CP-465,022, a selective noncompetitive AMPA receptor antagonist, blocks AMPA receptors but is not neuroprotective in vivo.
OBJECTIVE
Alpha-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.


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.
Menniti
Frank S
FS
CNS Discovery, Pfizer Global Research and Development, Groton, Conn 06340, USA. mennitifs@groton.pfizer.com
Buchan
Alistair M
AM
Chenard
Bertrand L
BL
Critchett
Donald J
DJ
Ganong
Alan H
AH
Guanowsky
Victor
V
Seymour
Patricia A
PA
Welch
Willard M
WM
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D006624:Hippocampus / Q000473:pathology / Q000502:physiology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010433:Pentylenetetrazole; D011799:Quinazolines / Q000097:blood / Q000627:therapeutic use*; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000502:physiology; D012640:Seizures / Q000139:chemically induced; D009435:Synaptic Transmission
D018696:Neuroprotective Agents; D011799:Quinazolines; D018091:Receptors, AMPA; C418042:CP 465,022; D010433:Pentylenetetrazole