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Protective effects of a selective L-type voltage-sensitive calcium channel blocker, S-312-d, on neuronal cell death
Authors:Yagami Tatsurou  Ueda Keiichi  Sakaeda Toshiyuki  Itoh Naohiro  Sakaguchi Gaku  Okamura Noboru  Hori Yozo  Fujimoto Masafumi
Affiliation:Discovery Research Laboratories, Shionogi and Co., Ltd., 12-4, Sagisu 5-Choume, Fukushima-Ku, Osaka 553-0002, Japan. yagami@pharmac.med.yokohama-cu.ac.jp
Abstract:
Amyloid beta protein (Abeta)- and human group IIA secretory phospholipase A(2) (sPLA(2)-IIA)-induced neuronal cell death have been established as in vitro models for Alzheimer's disease (AD) and stroke. Both sPLA(2)-IIA and Abeta causes neuronal apoptosis by increasing the influx of Ca(2+) through L-type voltage-sensitive Ca(2+) channel (L-VSCC). In the present study, we evaluated effects of a selective L-VSCC blocker, S-(+)-methyl 4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitro-phenyl)thieno[2,3-b]pyridine-5-carboxylate (S-312-d), on Abeta- and sPLA(2)-IIA-induced neuronal apoptosis in primary cultures of rat cortical neurons. S-312-d significantly rescued cortical neurons from Abeta- and sPLA(2)-IIA-induced cell death. Both cell death stimuli caused the appearance of apoptotic features such as plasma membrane blebs, chromatin condensation, and DNA fragmentation. S-312-d completely suppressed these apoptotic features. Before apoptosis, the two death ligands markedly enhanced an influx of Ca(2+) into neurons. S-312-d significantly prevented neurons from sPLA(2)-IIA- and Abeta-induced Ca(2+) influx. Furthermore, the neuroprotective effect of S-312-d was more potent than that of another L-VSCC blocker, nimodipine. On the other hand, blockers of other VSCCs such as the N-type and P/Q-type calcium channels had no effect on the neuronal cell death, apoptotic features and Ca(2+) influx. In conclusion, we demonstrated that S-312-d rescues cortical neurons from Abeta- and sPLA(2)-IIA-induced apoptosis.
Keywords:AA, arachidonic acid   AD, Alzheimer’s disease   Aβ, amyloid β protein   [Ca2+]i, concentration of intracellular Ca2+   ic50, concentration giving 50% inhibition   L-VSCC, L-type voltage-sensitive calcium channels   MCA, middle cerebral artery   MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide dye   PBS, phosphate-buffered saline   PG, prostaglandin   PLA2, phospholipase A2   sPLA2, secretory PLA2   sPLA2-IB, group IB sPLA2   sPLA2-IIA, group IIA sPLA2   S-312-d, S-(+)-methyl 4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitro-phenyl)thieno[2,3-b]pyridine-5-carboxylate   TUNEL, TdT-mediated dUTP-biotin nick end-labeling   ω-Aga-GVIA, ω-agatoxin GVIA   ω-CgTX-GVIA, ω-conotoxin GVIA   ω-CgTX-MVIIC, ω-conotoxin MVIIC
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