Neuroprotection from delayed postischemic administration of a metalloporphyrin catalytic antioxidant.
Reactive oxygen species contribute to ischemic brain injury. This study examined whether the porphyrin catalytic antioxidant manganese (III) meso-tetrakis (N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP(5+)) reduces oxidative stress and improves outcome from experimental cerebral ischemia. Rats that were subjected to 90 min focal ischemia and 7 d recovery were given MnTE-2-PyP(5+) (or vehicle) intracerebroventricularly 60 min before ischemia, or 5 or 90 min or 6 or 12 hr after reperfusion. Biomarkers of brain oxidative stress were measured at 4 hr after postischemic treatment (5 min or 6 hr). MnTE-2-PyP(5+), given 60 min before ischemia, improved neurologic scores and reduced total infarct size by 70%. MnTE-2-PyP(5+), given 5 or 90 min after reperfusion, reduced infarct size by 70-77% and had no effect on temperature. MnTE-2-PyP(5+) treatment 6 hr after ischemia reduced total infarct volume by 54% (vehicle, 131 +/- 60 mm(3); MnTE-2-PyP(5+), 300 ng, 60 +/- 68 mm(3)). Protection was observed in both cortex and caudoputamen, and neurologic scores were improved. No MnTE-2-PyP(5+) effect was observed if it was given 12 hr after ischemia. MnTE-2-PyP(5+) prevented mitochondrial aconitase inactivation and reduced 8-hydroxy-2'-deoxyguanosine formation when it was given 5 min or 6 hr after ischemia. In mice, MnTE-2-PyP(5+) reduced infarct size and improved neurologic scores when it was given intravenously 5 min after ischemia. There was no effect of 150 or 300 ng of MnTE-2-PyP(5+) pretreatment on selective neuronal necrosis resulting from 10 min forebrain ischemia and 5 d recovery in rats. Administration of a metalloporphyrin catalytic antioxidant had marked neuroprotective effects against focal ischemic insults when it was given up to 6 hr after ischemia. This was associated with decreased postischemic superoxide-mediated oxidative stress.
Mackensen
G B
GB
Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Patel
M
M
Sheng
H
H
Calvi
C L
CL
Batinic-Haberle
I
I
Day
B J
BJ
Liang
L P
LP
Fridovich
I
I
Crapo
J D
JD
Pearlstein
R D
RD
Warner
D S
DS
D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage* / Q000737:chemistry; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000209:etiology; D002384:Catalysis; D002544:Cerebral Infarction / Q000209:etiology / Q000517:prevention & control*; D004247:DNA / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005649:Fumarate Hydratase / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D008297:Male; D008665:Metalloporphyrins / Q000008:administration & dosage* / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000201:enzymology; D009336:Necrosis; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000737:chemistry; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome
D000975:Antioxidants; D008665:Metalloporphyrins; D018696:Neuroprotective Agents; C431023:manganese (III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin; D004247:DNA; D005649:Fumarate Hydratase; D000154:Aconitate Hydratase