Neuroprotective effect of STAZN, a novel azulenyl nitrone antioxidant, in focal cerebral ischemia in rats: dose-response and therapeutic window.
Stilbazulenyl nitrone (STAZN) is a potent antioxidant that, in a rat model of transient focal cerebral ischemia, confers significant enduring functional and morphological neuroprotection. This study investigated the influence of dose and time of administration on the neuroprotective effects of STAZN in the intraluminal suture model of middle cerebral artery occlusion (MCAo). Dose response: At 2 and 4 h after the onset of MCAo, animals received intravenously either STAZN (low dose=0.07 mg/kg, n=8; medium dose=0.7 mg/kg, n=9; high dose=3.5 mg/kg, n=9), an equivalent volume of vehicle (30% Solutol HS15 and 70% isotonic saline, 0.37 ml/kg, n=5) or saline (0.37 ml/kg, n=5). Only the medium dose improved scores (p<0.05) on a standardized neurobehavioral test at 1, 2 and 3 days after MCAo. Only the medium dose reduced the total infarction (51%, p=0.014) compared to controls. These results indicate that STAZN exhibits maximal neuroprotection at the 0.7 mg/kg dose. Therapeutic window: STAZN (0.6 mg/kg) dissolved in dimethylsulfoxide was given intra-peritoneally at 2 and 4 h (n=11), 3 and 5 h (n=10), 4 and 6 h (n=10) or 5 and 7 h (n=7) after the onset of MCAo. Additional doses were given at 24 and 48 h. Vehicle (dimethylsulfoxide, 2.0 ml/kg, n=6) was administered at 3, 5, 24 and 48 h. STAZN treatment initiated at 2 or 3 h after the onset of MCAo improved neurological scores (p<0.001) and reduced total infarction (42.2%, p<0.05) compared to controls.
Ley
James J
JJ
Cerebral Vascular Disease Research Center, Department of Neurology (D4-5) University of Miami Miller School of Medicine PO Box 016960 Miami, Florida 33101, USA.
Belayev
Ludmila
L
Saul
Isabel
I
Becker
David A
DA
Ginsberg
Myron D
MD
D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D001925:Brain Damage, Chronic / Q000209:etiology / Q000517:prevention & control*; D002545:Brain Ischemia / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes / Q000008:administration & dosage*; D013997:Time Factors
D018696:Neuroprotective Agents; D012717:Sesquiterpenes; C459743:stilbazulenyl nitrone