Transgenic CuZn-superoxide dismutase inhibits NO synthase induction in experimental subarachnoid hemorrhage.
OBJECTIVE
The expression of inducible NO synthase (iNOS) after experimental subarachnoid hemorrhage (SAH) has been postulated to play a critical role in the pathogenesis of SAH and subsequent cerebral vasospasm. The inhibitory effect of CuZn-superoxide dismutase (CuZn-SOD) on the induction of iNOS after SAH was examined by using transgenic mice overexpressing CuZn-SOD.


METHODS
SOD-transgenic mice and nontransgenic littermates were subjected to SAH by endovascular perforation of the left anterior cerebral artery. The iNOS mRNA expression after SAH was determined by reverse transcription-polymerase chain reaction, and the distribution of iNOS-positive cells was immunohistochemically examined. The nuclear expression of activated nuclear factor-kappaB, a major transcription factor of iNOS gene, was also immunohistochemically examined.


RESULTS
In nontransgenic mice, SAH-induced iNOS protein and mRNA expressions in the arteries of basal cistern as well as in the cerebral cortex were demonstrated by immunohistochemistry and reverse transcription-polymerase chain reaction. SAH-induced iNOS protein and mRNA expressions in those tissues were much reduced in SOD-transgenic mice compared with nontransgenic mice. Moreover, the nuclear expression of the activated form of nuclear factor-kappaB was immunohistochemically detected in the cerebral cortices of nontransgenic mice but not in those of SOD-transgenic mice.


CONCLUSIONS
These results indicate that oxygen-derived free radicals, particularly superoxide, play an important role in the iNOS gene expression after SAH and provide a molecular basis for the protective role of SOD against vasospasm after SAH.
Saito
A
A
Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan. atsushi@nsg.med.tohoku.ac.jp
Kamii
H
H
Kato
I
I
Takasawa
S
S
Kondo
T
T
Chan
P H
PH
Okamoto
H
H
Yoshimoto
T
T
D000818:Animals; D002536:Cerebral Arteries / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000096:biosynthesis; D013345:Subarachnoid Hemorrhage / Q000150:complications* / Q000201:enzymology* / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics*; D014158:Transcription, Genetic; D020301:Vasospasm, Intracranial / Q000209:etiology*
D016328:NF-kappa B; D012333:RNA, Messenger; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D013482:Superoxide Dismutase