Protective effect of DY-9760e, a calmodulin antagonist, against neuronal cell death

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Abstract

An excessive elevation of intracellular Ca2+ 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 Ca2+. 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 Ca2+-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 Ca2+-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. © 2004 Pharmaceutical Society of Japan.

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Takano, H., Sugimura, M., Kanazawa, Y., Uchida, T., Morishima, Y., & Shirasaki, Y. (2004). Protective effect of DY-9760e, a calmodulin antagonist, against neuronal cell death. Biological and Pharmaceutical Bulletin, 27(11), 1788–1791. https://doi.org/10.1248/bpb.27.1788

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