Effects of nitric oxide synthase inhibition on brain infarction in SOD-1-transgenic mice following transient focal cerebral ischemia.
To investigate the role of superoxide in the toxicity of nitric oxide (NO), we examined the effect of nitric oxide synthase (NOS) inhibition on brain infarction in transgenic mice overexpressing CuZn-superoxide dismutase (SOD-1). Male SOD-transgenic mice and non-transgenic littermates (30-35 g) were subjected to 60 min of middle cerebral artery occlusion followed by 24 h of reperfusion. Either NG-nitro-L-arginine methyl ester (L-NAME; 3 mg/kg), a mixed neuronal and endothelial NOS inhibitor, or 7-nitroindazole (7-NI; 25 mg/kg), a selective neuronal NOS inhibitor, was administered intraperitoneally 5 min after the onset of ischemia. At 24 h of reperfusion, the mice were decapitated and the infarct volume was evaluated in each group. In the nontransgenic mice, L-NAME significantly increased the infarct volume as compared with the vehicle, while 7-NI significantly decreased it. In the SOD-transgenic mice, L-NAME-treated animals showed a significantly larger infarct volume than vehicle-treated ones, whereas there were no significant differences between 7-NI- and vehicle-treated mice. Our findings suggest that selective inhibition of neuronal NOS ameliorates ischemic brain injury and that both neuronal and endothelial NOS inhibition may result in the deterioration of ischemic injury due to vasoconstriction of the brain. Since L-NAME increased infarct volume even in SOD-transgenic mice, the protective effect of SOD could result from the vasodilation by increased endothelial NO as well as the reduction of neuronal injury due to less production of peroxynitrite compared to wild-type mice. Moreover, the neurotoxic role of NO might not be dependent on NO itself, but the reaction with superoxide to form peroxynitrite, because of no additive effects of SOD and a neuronal NOS inhibitor.
Kamii
H
H
Department of Neurosurgery, Tohoku University School of Medicine, Sendai, Japan.
Mikawa
S
S
Murakami
K
K
Kinouchi
H
H
Yoshimoto
T
T
Reola
L
L
Carlson
E
E
Epstein
C J
CJ
Chan
P H
PH
D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D002544:Cerebral Infarction / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D007191:Indazoles / Q000008:administration & dosage*; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics*
D004791:Enzyme Inhibitors; D007191:Indazoles; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; C080122:7-nitroindazole; D019331:NG-Nitroarginine Methyl Ester