Journal
NEUROBIOLOGY OF DISEASE
Volume 178, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2023.106027
Keywords
Epilepsy; Astrocytes; Microglia; Cytokines; Neurotransmission; Excitotoxicity; Blood brain barrier; Cognitive deficit
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Inflammatory molecules and their receptors are induced in epileptogenic foci, contributing to both the occurrence and development of seizures in drug-resistant epilepsies. Animal models have shown that activation of specific inflammatory signals in neurons or glial cells can modify seizure thresholds. Inflammatory mediators have CNS-specific neuromodulatory functions, which affect the inhibitory/excitatory balance in neural networks underlying seizures. Understanding these effects may lead to novel therapies for controlling drug-resistant seizures.
A large set of inflammatory molecules and their receptors are induced in epileptogenic foci of patients with pharmacoresistant epilepsies of structural etiologies or with refractory status epilepticus. Studies in animal models mimicking these clinical conditions have shown that the activation of specific inflammatory signallings in forebrain neurons or glial cells may modify seizure thresholds, thus contributing to both ictogenesis and epileptogenesis. The search for mechanisms underlying these effects has highlighted that inflammatory mediators have CNS-specific neuromodulatory functions, in addition to their canonical activation of immune responses for pathogen recognition and clearance. This review reports the neuromodulatory effects of inflammatory mediators and how they contribute to alter the inhibitory/excitatory balance in neural networks that underlie seizures. In particular, we describe key findings related to the ictogenic role of prototypical inflammatory cytokines (IL-1 beta and TNF) and danger signals (HMGB1), their modulatory effects of neuronal excitability, and the mechanisms underlying these effects. It will be discussed how harnessing these neuromodulatory properties of immune mediators may lead to novel therapies to control drug-resistant seizures.
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