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Microsphere embolism (ME)-induced ischemia model in rat resembles to multiple brain embolism in human with several clinical features. We here tested whether nitric oxide (NO) production contributes to the neuronal injury in the ME model. A novel calmodulin antagonist, DY-9760e, having a potent inhibitory effect on neuronal nitric oxide synthase (nNOS), reduced brain infarct size in the ME-induced brain ischemia. Consistent with our previous observation with gerbil ischemia/reperfusion model, DY-9760e completely inhibited NO production immediately after and 24 or 48 h after ME. Unlike the gerbil ischemia/reperfusion model, protein tyrosine nitration markedly increased 6-48 h after ME. DY-9760e treatment completely inhibited the marked increase in the protein tyrosine nitration at 24 h after ME. These results suggest that the inhibition of NO production and protein tyrosine nitration by DY-9760e contribute to its neuroprotective action in the ME-induced brain damage.

DY-9760e (3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate), a calmodulin antagonist, provides protection against Ca(2+) overload-associated cytotoxicity and brain injury after cerebral ischemia in rats. In this study, we assessed the effect of DY-9760e on ischemic infarct volume in cats subjected to permanent focal cerebral ischemia. DY-9760e was infused for 6 h, beginning 5 min after occlusion of the middle cerebral artery. The infarct volume was measured at the end of drug infusion. DY-9760e, at the dose of 0.25 but not 0.1 mg/kg/h, significantly reduced cerebral infarct volume without affecting any physiological parameters, and its protective effect was mainly evident in the cerebral cortex, where the penumbra, a salvageable zone, exists. The present study demonstrates that DY-9760e protects against brain injury after focal ischemia in a gyrencephalic animal as well as in the rodents reported previously and suggests its therapeutic value for the treatment of acute stroke.

An excessive elevation of intracellular Ca(2+) levels is known to play a key role in the pathological events following cerebral ischemia. DY-9760e, 3-[2-[4-(3-chloro-2-methylphenylmethyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate, is a potent calmodulin antagonist that attenuates brain damage in focal ischemia models. In the present study, we investigated the effect of DY-9760e on neuronal cell death induced by a variety of cell-toxic stimuli that increase intracellular Ca(2+). Cell death was induced by the exposure of primary cultured neurons to excitotoxic agents such as glutamate and N-methyl-D-aspartate, membrane-depolarizing agents such as veratridine and high KCl, or thapsigargin an endoplasmic reticulum Ca(2+)-ATPase inhibitor. Treatment with DY-9760e resulted in a dose-dependent prevention of neuronal cell death elicited by excitotoxicity, voltage-gated channel opening, and inhibition of endoplasmic reticulum Ca(2+)-ATPase. These results indicate that DY-9760e can rescue neurons from various types of cell-toxic stimuli, which may contribute to attenuation of brain injury after cerebral ischemia.