Much progress has been made over the last few decades in the identification of new anti-epileptic drugs (AEDs). However, 30% of
epilepsy patients suffer poor seizure control. This underscores the need to identify alternative druggable
neurotransmitter systems and drugs with novel mechanisms of action. An emerging concept is that seizure generation involves a complex interplay between neurons and glial cells at the tripartite synapse and
neuroinflammation has been proposed as one of the main drivers of epileptogenesis. The
ATP-gated
purinergic receptor family is expressed throughout the brain and is functional on neurons and glial cells.
ATP is released in high amounts into the extracellular space after increased neuronal activity and during chronic
inflammation and cell death to act as a neuro- and gliotransmitter. Emerging work shows pharmacological targeting of
ATP-gated
purinergic P2 receptors can potently modulate seizure generation, inflammatory processes and seizure-induced brain damage. To date, work showing the functional contribution of P2 receptors has been mainly performed in animal models of acute
seizures, in particular, by targeting the ionotropic
P2X7 receptor subtype. Other ionotropic P2X and metabotropic P2Y receptor family members have also been implicated in
pathological processes following
seizures such as the
P2X4 receptor and the P2Y12 receptor. However, during
epilepsy, the characterization of P2 receptors was mostly restricted to the study of expressional changes of the different receptor subtypes. This review summarizes the work to date on
ATP-mediated signalling during
seizures and the functional impact of targeting the
ATP-gated
purinergic receptors on
seizures and seizure-induced pathology. This article is part of the Special Issue entitled '
Purines in Neurodegeneration and Neuroregeneration'.