Long-term neuroprotection from a potent redox-modulating metalloporphyrin in the rat.
Sustained oxidative stress is a known sequel to focal cerebral ischemia. This study examined the effects of treatment with a single dose or sustained infusion of the redox-modulating MnPorphyrin Mn(III)TDE-2-ImP(5+) on outcome from middle cerebral artery occlusion (MCAO) in the rat. Normothermic rats were subjected to 90 min MCAO followed by 90 min reperfusion and then were treated with a single intracerebroventricular dose of Mn(III)TDE-2-ImP(5+). Neurologic and histologic outcomes were assessed at 1 or 8 weeks postischemia. A single dose of Mn(III)TDE-2-ImP(5+) caused a dose-dependent improvement in histologic and neurologic outcome when assessed 1 week postischemia. Mn(III)TDE-2-ImP(5+) afforded preservation of brain aconitase activity at 5.5 h after reperfusion onset, consistent with its known antioxidant properties. Mn(III)TDE-2-ImP(5+) also attenuated postischemic NF-kappaB activation. Evidence for effects on cerebral infarct size and neurologic function had completely dissipated when rats were allowed to survive for 8 weeks postischemia. In contrast, a 1-week continuous intracerebroventricular Mn(III)TDE-2-ImP(5+) infusion caused persistent and substantive reduction in both cerebral infarct size and neurologic deficit at 8 weeks postischemia. Pharmacologic modulation of postischemic oxidative stress is likely to require sustained intervention for enduring efficacy in improving neurologic and histologic outcome from a transient focal ischemic insult.
Sheng
Huaxin
H
The Multidisciplinary Neuroprotection Laboratories, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.
Yang
Wei
W
Fukuda
Shiro
S
Tse
Hubert M
HM
Paschen
Wulf
W
Johnson
Kwame
K
Batinic-Haberle
Ines
I
Crapo
James D
JD
Pearlstein
Robert D
RD
Piganelli
Jon
J
Warner
David S
DS
D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy*; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology* / Q000627:therapeutic use; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome
D008665:Metalloporphyrins; C546619:Mn(III) tetrakis(N,N'-diethylimidazolium-2-yl)porphyrin; D016328:NF-kappa B; D018696:Neuroprotective Agents; C431023:manganese (III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin; D000154:Aconitate Hydratase