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The Journal of Neuroscience, July 1, 2001, 21(13):4582-4592

Neuroprotection from Delayed Postischemic Administration of a Metalloporphyrin Catalytic Antioxidant

G. Burkhard Mackensen¹, Manisha Patel², Huaxin Sheng¹, Carla L. Calvi¹, Ines Batini-Haberle³, Brian J. Day², Li Ping Liang², Irwin Fridovich³, James D. Crapo², Robert D. Pearlstein⁴, and David S. Warner^{1, 4}

¹ Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina 27710, ² Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado 80206, and Departments of ³ Biochemistry and ⁴ Surgery, Duke University Medical Center, Durham, North Carolina 27710

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-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 mm³; MnTE-2-PyP⁵⁺, 300 ng, 60 ± 68 mm³). 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.

Key words: free radical; superoxide; brain; ischemia; metalloporphyrin; rat; mouse; mimetic

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21134582-11$05.00/0

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