Increasing evidence supports the involvement of immune and inflammatory processes in the etiopathogenesis of
seizures. In particular, activation of innate immune mechanisms and the subsequent inflammatory responses, that are induced in the brain by
infection,
febrile seizures, neurotrauma,
stroke are well documented conditions associated with acute symptomatic
seizures and with a high risk of developing
epilepsy. A decade ago, pharmacological experiments showed that elevated brain levels of the anti-inflammatory molecule
IL-1 receptor antagonist reduced
seizures in
epilepsy models. This observation, together with the evidence of in situ induction of inflammatory mediators and their receptors in experimental and human epileptogenic brain tissue, established the proof-of-concept evidence that the activation of innate immunity and
inflammation in the brain are intrinsic features of the pathologic hyperexcitable tissue. Recent breakthroughs in understanding the molecular organization of the innate immune system first in macrophages, then in the different cell types of the CNS, together with pharmacological and genetic studies in
epilepsy models, showed that the activation of
IL-1 receptor/
Toll-like receptor (IL-1R/TLR) signaling significantly contributes to
seizures. IL-1R/TLR mediated pro-excitatory actions are elicited in the brain either by mimicking bacterial or
viral infections and inflammatory responses, or via the action of endogenous
ligands. These
ligands include proinflammatory
cytokines, such as IL-1beta, or danger signals, such as
HMGB1, released from activated or injured cells. The IL-1R/TLR signaling mediates rapid post-translational changes in voltage- and
ligand-gated ion channels that increase excitability, and transcriptional changes in genes involved in neurotransmission and synaptic plasticity that contribute to lower seizure thresholds chronically. The
anticonvulsant effects of inhibitors of the IL-1R/TLR signaling in various
seizures models suggest that this system could be targeted to inhibit
seizures in presently pharmaco-resistant
epilepsies.