The neuroprotective effect of a novel calmodulin antagonist, 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5, 6-dimethoxy-1-(4-imidazolylmethyl)-1h-indazole dihydrochloride 3.5 hydrate, in transient forebrain ischemia

A. Hashiguchi, T. Kawano, S. Yano, M. Morioka, J. Hamada, T. Sato, Y. Shirasaki, Y. Ushio, K. Fukunaga

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

A 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, potently inhibits CaM-dependent nitric oxide synthase in situ. In the present study, we determined whether DY-9760e inhibits nitric oxide (NO) production and protein nitration by peroxynitrite (ONOO-) formation in the hippocampal CA1 region of gerbils after transient forebrain ischemia. In freely moving gerbils, NO production after 10-minute forebrain ischemia was monitored consecutively with in vivo brain microdialysis. Pretreatment with DY-9760e (50 mg/kg i.p.) significantly decreased the increased levels of NOx- (NO metabolites, NO2- plus NO3-) immediately after, 24 h after cerebral ischemia-reperfusion to the control levels of sham-operated animals. Western blot and immunohistochemical analyses using an anti-nitrotyrosine antibody as a marker of ONOO- formation indicated a marked increase in nitrotyrosine immunoreactivity in the pyramidal neurons of the CA1 region 2 h after reperfusion, and DY-9760e significantly inhibited increased nitrotyrosine immunoreactivity. Coincident with the inhibition of the NO production and protein tyrosine nitration, pretreatment with DY-9760e rescued the delayed neuronal death in the hippocampal CA1 region. These results suggest that the inhibitory effects of DY-9760e on the NO-ONOO- pathway partly account for its neuroprotective effects in cerebral ischemia.

Original languageEnglish
Pages (from-to)379-386
Number of pages8
JournalNeuroscience
Volume121
Issue number2
DOIs
Publication statusPublished - 2003 Oct 6

Keywords

  • Gerbil
  • Microdialysis
  • Nitric oxide
  • Nitrotyrosine

ASJC Scopus subject areas

  • Neuroscience(all)

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