Peroxynitrite and caspase-3 expression after ischemia/reperfusion in mouse cardiac arrest model.
NO is a putative neurotransmitter and neuromodulator in the brain. NO is not functioning as a direct neurotoxin. NO with the superoxide radical product peroxynitrite (ONOO-) is much more cytotoxic under tissue impairment conditions. Caspase-3, a potent effector of apoptosis that is triggered via several different signaling pathways, may play a very important role in neuronal cell death caused by various brain injuries. The relationship between mouse caspase-3 and peroxynitrite remains unclear. In the present study, we examined the in vivo expression of 3-nitrotyrosine (a metabolite of peroxinitrite) and caspase-3 after cerebral ischemia produced in a global ischemia model using mice (i.e., a cardiac arrest model). 3-nitrotyrosine immunoreactivity was detected in neuronal cells in the hippocampal dentate nucleus, and cortical regions starting at 12 hrs after ischemia. In particular, numerous neuronal cells were highly immunoreactive for 3-nitrotyrosine in the cortical regions. In hippocampal CA1 pyramidal neurons, 3-nitrotyrosine immunoreactivity was detected from 24 hrs. Caspase-3 immunopositive cells were observed in approximately the same area in which the positive reaction to the anti-nitrotyrosine antibody was observed. These results provide direct evidence for the induction of 3-nitrotyrosine and caspase-3 expression in vivo in an ischemia model using mice. The present findings suggest that peroxynitrite generated by cerebral ischemia/ reperfusion was strongly cytotoxic and induced neuronal cell death (apoptosis) mediated by caspase-3.
Dohi
K
K
Department of Critical Care and Emergency Medicine, School of Medicine, Showa University, Tokyo, Japan. kdop@med.showa-u.ac.jp
Ohtaki
H
H
Inn
R
R
Ikeda
Y
Y
Shioda
H S
HS
Aruga
T
T
D000818:Animals; D002545:Brain Ischemia / Q000209:etiology / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D006324:Heart Arrest, Induced; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D030421:Peroxynitrous Acid / Q000378:metabolism*; D015427:Reperfusion Injury / Q000209:etiology / Q000378:metabolism*; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D030421:Peroxynitrous Acid; C002744:3-nitrotyrosine; D014443:Tyrosine; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases