Synergistic induction of heme oxygenase-1 by nicaraven after subarachnoid hemorrhage to prevent delayed cerebral vasospasm.
Cerebral vasospasm remains a major cause of morbidity and mortality in patients with subarachnoid hemorrhage. Heme oxygenase-1 (HO-1) is an oxidative stress-inducible enzyme with multiple protective functions against vascular and neurological diseases, including delayed cerebral vasospasm. In the present study, intravenous administration (i.v.) of nicaraven (1 mg/kg/min, for 2 days after subarachnoid hemorrhage) ameliorated delayed cerebral vasospasm in rat subarachnoid hemorrhage models, marked synergistic induction of HO-1 protein (> 2.5-fold than 'subarachnoid hemorrhage with saline i.v.'), and elicited a rapid increase of cGMP accumulation in the basilar arteries. In the sham-operated rats, nicaraven could not induce HO-1 expression. Antisense HO-1 oligodeoxynucleotides abrogated this HO-1 induction and the antivasospastic effect of nicaraven. In vitro study using Hela cells, nicaraven enhanced the human HO-1 promoter (-4.5 kbp) activity, which was pre-activated with the blood component oxyhemoglobin to mimic the ability of subarachnoid hemorrhage. These results suggest that this enhanced HO-1 expression through a combination of pathological state and pharmacological agent could be an effective strategy to improve the prognosis of heme- and oxidative stress-induced diseases, such as delayed cerebral vasospasm.
Shimada
Yasuhito
Y
Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
Tsunoda
Hiroshi
H
Zang
Liqing
L
Hirano
Minoru
M
Oka
Takehiko
T
Tanaka
Toshio
T
D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000378:metabolism; D002533:Cerebral Angiography; D006152:Cyclic GMP / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008297:Male; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics / Q000378:metabolism; D010108:Oxyhemoglobins / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000150:complications* / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000503:physiopathology; D013997:Time Factors; D020301:Vasospasm, Intracranial / Q000209:etiology* / Q000517:prevention & control*
D020319:Oligodeoxyribonucleotides, Antisense; D010108:Oxyhemoglobins; D009536:Niacinamide; D051547:Heme Oxygenase-1; D006152:Cyclic GMP; C042625:nicaraven