Okadaic acid induces cycloheximide and caspase sensitive apoptosis in immature neurons.
Previous studies have shown that okadaic acid (OA) evokes tau phosphorylation and neurofibrillary changes in vivo, and in cultured neurons, that resemble Alzheimer's disease pathogenesis. In order to investigate the mechanism of OA-neurotoxicity, we treated cultured rat neurons with OA and examined nuclear morphology, phosphatidylserine (PS) externalization, alpha-fodrin cleavage, and the effects of cell death inhibitors. Our results demonstrated that cycloheximide (CHX) and the broad-spectrum caspase inhibitor, ZVAD, significantly reduced cell death in a dose-dependent manner. Nuclear fragmentation, a hallmark of apoptosis, occurred after OA treatment and was inhibited by CHX or ZVAD. PS externalization was apparent in 6-12 h in neurites and in cell bodies, and peaked at 24 h after OA treatment. Cleavage of alpha-fodrin as visualized by the appearance of 150- and 120-kDa bands appeared with a time course similar to PS externalization. These results suggest that OA induce CHX and caspase sensitive neuronal apoptosis.
Kim
D H
DH
Department of Anatomy, University of Ulsan College of Medicine, Seoul, Korea. dhkim@www.amc.seoul.kr
Hong
H N
HN
Lee
J H
JH
Park
H S
HS
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D061945:Caspase Inhibitors; D016923:Cell Death / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000166:cytology / Q000196:embryology; D008840:Microfilament Proteins / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D019319:Okadaic Acid / Q000494:pharmacology*; D010718:Phosphatidylserines / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D013049:Spectrin
D000590:Amino Acid Chloromethyl Ketones; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D003513:Cycloheximide; D008840:Microfilament Proteins; D019319:Okadaic Acid; D010718:Phosphatidylserines; D013049:Spectrin; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone