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

Abstract

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.

• Authors: G P Schielke, N C Kupina, P A Boxer, C F Bigge, D F Welty, C Iadecola
• Journal: Stroke (Stroke) Vol. 30 Issue 7 Pg. 1472-7 (Jul 1999) ISSN: 0039-2499 [Print] United States
• PMID: 10390325 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Neuroprotective Agents
• PD 152247
• Quinoxalines
• Receptors, AMPA

Topics

• Animals
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Hypothermia, Induced
• Infusions, Intravenous
• Ischemic Attack, Transient (drug therapy, prevention & control)
• Male
• Neuroprotective Agents (therapeutic use)
• Quinoxalines (therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Receptors, AMPA (antagonists & inhibitors)