Gb. Mackensen et al., Neuroprotection from delayed postischemic administration of a metalloporphyrin catalytic antioxidant, J NEUROSC, 21(13), 2001, pp. 4582-4592
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.