DY-9760e, a novel calmodulin antagonist, reduces brain damage induced by transient focal cerebral ischemia

Perturbations in Ca2+ homeostasis have been proposed to lead to neuronal damage after cerebral ischemia. DY-9760e (3-[2-[4-(3- chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1 H-indazole dihydrochloride 3.5 hydrate) is a novel calmodulin antagonist. In this study, we examined the effects of DY-9760e on brain damage in rats subjected to transient (1 h) focal cerebral ischemia. DY-9760e (0.25-1.00 mg kg(-1) h(-1)) was intravenously infused for 6 h, starting 1 h after middle cerebral artery occlusion. Treatment with DY-9760e 0.25, 0.50 and 1.00 mg kg(-1) h(-1) reduced infarct volume by 30, 42 (P < 0.05), and 60% (P < 0.05), respectively. Furthermore, the effect of DY-9760e on ischemia-induced fodrin breakdown was examined in the same model. Pronounced fodrin breakdown was observed in the cerebral cortex and striatum at 24 h after ischemia. DY-9760e caused potent suppression of fodrin breakdown in the cerebral cortex at the same doses as those that had a protective action against cerebral infarction. From these results DY-9760e may have a therapeutic effect against cerebral ischemic damage in the acute stage. (C) 1999 Elsevier Science B.V. All rights reserved.