms could open up new avenues for drug development targeting neuroinflammation. In this Review, we discuss the mechanisms and status of different anti-inflammatory drug candidates for AD that have undergone or are undergoing clinical trials and explore new opportunities for targeting neuroinflammation in AD drug development.
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Affiliation(s)
| | | | - Nancy Y. Ip
- Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, HKUST Shenzhen Research Institute, Shenzhen, Guangdong, China
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49
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Mukherjee A, Mehta BK, Sen KK, Banerjee S. Metabolic syndrome-associated cognitive decline in mice: Role of minocycline. Indian J Pharmacol 2018; 50:61-68. [PMID: 30100653 PMCID: PMC6044134 DOI: 10.4103/ijp.ijp_110_18] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
OBJECTIVE: The objective of the study was to characterize the mechanism associated with metabolic syndrome (MetS)-associated cognitive decline and determine the effect of minocycline on the above condition in mice. MATERIALS AND METHODS: We developed a HFHC diet-induced MetS model in mice. Diagnostic characteristics of MetS including waist circumference, lipid levels, blood pressure, and fasting blood glucose were measured in these Swiss albino mice. Cognitive parameters were measured using passive avoidance and elevated plus maze test. Hippocampal acetylcholine esterase (AchE), reduced glutathione (GSH), and cytokine levels were measured and histopathological evaluation conducted. The MetS animals were administered minocycline (50 mg/kg; 10 days) and the above parameters were measured. RESULTS: We successfully induced MetS using HFHC diet in mice. Animals showed significantly higher fasting blood glucose levels (P < 0.001), systolic blood pressure (P < 0.01), waist circumference (P < 0.001), low-density lipoprotein (P < 0.001), and triglyceride (P < 0.01) and reduced high density lipoprotein levels (P < 0.05) compared to control animals. Both scopolamine and MetS significantly lowered (P < 0.01) step-down latency and increased transfer latency (P < 0.001). MetS animals showed significantly higher AchE (P < 0.001) and tumor necrosis factor-α (P < 0.001) and Interleukin-1 β (P < 0.01) and lower GSH (P < 0.001) levels and reduced both CA1 (P < 0.001) and CA3 (P < 0.01) neuronal density compared to controls. Minocycline treatment partially reversed the above neurobehavioral and biochemical changes and improved hippocampal neuronal density in MetS animals. CONCLUSION: MetS led to hippocampal oxidative stress and neuroinflammatory changes with a corresponding loss of hippocampal neuronal density and cognitive decline. Anti-inflammatory and antioxidant property of minocycline may be responsible for its neuroprotective actions in these animals.
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Affiliation(s)
- Aniruddha Mukherjee
- Department of Pharmacology, Gupta College of Technological Sciences, Asansol, West Bengal, India
| | - Bina K Mehta
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, India
| | - Kalyan K Sen
- Department of Pharmacology, Gupta College of Technological Sciences, Asansol, West Bengal, India
| | - Sugato Banerjee
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, India
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Walker AK, Chang A, Ziegler AI, Dhillon HM, Vardy JL, Sloan EK. Low dose aspirin blocks breast cancer-induced cognitive impairment in mice. PLoS One 2018; 13:e0208593. [PMID: 30532184 PMCID: PMC6287899 DOI: 10.1371/journal.pone.0208593] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Accepted: 11/20/2018] [Indexed: 12/28/2022] Open
Abstract
Cancer patients with non-central nervous system tumors often suffer from cognitive impairment. While chemotherapy has long been attributed as the cause of these memory, learning and concentration difficulties, we recently observed cognitive impairment in cancer patients prior to treatment. This suggests the cancer alone may be sufficient to induce cognitive impairment, however the mechanisms are unknown. Here, we show that we can experimentally replicate the clinical phenomenon of cancer-associated cognitive impairment and we identify inflammation as a causal mechanism. We demonstrate that a peripheral tumor is sufficient to induce memory loss. Using an othotopic mouse model of breast cancer, we found that mice with 4T1.2 or EO771 mammary tumors had significantly poorer memory than mice without tumors. Memory impairment was independent of cancer-induced sickness behavior, which was only observed during the later stage of cancer progression in mice with high metastatic burden. Tumor-secreted factors were sufficient to induce memory impairment and pro-inflammatory cytokines were elevated in the plasma of tumor-bearing mice. Oral treatment with low-dose aspirin completely blocked tumor-induced memory impairment without affecting tumor-induced sickness or tumor growth, demonstrating a causal role for inflammation in cognitive impairment. These findings suggest that anti-inflammatories may be a safe and readily translatable strategy that could be used to prevent cancer-associated cognitive impairment in patients.
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Affiliation(s)
- Adam K. Walker
- Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
- Neuroscience Research Australia, Randwick, New South Wales, Australia
- School of Psychiatry, University of New South Wales, Randwick, New South Wales, Australia
- Division of Cancer Surgery, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
- * E-mail:
| | - Aeson Chang
- Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Alexandra I. Ziegler
- Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Haryana M. Dhillon
- Centre for Medical Psychology & Evidence-based Decision-Making, School of Psychology, Faculty of Science, University of Sydney, Camperdown, New South Wales, Australia
| | - Janette L. Vardy
- Concord Clinical School, Sydney Medical School, University of Sydney, Camperdown, New South Wales, Australia
- Concord Cancer Centre, Concord Repatriation General Hospital, Concord, New South Wales, Australia
| | - Erica K. Sloan
- Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
- Division of Cancer Surgery, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
- Cousins Center for PNI, UCLA Semel Institute, Jonsson Comprehensive Cancer Center, and UCLA AIDS Institute, University of California Los Angeles, Los Angeles, California, United states of America
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