The dual role of prostaglandin E(2) in excitotoxicity and preconditioning-induced neuroprotection.

Cyclooxygenase-2 is harmful in models of cerebral ischemia yet plays a protective role in preconditioning-induced ischemic tolerance in the heart. This study examined the mechanisms underlying cyclooxygenase-2-mediated neurotoxicity and preconditioning-induced neuroprotection in an in vitro model of cerebral ischemia. Inhibition of cyclooxygenase-2 protects cortical neuronal cultures from death induced by oxygen-glucose deprivation and reduces oxygen-glucose deprivation-induced increases in intracellular Ca(2+) ([Ca(2+)](i)). In the present study, we determined if prostaglandin E(2) (PGE(2)) is responsible for this cyclooxygenase-2-mediated effect. Rat cortical cultures expressed mRNA for the prostanoid EP(1)-EP(4) receptors. PGE(2) reversed the attenuation in [Ca(2+)](i) and the protection offered by cyclooxygenase-2 inhibition during oxygen-glucose deprivation. These effects likely occur via activation of the prostanoid EP(1) receptor since blocking this receptor during oxygen-glucose deprivation reduced [Ca(2+)](i) and neurotoxicity. Next, we considered if the moderate activation of this pathway, by preconditioning cultures with sub-lethal oxygen-glucose deprivation, influenced the development of tolerance to an otherwise lethal oxygen-glucose deprivation insult, 48 h later. Inhibition of cyclooxygenase-2 during oxygen-glucose deprivation-preconditioning abolished preconditioning-induced protection. Furthermore, cultures were rendered tolerant to oxygen-glucose deprivation by the transient exposure to exogenous PGE(2) 24 h prior to the insult, indicating that this product of the cyclooxygenase-2 pathway is sufficient to induce ischemic tolerance. This study shows that cyclooxygenase-2 and PGE(2) are involved in both oxygen-glucose deprivation-induced neurotoxicity and preconditioning-induced neuroprotection. While neurotoxic in the context of lethal oxygen-glucose deprivation, the moderate activation of this signalling pathway confers ischemic tolerance.