The role of cytokines in the pathophysiology of epilepsy.
ABSTRACT Recent findings in experimental models and in the clinical setting highlight the possibility that inflammatory processes in the brain contribute to the etiopathogenesis of seizures and to the establishment of a chronic epileptic focus. Prototypical inflammatory cytokines such as IL-1 beta, TNF-alpha and IL-6 have been shown to be overexpressed in experimental models of seizures in brain areas of seizure generation and propagation, prominently by glia and to a lesser extent by neurons. Cytokines receptors are also upregulated, and the related intracellular signalling is activated, in both cell populations highlighting autocrine and paracrine actions of cytokines in the brain. Cytokines have been shown to profoundly affect seizures in rodents; in particular, IL-1 beta is endowed of proconvulsant activity in a large variety of seizure models. The recent demonstration of functional interactions between cytokines and classical neurotransmitters such as glutamate and GABA, suggest the possibility that these interactions underlie the cytokine-mediated changes in neuronal excitability, thus promoting seizure phenomena and the associated neuropathology. These findings point out at novel glio-neuronal communications in diseased conditions and highlight potential new targets for therapeutic intervention.
Neurologia i neurochirurgia polska 01/2011; 45(3):275-285. DOI:10.1016/S0028-3843(14)60080-3 · 0.54 Impact Factor
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ABSTRACT: Abstract Gene-regulatory network analysis is a powerful approach to elucidate the molecular processes and pathways underlying complex disease. Here we employ systems genetics approaches to characterize the genetic regulation of pathophysiological pathways in human temporal lobe epilepsy (TLE). Using surgically acquired hippocampi from 129 TLE patients, we identify a gene-regulatory network genetically associated with epilepsy that contains a specialized, highly expressed transcriptional module encoding proconvulsive cytokines and Toll-like receptor signalling genes. RNA sequencing analysis in a mouse model of TLE using 100 epileptic and 100 control hippocampi shows the proconvulsive module is preserved across-species, specific to the epileptic hippocampus and upregulated in chronic epilepsy. In the TLE patients, we map the trans-acting genetic control of this proconvulsive module to Sestrin 3 (SESN3), and demonstrate that SESN3 positively regulates the module in macrophages, microglia and neurons. Morpholino-mediated Sesn3 knockdown in zebrafish confirms the regulation of the transcriptional module, and attenuates chemically induced behavioural seizures in vivo. PMID: 25615886 [PubMed - as supplied by publisherNature Communications 01/2015; 6. DOI:10.1038/ncomms7031 · 10.74 Impact Factor
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ABSTRACT: Gene expression studies identified the interleukin-1 receptor type I (IL-1R1) as part of a pathway associated with a genetic predisposition to high alcohol consumption, and lack of the endogenous IL-1 receptor antagonist (IL-1ra) strongly reduced ethanol intake in mice. Here, we compared ethanol-mediated behaviors in mice lacking Il1rn or Il1r1. Deletion of Il1rn (the gene encoding IL-1ra) increases sensitivity to the sedative/hypnotic effects of ethanol and flurazepam and reduces severity of acute ethanol withdrawal. Conversely, deletion of Il1r1 (the gene encoding the IL-1 receptor type I, IL-1R1) reduces sensitivity to the sedative effects of ethanol and flurazepam and increases the severity of acute ethanol withdrawal. The sedative effects of ketamine and pentobarbital were not altered in the knockout (KO) strains. Ethanol intake and preference were not changed in mice lacking Il1r1 in three different tests of ethanol consumption. Recovery from ethanol-induced motor incoordination was only altered in female mice lacking Il1r1. Mice lacking Il1rn (but not Il1r1) showed increased ethanol clearance and decreased ethanol-induced conditioned taste aversion. The increased ethanol- and flurazepam-induced sedation in Il1rn KO mice was decreased by administration of IL-1ra (Kineret), and pre-treatment with Kineret also restored the severity of acute ethanol withdrawal. Ethanol-induced sedation and withdrawal severity were changed in opposite directions in the null mutants, indicating that these responses are likely regulated by IL-1R1 signaling, whereas ethanol intake and preference do not appear to be solely regulated by this pathway. Copyright © 2015. Published by Elsevier Ltd.Neuropharmacology 03/2015; DOI:10.1016/j.neuropharm.2015.03.015 · 4.82 Impact Factor