The Post-ischemic Administration of 3-[2-[4-(3-Chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate (DY-9760e), a Novel Calmodulin Antagonist, Prevents Delayed Neuronal Death in Gerbil Hi
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概要
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The novel calmodulin (CaM) antagonist DY-9760e (3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate) with an apparent neuroprotective effect in vivo preferentially inhibits neuronal nitric oxide synthase (nNOS), Ca2+/CaM-dependent protein kinase IIα (CaMKIIα), and calcineurin in vitro. In the present study, we investigated the molecular mechanism underlying its neuroprotective effect with the gerbil transient forebrain ischemia model, by focusing on its inhibition of these Ca2+/CaM-dependent enzymes. Post-ischemic DY-9760e treatment (5 mg/kg, i.p.) immediately after 5-min ischemia significantly reduced the delayed neuronal death in the hippocampal CA1 region. CaMKIIα was transiently autophosphorylated immediately after reperfusion with concomitant sustained decrease in its total amounts in the Triton X-100-soluble fractions. Calcineurin activity, accessed by the phosphorylation state of dopamine- and cAMP-regulated phosphoprotein of Mr 32,000 (DARPP-32) at Thr34, was elevated at 6 h after reperfusion. Post-treatment of DY-9760e had no effects on both CaMKIIα and DARPP-32 phosphorylation at 6 h after reperfusion. However, DY-9760e significantly inhibited nitrotyrosine formation, as a biomarker of NO, and in turn, peroxynitrite (ONOO−) production. These results suggest that DY-9760e primarily inhibits Ca2+/CaM-dependent neuronal NOS, without any effects on CaMKII and calcineurin, and the inhibition of NO production possibly accounts for its neuroprotective action in brain ischemic injury.
著者
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Fukunaga Kohji
Department Of Pharmacology Graduate School Of Pharmaceutical Sciences Tohoku University
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Hamada Junichiro
Department Of Histology And Neurobiology And Orthopedics Dokkyo University School Of Medicine
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Hashiguchi Akihito
Department Of Neurosurgery Kumamoto University School Of Medicine
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Morioka Motohiro
Department Of Neurosurgery Faculty Of Medical And Pharmaceutical Sciences Kumamoto University Gradua
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Shirasaki Yasufumi
New Product Research Laboratories Ii Daiichi Pharmaceutical
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Yano Shigetoshi
Department Of Diagnostic Radiology Graduate School Of Medical Sciences Kumamoto University
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Kochi Masato
Department Of Neurosurgery Kumamoto University Medical School
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FUKUNAGA Kohji
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University
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SHIRASAKI Yasufumi
New Product Research Laboratories II, Daiichi Pharmaceutical
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Hamada Junichiro
Department of Neurosurgery, Kumamoto University School of Medicine
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