Anales RANF

P.40 CONTEXT-SPECIFIC SWITCH FROM ANTI- TO PRO- EPILEPTOGENIC FUNCTION OF THE P2Y 1 RECEPTOR IN EXPERIMENTAL EPILEPSY M. Alves 1 , L. De Diego Garcia 1 , G. Conte1 1 , DC. Henshall 1,2 and T. Engel 1,2 1 .Department of Physiology and Medical Physics, RCSI, Dublin, Ireland; 2 .FutureNeuro Centre, RCSI, Dublin, Ireland. Extracellular ATP activates inflammatory responses to tissue injury and is also implicated in establishing lasting network hyperexcitability in the brain by acting upon independent receptor systems. Here, we demonstrate that the metabotropic P2Y 1 receptor mediates both pro- and anti-convulsive responses, depending on context. Using different mouse models of status epilepticus and genetic and pharmacologic tools, we show that activation of the P2Y 1 receptor prior to seizure onset is anticonvulsant. Once seizure activity has been triggered, however, activation of the P2Y 1 receptor is pro- convulsive. Pharmacologic P2Y 1 blockade during status epilepticus reduced seizure severity and attendant brain damage, delayed the development of epilepsy and, when applied during epilepsy, suppressed the occurrence of spontaneous seizures, in mice. Our data demonstrates that the effect of targeting P2Y 1 is dependent on the switching behavior of this metabotropic receptor and provides evidence that drugs targeting P2Y 1 may be useful in the treatment of drug refractory status epilepticus and epilepsy.