The neuroprotective effect of the novel AMPA receptor antagonist PD152247 (PNQX) in temporary focal ischemia in the rat

Background and Purpose-Evidence suggests that glutamate contributes to isch emic brain damage through activation of the alpha-amino-3-hydroxy-5-methyl- 4-isoxazole propionate (AMPA) receptor. We tested the novel, selective AMPA . receptor antagonist PD152247 (PNQX) in a model of temporary focal ischemi a to determine the dose-response relationship and to investigate the contri bution of drug-induced hypothermia to the neuroprotective action of AMPA re ceptor antagonists, Methods-Temporary focal cerebral ischemia was induced in Sprague-Dawley rat s by occluding the middle cerebral artery and both carotid arteries for 3 h ours. Body temperature was monitored by telemetry. PNQX was administered in traperitoneally or by intravenous infusion with various doses for 6 hours. Lesion volume was determined after 3 days by stereological methods. Results-PNQX reduced the lesion volume by 51% after intraperitoneal adminis tration. The intravenous dose-response study demonstrated that the lowest e ffective dose of PNQX was 1.0 mg/kg per hour, which corresponded to a stead y state plasma level of 685 ng/mL. Neuroprotection was demonstrated at PNQX plasma concentrations that did not lower body temperature over the entire course of the experiment. Conclusions-AMPA receptor activation plays an important role in the develop ment of ischemic brain damage. Thus, novel AMPA receptor antagonists may be useful for the treatment of stroke in humans.