on December 12, 2002
Published online before print December 12, 2002, doi: 10.1161/01.STR.0000048216.90221.9C
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Submitted on July 17, 2002
From CNS Discovery, Pfizer Global Research and Development, Groton, Conn (F.S.M., D.J.C., A.H.G., V.G., P.A.S., W.M.W.); Department of Clinical Neuroscience, University of Calgary, Calgary, Alberta, Canada (A.M.B.); and Neurogen Corporation, Branford, Conn (B.L.C.). * To whom correspondence should be addressed. E-mail: mennitifs{at}groton.pfizer.com.
Background and Purpose— Methods—To demonstrate that CP-465,022 gains access to the brain, the effects of systemic administration of CP-465,022 were investigated on AMPA receptor-mediated electrophysiological responses in hippocampus and on chemically induced seizures in rats. The compound was then investigated for neuroprotective efficacy in rat global and focal ischemia models at doses demonstrated to be maximally effective in the electrophysiology and seizure models. Results—CP-465,022 potently and efficaciously inhibited AMPA receptor-mediated hippocampal synaptic transmission and the induction of seizures. However, at comparable doses, CP-465,022 failed to prevent CA1 neuron loss after brief global ischemia or to reduce infarct volume after temporary middle cerebral artery occlusion. Conclusions—Given the high selectivity of CP-465,022 for AMPA over kainate and N-methyl-D-aspartate subtypes of glutamate receptors, the lack of neuroprotective efficacy of the compound calls into question the neuroprotective efficacy of AMPA receptor inhibition after ischemia.
Accepted on August 21, 2002
CP-465,022, a Selective Noncompetitive AMPA Receptor Antagonist, Blocks AMPA Receptors but Is Not Neuroprotective In Vivo
Frank S. Menniti PhD*;
-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor inhibition has been hypothesized to provide neuroprotective efficacy after cerebral ischemia on the basis of the activity in experimental ischemia models of a variety of compounds with varying selectivity for AMPA over other glutamate receptor subtypes. CP-465,022 is a new, potent, and selective noncompetitive AMPA receptor antagonist. The present study investigated the ability of this compound to reduce neuronal loss after experimental cerebral ischemia to probe the neuroprotective potential of AMPA receptor inhibition.
Key words: excitatory amino acid antagonists • receptors, AMPA • receptors, glutamate • stroke