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 Hippocampus

Journal of Pharmacological Sciences

Masato Kochi²  Motohiro Morioka²  Akihito Hashiguchi²  Kohji Fukunaga³  Shigetoshi Yano²  Yasufumi Shirasaki¹  Junichiro Hamada² 

[1] New Product Research Laboratories II, Daiichi Pharmaceutical;Department of Neurosurgery, Kumamoto University School of Medicine;Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University

关键词: cerebral ischemia;    nitric oxide synthase (NOS);    Ca2+/calmodulin-dependent protein kinase II (CaMKII);    calcineurin;    dopamine- and cAMP-regulated phosphoprotein of Mr 32;    000 (DARPP-32);   

DOI  :  10.1254/jphs.FP0040348

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(39)Cited-By(8)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.

【 授权许可】

Unknown