Neuroprotection from delayed postischemic administration of a metalloporphyrin catalytic antioxidant

Reactive oxygen species contribute to ischemic brain injury. This study exa mined whether the porphyrin catalytic antioxidant manganese (III) meso-tetr akis (N-ethylpyridinium-2yl)porphyrin (MnTE-2-PyP5+) reduces oxidative stre ss 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 reperfusi on, 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% (v ehicle, 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 im proved. No MnTE-2-PyP5+ effect was observed if it was given 12 hr after isc hemia. MnTE-2-PyP5+ prevented mitochondrial aconitase inactivation and redu ced 8-hydroxy-2'-deoxyguanosine formation when it was given 5 min or 6 hr a fter ischemia. In mice, MnTE-2-PyP5+ reduced infarct size and improved neur ologic scores when it was given intravenously 5 min after ischemia. There w as no effect of 150 or 300 ng of MnTE-2-PyP5+ pretreatment on selective neu ronal necrosis resulting from 10 min forebrain ischemia and 5 d recovery in rats. Administration of a metalloporphyrin catalytic antioxidant had marke d 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.