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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.
Warner1, 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
Copyright © 2001 Society for Neuroscience 0270-6474/01/21134582-11$05.00/0
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