Background And Purpose: Evidence suggests that glutamate contributes to ischemic 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 ischemia to determine the dose-response relationship and to investigate the contribution of drug-induced hypothermia to the neuroprotective action of AMPA receptor antagonists.
Methods: Temporary focal cerebral ischemia was induced in Sprague-Dawley rats by occluding the middle cerebral artery and both carotid arteries for 3 hours. Body temperature was monitored by telemetry. PNQX was administered intraperitoneally 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 administration. The intravenous dose-response study demonstrated that the lowest effective dose of PNQX was 1.0 mg/kg per hour, which corresponded to a steady 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 development of ischemic brain damage. Thus, novel AMPA receptor antagonists may be useful for the treatment of stroke in humans.
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