Protective effects of a selective L-type voltage-sensitive calcium channel blocker, S-312-d, on neuronal cell death.
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.
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
Tatsurou
T
Yagami
Keiichi
K
Ueda
Toshiyuki
T
Sakaeda
Naohiro
N
Itoh
Gaku
G
Sakaguchi
Noboru
N
Okamura
Yozo
Y
Hori
Masafumi
M
Fujimoto
D016229:Amyloid beta-Peptides; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism*; D016923:Cell Death; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002843:Chromatin / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004095:Dihydropyridines / Q000494:pharmacology*; D004347:Drug Interactions; D008853:Microscopy; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D010446:Peptide Fragments; D010741:Phospholipases A / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology*; D051381:Rats
D016229:Amyloid beta-Peptides; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D002843:Chromatin; D004095:Dihydropyridines; D010446:Peptide Fragments; D020011:Protective Agents; C074636:amyloid beta-protein (25-35); C059447:S 312; D010741:Phospholipases A; D002118:Calcium