Effects of endothelin B receptor agonists on amyloid beta protein (25-35)-induced neuronal cell death.
Endothelin (ET), a vasoconstrictive peptide, acts as an anti-apoptotic factor, and endothelin receptor B (ET(B) receptor) is associated with neuronal survival in the brain. In the Alzheimer's disease (AD) brain, accumulation of amyloid beta protein (Abeta) is thought to cause neuronal cell death via apoptosis. In the present study, we investigated effects of ET(B) receptor agonists on Abeta-induced neuronal cell death. In primary cultures of rat cortical neurons, Abeta(25-35) caused neuronal cell death in a concentration- and time-dependent manner. Abeta(25-35)-induced neuronal cell death was accompanied by chromatin condensation and DNA fragmentation, exhibiting apoptotic features. ET-3 and IRL-1620, ET(B) receptor agonists, significantly prevented neurons from undergoing Abeta(25-35)-induced cell death. Prior to cell death, Abeta increased concentration of intracellular Ca(2+) ([Ca(2+)](i)). Nimodipine, an L-type voltage-sensitive Ca(2+) channel (L-VSCC) blocker, suppressed the Abeta-induced Ca(2) influx, and attenuated Abeta-induced neuronal apoptosis. On the other hand, omega-conotoxin GIVA, an N-type VSCC blocker and omega-conotoxin MVIIC and omega-agatoxin IVA, P/Q-type VSCC blockers, had no effect. ET-3 and IRL-1620 significantly blocked Abeta(25-35)-induced Ca(2) influx. Furthermore, BQ788, an ET(B) receptor antagonist, inhibited both an anti-apoptotic effect and an L-VSCC-inactivating effect of ET(B) receptor agonists. In conclusion, ET(B) receptor agonists exhibit a protective effect against neurotoxicity of Abeta. Furthermore, these agonists appear to act as anti-apoptotic factors by blocking of L-VSCCs.
Yagami
Tatsurou
T
Discovery Research Laboratories, Shionogi and Co, Ltd, 12-4 Sagisu 5-Chome, Fukushima-ku, Osaka 553-0002, Japan. tasurou.yagami@shionogi.co.jp
Ueda
Keiichi
K
Asakura
Kenji
K
Kuroda
Takayuki
T
Hata
Satoshi
S
Sakaeda
Toshiyuki
T
Kambayashi
Yoshikazu
Y
Fujimoto
Masafumi
M
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000493:pharmacokinetics; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival; D002478:Cells, Cultured; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019334:Endothelin-3 / Q000494:pharmacology; D005456:Fluorescent Dyes; D020287:In Situ Nick-End Labeling; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000819:agonists*
D016229:Amyloid beta-Peptides; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D065128:Endothelin Receptor Antagonists; D019334:Endothelin-3; D005456:Fluorescent Dyes; D018696:Neuroprotective Agents; D009842:Oligopeptides; D010446:Peptide Fragments; D010880:Piperidines; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C078592:amyloid beta-protein (1-40); C074636:amyloid beta-protein (25-35); C086539:BQ 788; D002118:Calcium