In the present study, by using a unilateral mouse model of status epilepticus, we report an overall increase in the expression of the P2Y receptor family in the cortex following status epilepticus and that P2Y1 antagonism reduces harmful HFHA polyspiking during status epilepticus and protects the cortex from seizure-induced neurodegeneration. The gene discussed is P2RY1; the disease is status epilepticus.