AM-36, a novel neuroprotective agent, profoundly reduces reactive oxygen species formation and dopamine release in the striatum of conscious rats after endothelin-1-induced middle cerebral artery occlusion.
Elevated generation of reactive oxygen species (ROS) has been demonstrated during ischemia and reperfusion. Dopamine (DA) autooxidation may contribute to increased ROS generation. The novel neuroprotective agent AM-36 has antioxidant and Na(+) channel blocking activity and reduces neuronal damage in both cortex and striatum after middle cerebral artery (MCA) occlusion. Here we sought in vivo evidence of the ability of AM-36 to inhibit intrastriatal ROS generation and DA release after ischemia. Salicylate hydroxylation coupled with in vivo microdialysis in the striatum of conscious Long Evans rats was performed during MCA occlusion by perivascular microinjection of endothelin-1 (ET-1). AM-36 (6 mg/kg) was administered intraperitoneally 30 min after MCA occlusion. Dialysates were analysed using high performance liquid chromatography with electrochemical detection for the salicylate hydroxylation product, 2,3-dihydroxybenzoic acid (2,3 DHBA) and for DA and metabolites. MCA occlusion resulted in a marked increase in 2,3 DHBA and a secondary increase in all analytes, 180-300 min later. Increased DA release coincided with 2,3 DHBA formation. AM-36 significantly reduced ischemia induced increases in 2,3 DHBA and DA, and infarct volume in the striatum. Significant improvements in a battery of behavioural tests was also found in AM-36 treated rats. This study has demonstrated profound inhibition of ROS generation by a novel compound with antioxidant activity, administered post-ischemia in conscious rats.
Callaway
J K
JK
Department of Pharmacology, PO Box 13E, Monash University, Clayton, Victoria 3800, Australia. jennifer.callaway@med.monash.edu.au
Lawrence
A J
AJ
Jarrott
B
B
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000139:chemically induced*; D001921:Brain / Q000473:pathology; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1; D017665:Hydroxyl Radical / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007274:Injections, Intraperitoneal; D008297:Male; D017551:Microdialysis; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D020318:Rats, Long-Evans; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013997:Time Factors; D016896:Treatment Outcome
D019332:Endothelin-1; D018696:Neuroprotective Agents; D010879:Piperazines; D017382:Reactive Oxygen Species; C401121:AM 36; D017665:Hydroxyl Radical; D004298:Dopamine