Neuroprotection from delayed postischemic administration of a metalloporphyrin catalytic antioxidant

被引:145
作者
Mackensen, GB
Patel, M
Sheng, HX
Calvi, CL
Batinic-Haberle, I
Day, BJ
Liang, LP
Fridovich, I
Crapo, JD
Pearlstein, RD
Warner, DS
机构
[1] Duke Univ, Med Ctr, Dept Anesthesiol, Durham, NC 27710 USA
[2] Natl Jewish Med & Res Ctr, Dept Med, Denver, CO 80206 USA
[3] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA
[4] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA
关键词
free radical; superoxide; brain; ischemia; metalloporphyrin; rat; mouse; mimetic;
D O I
10.1523/JNEUROSCI.21-13-04582.2001
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Reactive oxygen species contribute to ischemic brain injury. This study examined whether the porphyrin catalytic antioxidant manganese (III) meso-tetrakis (N-ethylpyridinium-2yl)porphyrin (MnTE-2-PyP5+) 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-PyP5+ (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-PyP5+, given 60 min before ischemia, improved neurologic scores and reduced total infarct size by 70%. MnTE-2-PyP5+, given 5 or 90 min after reperfusion, reduced infarct size by 70-77% and had no effect on temperature. MnTE-2-PyP5+ treatment 6 hr after ischemia reduced total infarct volume by 54% (vehicle, 131 +/- 60 mm 3; MnTE-2-PyP5+, 300 ng, 60 +/- 68 mm 3). Protection was observed in both cortex and caudoputamen, and neurologic scores were improved. No MnTE-2-PyP5+ effect was observed if it was given 12 hr after ischemia. MnTE-2-PyP5+ 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-PyP5+ 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-PyP5+ 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.
引用
收藏
页码:4582 / 4592
页数:11
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