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Neuroprotection from delayed postischemic administration of a metalloporphyrin catalytic antioxidant
G B Mackensen1, M Patel, H Sheng
1Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Abstract:
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.
Insights
Manganese porphyrin antioxidant MnTE-2-PyP(5+) significantly reduced brain damage and improved outcomes in experimental ischemic stroke when administered up to six hours after reperfusion, decreasing oxidative stress.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Reactive oxygen species (ROS) play a critical role in the pathophysiology of ischemic brain injury.
- Oxidative stress is a key mechanism contributing to neuronal damage and functional deficits following cerebral ischemia.
Purpose of the Study:
- To investigate the neuroprotective potential of the catalytic antioxidant manganese (III) meso-tetrakis (N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP(5+)) against experimental cerebral ischemia.
- To determine the efficacy of MnTE-2-PyP(5+) in reducing oxidative stress and improving outcomes when administered at various time points before and after ischemic insult.
Main Methods:
- Rats underwent 90 minutes of focal cerebral ischemia followed by 7 days of recovery.
- MnTE-2-PyP(5+) or vehicle was administered intracerebroventricularly before ischemia or at different time points after reperfusion (5 min, 90 min, 6 hr, 12 hr).
- Biomarkers of oxidative stress, infarct size, and neurological scores were assessed. Studies were also conducted in mice using intravenous administration.
Main Results:
- Preischemic administration of MnTE-2-PyP(5+) reduced infarct size by 70% and improved neurological scores.
- Postischemic administration at 5 min or 90 min reduced infarct size by 70-77%.
- Treatment up to 6 hours after ischemia significantly reduced infarct volume (by 54%) and improved neurological function, with no effect observed at 12 hours. MnTE-2-PyP(5+) prevented mitochondrial aconitase inactivation and reduced oxidative damage markers.
Conclusions:
- Metalloporphyrin catalytic antioxidant MnTE-2-PyP(5+) demonstrates significant neuroprotective effects against focal ischemic brain injury.
- Therapeutic window for MnTE-2-PyP(5+) extends up to 6 hours post-ischemia, associated with reduced postischemic oxidative stress.
- These findings highlight the potential of MnTE-2-PyP(5+) as a therapeutic agent for ischemic stroke.