Treatment of
epilepsy remains a clinical challenge, with >30% of patients not responding to current antiseizure drugs (ASDs). Moreover, currently available ASDs are merely symptomatic without altering significantly the progression of the disease.
Inflammation is increasingly recognized as playing an important role during the generation of hyperexcitable networks in the brain. Accordingly, the suppression of chronic
inflammation has been suggested as a promising therapeutic strategy to prevent epileptogenesis and to treat
drug-refractory epilepsy. As a consequence, a strong focus of ongoing research is identification of the mechanisms that contribute to sustained
inflammation in the brain during
epilepsy and whether these can be targeted.
ATP is released in response to several pathological stimuli, including increased neuronal activity within the central nervous system, where it functions as a neuro- and gliotransmitter. Once released,
ATP activates
purinergic P2 receptors, which are divided into metabotropic P2Y and ionotropic P2X receptors, driving inflammatory processes. Evidence from experimental models and patients demonstrates widespread expression changes of both P2Y and P2X receptors during
epilepsy, and critically, drugs targeting both receptor subtypes, in particular the P2Y1 and P2X7 subtypes, have been shown to possess both anticonvulsive and
antiepileptic potential. This review provides a detailed summary of the current evidence suggesting
ATP-gated receptors as novel
drug targets for
epilepsy and discusses how P2 receptor-driven
inflammation may contribute to the generation of
seizures and the development of
epilepsy.