Chronic inflammation in refractory hippocampal sclerosis-related temporal lobe epilepsy

Gales, Jordan; Prayson, Richard A.

doi:10.1016/j.anndiagpath.2017.05.009

Cited by 33 publications

(29 citation statements)

References 30 publications

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“…Neuronal apoptosis and inflammatory response play critical roles in the development of epilepsy [6,25]. Chronic inflammation is a common component of hippocampal sclerosis-associated temporal lobe epilepsy [26]. miRNA is a novel regulator of the pathogenesis of temporal lobe epilepsy, which can have important effects on neuronal apoptosis, as well as affecting immune and inflammatory processes [15].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-27a-3p Downregulation Inhibits Inflammatory Response and Hippocampal Neuronal Cell Apoptosis by Upregulating Mitogen-Activated Protein Kinase 4 (MAP2K4) Expression in Epilepsy: In Vivo and In Vitro Studies

Lü

Zhou

Yang³

et al. 2019

Med Sci Monit

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Departmental sources Background: This study aimed to discover the effect and mechanism of microRNA-27a-3p (miR-27a-3p) in epilepsy. Material/Methods: To perform our investigation, in vivo and in vitro models of epilepsy were induced using kainic acid (KA). Expression of miR-27a-3p in the hippocampus of epileptic rats or normal rats or neuronal cells was detected using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Racine score was used to assess seizures in epileptic rats. Cell viability and cell apoptosis were analyzed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and flow cytometry. Enzyme-linked immunosorbent assay (ELISA) was performed to detect inflammatory factors expression. Results: Significantly higher expression of miR-27a-3p in the hippocampus of epileptic rats and in KA-induced neurons was observed. We found that miR-27a-3p inhibitor alleviated seizures in epileptic rats. miR-27a-3p inhibitor also inhibited apoptosis of hippocampal neurons in epileptic rats, promoted Bcl2 expression, and decreased Bax and Caspase3 expression. The results showed that miR-27a-3p inhibitor effectively reduced the expression levels of interleukin-1b (IL-1b), IL-6, and tumor necrosis factor-a (TNF-a) in hippocampal tissues of epileptic rats. Dual luciferase reporter assay showed that mitogen-activated protein kinase 4 (MAP2K4) was a direct target of miR-27a-3p. miR-27a-3p inhibitor significantly promoted the cell viability of KA-induced neurons, inhibited cell apoptosis, promoted the expression of Bcl-2, and decreased Bax and Caspase3 expression, and all these changes were abolished by MAP2K4-siRNA co-transfection. Conclusions: Our preliminary findings indicated that miR-27a-3p inhibitor protected against epilepsy-induced inflammatory response and hippocampal neuronal apoptosis by targeting MAP2K4.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-27a-3p Downregulation Inhibits Inflammatory Response and Hippocampal Neuronal Cell Apoptosis by Upregulating Mitogen-Activated Protein Kinase 4 (MAP2K4) Expression in Epilepsy: In Vivo and In Vitro Studies

Lü

Zhou

Yang³

et al. 2019

Med Sci Monit

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“…We chose to study the pilocarpine model in the latent phase, which comprises the period where epileptogenesis occurs (Löscher & Brandt, 2010;Pitkänen et al, 2007). Although previous studies have identified several mechanisms that participate in this phenomenon (Cho et al, 2015;Cloix & Hévor, 2009;Devinsky, Vezzani, Najjar, De Lanerolle, & Rogawski, 2013;Gales & Prayson, 2017;Parent et al, 1997;Ravizza, Balosso, & Vezzani, 2011;Rowley & Patel, 2013), all of these studies are hypothesis-driven and, therefore, biased toward the specific mechanism they sought to investigate. In the present study, we adopted two high throughput agnostic approaches capable of providing a view of the biological interactions occurring during the epileptogenic process in the pilocarpine model of MTLE.…”

Section: Discussionmentioning

confidence: 99%

“…An inflammatory response is frequently implicated in several neurological disorders (Akiyama et al, 2000;Chen et al, 2018;Crotti & Glass, 2015;Onore, Careaga, & Ashwood, 2012;Ray, Juranek, & Rai, 2016), including epilepsy (Devinsky et al, 2013;Gales & Prayson, 2017); however, it is often unclear whether inflammation is related to the cause or is a consequence of the pathological mechanism underlying these disorders. Here, we identified several upregulated pathways involved with inflammation, and the immune response in all areas and sub-fields analyzed.…”

