To investigate the role of purinergic P2 receptors under ischemia, we studied the effect of P2 receptor antagonists on synaptic transmission and mitogen-activated protein kinase (MAPK) activation under oxygen and glucose deprivation (OGD) in rat hippocampal slices. The effect of the P2 antagonists pyridoxalphosphate-6-azophenyl-2′,4′-disulfonate (PPADS, unselective, 30 μm), N 6-methyl-2′-deoxyadenosine-3′,5′-bisphosphate (MRS2179, selective for P2Y1 receptor, 10 μm), Brilliant Blue G (BBG, selective for P2X7 receptor, 1 μm), and 5-[[[(3-phenoxyphenyl)methyl][(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]carbonyl]-1,2,4-benzenetricarboxylic acid (A-317491, selective for P2X3 receptor, 10 μm), and of the newly synthesized P2X3 receptor antagonists 2-amino-9-(5-iodo-2-isopropyl-4-methoxybenzyl)adenine (PX21, 1 μm) and 2-amino-9-(5-iodo-2-isopropyl-4-methoxybenzyl)-N 6-methyladenine (PX24, 1 μm), on the depression of field excitatory postsynaptic potentials (fEPSPs) and anoxic depolarization (AD) elicited by 7 min of OGD were evaluated. All antagonists significantly prevented these effects. The extent of CA1 cell injury was assessed 3 h after the end of 7 min of OGD by propidium iodide staining. Substantial CA1 pyramidal neuronal damage, detected in untreated slices exposed to OGD injury, was significantly prevented by PPADS (30 μm), MRS2179 (10 μm), and BBG (1 μm). Western blot analysis showed that, 10 min after the end of the 7 min of OGD, extracellular signal-regulated kinase (ERK)1/2 MAPK activation was significantly increased. MRS2179, BBG, PPADS and A-317491 significantly counteracted ERK1/2 activation. Hippocampal slices incubated with the ERK1/2 inhibitors 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene (U0126, 10 μm) and α-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl) benzeneacetonitrile (SL327, 10 μm) showed significant fEPSP recovery after OGD and delayed AD, supporting the involvement of ERK1/2 in neuronal damage induced by OGD. These results indicate that subtypes of hippocampal P2 purinergic receptors have a harmful effect on neurotransmission in the CA1 hippocampus by participating in AD appearance and activation of ERK1/2.