Delayed treatment with AM-36, a novel neuroprotective agent, reduces neuronal damage after endothelin-1-induced middle cerebral artery occlusion in conscious rats.
OBJECTIVE
AM-36 is a novel arylalkylpiperazine with combined antioxidant and Na(+) channel blocking actions. Individually, these properties have been shown to confer neuroprotection in a variety of in vitro and in vivo animal models of stroke. Preliminary studies have shown that AM-36 is neuroprotective in vivo. The purpose of the present study was to assess the neuroprotective and behavioral outcome after delayed administration of AM-36 in an endothelin-1-induced, middle cerebral artery model of cerebral ischemia in conscious rats.


METHODS
Conscious male hooded Wistar rats were subjected to middle cerebral artery occlusion by perivascular microinjection of endothelin-1 via a previously implanted cannula. AM-36 (6 mg/kg IP) or vehicle was administered intraperitoneally 30, 60, or 180 minutes after middle cerebral artery occlusion. Functional outcome was determined 24, 48, and 72 hours after stroke by neurological deficit score, motor performance, and sensory hemineglect tests. Rats were killed at 72 hours, and infarct area and volume were determined by histology and computerized image analysis.


RESULTS
Endothelin-1-induced middle cerebral artery occlusion resulted in marked functional deficits and neuronal damage. AM-36 significantly reduced cortical damage when administration was delayed until 30, 60, or 180 minutes after stroke. Interestingly, neuronal damage was time-dependently reduced, with the greatest protection found when AM-36 was administered 180 minutes after stroke. Striatal damage was significantly reduced after treatment with AM-36 at 180 minutes after stroke. Functional outcome paralleled histopathology. Rota-rod performance, sensory hemineglect, and neurological deficit scores returned to preischemia levels in AM-36-treated rats by 72 hours after stroke when administration was delayed by 180 minutes after stroke.


CONCLUSIONS
AM-36 potently protects against both neuronal damage and functional deficits even when administered up to 180 minutes after induction of stroke. In fact, the greatest protection was found when administration was delayed by 180 minutes after stroke. The possible mechanisms of action of AM-36 are discussed. The present findings suggest that AM-36 may have great promise in the acute treatment of human stroke.
Callaway
J K
JK
Department of Pharmacology, Monash University, Clayton, Australia. Jennifer.Calloway@med.monash.edu.au
Knight
M J
MJ
Watkins
D J
DJ
Beart
P M
PM
Jarrott
B
B
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D019332:Endothelin-1; D020244:Infarction, Middle Cerebral Artery / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D007274:Injections, Intraperitoneal; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome
D019332:Endothelin-1; D018696:Neuroprotective Agents; D010879:Piperazines; C401121:AM 36