Section: Discussionmentioning

confidence: 99%

Multi‐omics analysis suggests enhanced epileptogenesis in the Cornu Ammonis 3 of the pilocarpine model of mesial temporal lobe epilepsy

et al. 2020

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Mesial temporal lobe epilepsy (MTLE) is a chronic neurological disorder characterized by the occurrence of seizures, and histopathological abnormalities in the mesial temporal lobe structures, mainly hippocampal sclerosis (HS). We used a multi-omics approach to determine the profile of transcript and protein expression in the dorsal and ventral hippocampal dentate gyrus (DG) and Cornu Ammonis 3 (CA3) in an animal model of MTLE induced by pilocarpine. We performed label-free proteomics and RNAseq from laser-microdissected tissue isolated from pilocarpine-induced Wistar rats. We divided the DG and CA3 into dorsal and ventral areas and analyzed them separately. We performed a data integration analysis and evaluated enriched signaling pathways, as well as the integrated networks generated based on the gene ontology processes. Our results indicate differences in the transcriptomic and proteomic profiles among the DG and the CA3 subfields of the hippocampus. Moreover, our data suggest that epileptogenesis is enhanced in the CA3 region when compared to the DG, with most abnormalities in transcript and protein levels occurring in the CA3. Furthermore, our results show that the epileptogenesis in the pilocarpine model involves predominantly abnormal regulation of excitatory neuronal mechanisms mediated by N-methyl D-aspartate (NMDA) receptors, changes in the serotonin signaling, and neuronal activity controlled by calcium/calmodulin-dependent protein Amanda M. Canto and Alexandre H. B. Matos should be considered joint first author.

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“…CB2Rs play a well-documented role in reducing neuroinflammation in mouse models of neurological disease. 65,66 Given the reduction in inflammation that is observed following CB2R activation, treatments targeting CB2R might prove to be particularly efficacious in epilepsy disorders like MTLE. [60][61][62] This reduction in neuroinflammation has been associated with improved outcomes in these models.…”

Section: Discussionmentioning

confidence: 99%

“…[62][63][64] Several forms of drug-resistant epilepsy, such as mesial temporal lobe epilepsy (MTLE), are characterized by high levels of neuroinflammation. 65,66 Given the reduction in inflammation that is observed following CB2R activation, treatments targeting CB2R might prove to be particularly efficacious in epilepsy disorders like MTLE.…”

Section: Discussionmentioning

confidence: 99%

Reduced cannabinoid 2 receptor activity increases susceptibility to induced seizures in mice

2019

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Objective: The endocannabinoid system (ECS) is comprised of cannabinoid receptors 1 and 2 (CB1R and CB2R), endogenous ligands, and regulatory enzymes, and serves to regulate several important physiological functions throughout the brain and body. Recent evidence suggests that the ECS may be a promising target for the treatment of epilepsy, including epilepsy subtypes that arise from mutations in the voltage-gated sodium channel SCN1A. The objective of this study was to explore the effects of modulating CB2R activity on seizure susceptibility. Methods: We examined susceptibility to induced seizures using a number of paradigms in CB2R knockout mice (Cnr2 −/− ), and determined the effects of the CB2R agonist, JWH-133, and the CB2R antagonist, SR144528, on seizure susceptibility in wild-type mice. We also examined seizure susceptibility in Cnr2 mutants harboring the human SCN1A R1648H (RH) epilepsy mutation and performed Electroencephalography (EEG) analysis to determine whether the loss of CB2Rs would increase spontaneous seizure frequency in Scn1a RH mutant mice. Results: Both heterozygous (Cnr2 +/− ) and homozygous (Cnr2 −/− ) knockout mice exhibited increased susceptibility to pentylenetetrazole (PTZ)-induced seizures. The CB2R agonist JWH-133 did not significantly alter seizure susceptibility in wildtype mice; however, administration of the CB2R antagonist SR144528 resulted in increased susceptibility to PTZ-induced seizures. In offspring from a cross between the Cnr2 × RH lines, both Cnr2 and RH mutants were susceptible to PTZ-induced seizures; however, seizure susceptibility was not significantly increased in mutants expressing both mutations. No spontaneous seizures were observed in either RH or Cnr2/RH mutants during 336-504 hours of continuous EEG recordings. Significance: Our results demonstrate that reduced CB2R activity is associated with increased seizure susceptibility. CB2Rs might therefore provide a therapeutic target for the treatment of some forms of epilepsy. K E Y W O R D Scannabinoid 2 receptor, CB2R agonist, CB2R antagonist, SCN1A, seizure susceptibility 2360 | SHAPIRO et Al.

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Chronic inflammation in refractory hippocampal sclerosis-related temporal lobe epilepsy

Cited by 33 publications

References 30 publications

MicroRNA-27a-3p Downregulation Inhibits Inflammatory Response and Hippocampal Neuronal Cell Apoptosis by Upregulating Mitogen-Activated Protein Kinase 4 (MAP2K4) Expression in Epilepsy: In Vivo and In Vitro Studies

MicroRNA-27a-3p Downregulation Inhibits Inflammatory Response and Hippocampal Neuronal Cell Apoptosis by Upregulating Mitogen-Activated Protein Kinase 4 (MAP2K4) Expression in Epilepsy: In Vivo and In Vitro Studies

Multi‐omics analysis suggests enhanced epileptogenesis in the Cornu Ammonis 3 of the pilocarpine model of mesial temporal lobe epilepsy

Reduced cannabinoid 2 receptor activity increases susceptibility to induced seizures in mice

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