COX2-derived primary and cyclopentenone prostaglandins are increased after asphyxial cardiac arrest

• COX2 is induced in brain following asphyxial cardiac arrest.
• Prostaglandins, including cyclopentenone species, are increased in ischemic brain.
• Concentrations peak at 24 h after ischemia.
• Prostaglandin production is completely ablated by a COX-2 inhibitor.

BackgroundCyclopentenone prostaglandins have been identified as potential neurotoxic agents in the setting of hypoxia-ischemia. Cyclooxygenase-2 (COX-2), the upstream enzyme responsible for prostaglandin production is upregulated following hypoxic-ischemic brain injury. However, the temporal production and concentration of cyclopentenone prostaglandins has not been described following global brain ischemia.MethodsGlobal brain ischemia was induced in rats by asphyxial cardiac arrest (ACA) followed by resuscitation. Rats were sacrificed between 24 h and 7 days following resuscitation and their brains removed. Western blot, immunohistochemistry, and mass spectroscopy were performed. A cohort of rats was pretreated with the COX-2 inhibitor SC58125.ResultsCOX-2 is induced in hippocampus at 24 h following ACA. Multiple prostaglandins, including cyclopentenone prostaglandin species, are increased in hippocampus as 24 h following ACA. Prostaglandin and cyclopentenone prostaglandin concentrations are returned to baseline at 3 and 7 days post-ischemia. The COX-2 inhibitor SC58125 completely abrogates the post-ischemic increase in prostaglandins and cyclopentenone prostaglandins.ConclusionsProstaglandins, including cyclopentenone prostaglandins, are increased in ischemic brain, peak at 24 h and can be attenuated by the COX-2 inhibitor SC58125. These data establish the presence of potentially neurotoxic cyclopentenone prostaglandins in post-ischemic brains, thus identifying a target and therapeutic window for neuroprotective therapies.