Stilbazulenyl nitrone, a novel antioxidant, is highly neuroprotective in focal ischemia.
Azulenyl nitrones are novel chain-breaking antioxidants with low oxidation potentials and high lipophilicity-properties favoring their efficacy as neuroprotectants. We tested the second-generation azulenyl nitrone, stilbazunenlyl nitrone (STAZN), in focal ischemic stroke. Physiologically monitored rats received 2 hours of middle cerebral artery occlusion by intraluminal suture, resulting in substantial cortical and striatal infarcation. Neurobehavior was quantified on a standard battery, and brains were perfusion-fixed for quantitative histopathology at 3 days. In 3 independent series, rats were treated at either 2h + 4h, or 2h + 4h + 24h + 48h, after onset of ischemia; vehicle-treated rats received dimethylsulfoxide or saline. All animals (n = 52) developed high-grade neurological deficits (score 11 of 12) during ischemia, which improved, in STAZN-treated rats, within 1-1.5 h of the initial dose and fell to a median score of 3 at 72 h, compared to 8 in vehicle rats. STAZN treatment reduced mean cortical infarct volume by 64-97%, and total infarct volume by 42-72%. In over one-half of STAZN-treated animals, cortical infarction was virtually abolished. Regression analysis predicted that STAZN would confer approximately 50% cortical neuroprotection even in the most severely affected cases. The potency of STAZN was orders-of-magnitude greater than other nitrones such as NXY-059. These results suggest that STAZN has great promise for ischemic stroke.
Ginsberg
Myron D
MD
Cerebral Vascular Disease Research Center, Department of Neurology (D4-5), University of Miami School of Medicine, PO Box 016960, Miami, FL 33101, USA. mdginsberg@stroke.med.miami.edu
Becker
David A
DA
Busto
Raul
R
Belayev
Andrey
A
Zhang
Yongbo
Y
Khoutorova
Larissa
L
Ley
James J
JJ
Zhao
Weizhao
W
Belayev
Ludmila
L
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000473:pathology* / Q000503:physiopathology; D001929:Brain Edema / Q000188:drug therapy; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004195:Disease Models, Animal; D016166:Free Radical Scavengers / Q000494:pharmacology; D007091:Image Processing, Computer-Assisted; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D018696:Neuroprotective Agents / Q000097:blood / Q000627:therapeutic use*; D009589:Nitrogen Oxides / Q000097:blood / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes
D000975:Antioxidants; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; D012717:Sesquiterpenes; C459743:stilbazulenyl nitrone; D004121:Dimethyl Sulfoxide