title: Protective effect of DY-9760e, a calmodulin antagonist, against neuronal cell death.
abstract: 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.
authors.affiliation: New Product Research Laboratories II, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Takano
authors.forename: Masunobu
authors.initials: M
authors.lastname: Sugimura
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Kanazawa
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Uchida
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Morishima
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Shirasaki
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000201:enzymology; D018698:Glutamic Acid / Q000633:toxicity; D007191:Indazoles / Q000008:administration & dosage / Q000494:pharmacology*; D015640:Ion Channel Gating; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011189:Potassium Chloride / Q000633:toxicity; D051381:Rats; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology; D019284:Thapsigargin / Q000633:toxicity; D014701:Veratridine / Q000633:toxicity
chemical_list: C109602:3-(2-(4-(3-chloro-2-methylphenyl)1-piperazinyl)ethyl)5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazol dihydrochloride 3.5 hydrate; D015220:Calcium Channels; D002147:Calmodulin; D007191:Indazoles; D018696:Neuroprotective Agents; D015222:Sodium Channels; D018698:Glutamic Acid; D016202:N-Methylaspartate; D011189:Potassium Chloride; D019284:Thapsigargin; D014701:Veratridine; D000252:Calcium-Transporting ATPases; D002118:Calcium