Context-Specific Switch from Anti- to Pro-epileptogenic Function of the P2Yl Receptor in Experimental Epilepsy.

Extracellular ATP activates inflammatory responses to tissue injury. It is also implicated in establishing lasting network hyperexcitability in the brain by acting upon independent receptor systems. Whereas the fast-acting P2X channels have well-established roles driving neuroinflammation and increasing hyperexcitability, the slower-acting metabotropic P2Y receptors have received much less attention. Recent studies of P2Y, receptor function in seizures and epilepsy have produced contradictory results, suggesting that the role of this receptor during seizure pathology may be highly sensitive to context. Here, by using male mice, we demonstrate that the metabotropic P2Y, receptor mediates either proconvulsive or anticonvulsive responses, dependent on the time point of activation in relation to the induction of status epilepticus. P2Y, deficiency or a P2Y, antagonist (MRS2500) administered before a chemoconvulsant, exacerbates epileptiform activity, whereas a P2Yj agonist (MRS2365) administered at this time point is anticonvulsant. When these drugs are administered after the onset of status epilepticus, however, their effect on seizure severity is reversed, with the antagonist now anticonvulsant and the agonist proconvulsant. This result was consistent across two different mouse models of status epilepticus (intraamygdala kainic acid and intraperitoneal pilocarpine). Pharmacologic P2Y, blockade during status epilepticus reduces also associated brain damage, delays the development of epilepsy and, when applied during epilepsy, suppresses spontaneous seizures, in mice. Our data show a context-specific role for P2Y, during seizure pathology and demonstrate that blocking P2Y, after status epilepticus and during epilepsy has potent anticonvulsive effects, suggesting that P2Y, may be a novel candidate for the treatment of drug-refractory status epilepticus and epilepsy. [ABSTRACT FROM AUTHOR]