The Metabotropic Purinergic P2Y Receptor Family as Novel Drug Target in Epilepsy

Abstract

Epilepsy encompasses a heterogeneous group of neurological syndromes which are characterized by recurrent seizures affecting over 60 million people worldwide. Current anti-epileptic drugs (AEDs) are mainly designed to target ion channels and/or GABA or glutamate receptors. Despite recent advances in drug development, however, pharmacoresistance in epilepsy remains as high as 30%, suggesting the need for the development of new AEDs with a non-classical mechanism of action. Neuroinflammation is increasingly recognized as one of the key players in seizure generation and in the maintenance of the epileptic phenotype. Consequently, targeting signaling molecules involved in inflammatory processes may represent new avenues to improve treatment in epilepsy. Nucleotides such as adenosine-5'-triphosphate (ATP) and uridine-5'-triphosphate (UTP) are released in the brain into the extracellular space during pathological conditions such as increased neuronal firing or cell death. Once released, these nucleotides bind to and activate specific purinergic receptors termed P2 receptors where they mediate the release of gliotransmitters and drive neuronal hyperexcitation and neuroinflammatory processes. This includes the fast acting ionotropic P2X channels and slower-acting G-protein-coupled P2Y receptors. While the expression and function of P2X receptors has been well-established in experimental models of epilepsy, emerging evidence is now also suggesting a prominent role for the P2Y receptor subfamily in seizure generation and the maintenance of epilepsy. In this review we discuss data supporting a role for the P2Y receptor family in epilepsy and the most recent finding demonstrating their involvement during seizure-induced pathology and in epilepsy.

Keywords: epilepsy; metabotropic P2Y receptors; pharmacoresistance; purinergic signaling; status epilepticus.

FIGURE 1

Divergent effects on seizures and seizure-induced pathology of different P2Y agonists. (A) Representative EEG traces recorded during intraamygdala KA-induced status epilepticus showing pro-convulsive effects of ADP treatment, while UTP acts as potent anti-convulsive. (B) UTP protects against neuronal cell death following status epilepticus, visualized with the neuronal-cell death marker Fluoro-Jade B. (C) Hypothetical model of P2Y receptor function during and after status epilepticus or damaging seizures. During and following status epilepticus, purines (e.g., ATP and UTP) are actively released from different cell types including neurons, astrocytes and microglia or enter the extracellular space from damaged/necrotic cells. While the activation of UTP/UDP-sensitive P2Y receptors (P2Y₂, P2Y₄, and P2Y₆) may has anticonvulsive and neuroprotective effects, the activation of ATP/ADP-sensitive P2Y receptors (P2Y₁ and P2Y₁₃) may be pro-convulsive. The role of P2Y₁₁ and P2Y₁₄ have not been studied so far and therefore are unknown. Counterintuitively, P2Y₁₂ is ATP/ADP-sensitive, but seems to be anticonvulsive and neuroprotective.