Free radical spin trap alpha-phenyl-N-tert-butyl-nitron inhibits caspase-3 activation and reduces brain damage following a severe forebrain ischemic injury.
It has been documented that alpha-phenyl-N-tert-butyl-nitron (PBN) possesses a potent neuroprotective effect when administered after transient focal cerebral ischemia. However, contradicting results were reported regarding its effect in transient global ischemia. To further elucidate the mechanism of PBN action, we have studied the effect of PBN on animal survival, histopathological outcome, and activation of caspase-3 following 30 min of global ischemia in vehicle- and PBN-treated rats. The results showed that 30 min of global ischemia was such a severe insult that no animal could survive beyond 2 d of reperfusion. Histopathological evaluation showed severe tissue edema and microinfarct foci in the neocortex and thalamus. Close to 100% damage was observed in the stratum and hippocampal CA1, CA3, and dentate gyrus subregions. Postischemic PBN treatment significantly enhanced animal survival and reduced damage in the neocortex, thalamus, and hippocampus. Immunohistochemistry demonstrated that caspase-3 was activated following ischemia in the striatum and the neocortex. PBN suppressed the activation of caspase-3 in both structures. It is concluded that PBN is a potent neuroprotectant against both focal and global ischemia; besides its function as a free radical scavenger, PBN may reduce ischemic brain damage by blocking cell death pathways that involve caspase-3 activation.
Li
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PA
Pacific Biomedical Research Center, University of Hawaii, Honolulu, HI 96822, USA. pali@pbrc.hawaii.edu
He
Q P
QP
Nakamura
L
L
Csiszar
K
K
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D053148:Caspase 3; D061945:Caspase Inhibitors; D003497:Cyclic N-Oxides; D004195:Disease Models, Animal; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009589:Nitrogen Oxides / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D019097:Spin Trapping; D015996:Survival Rate
D061945:Caspase Inhibitors; D003497:Cyclic N-Oxides; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; C029217:phenyl-N-tert-butylnitrone; C505410:Casp3 protein, rat; D053148:Caspase 3