Roles of Bcl-2 and caspases in hypoxia-induced neuronal cell death: a possible neuroprotective mechanism of peptide growth factors.
We examined whether apoptosis is involved in hypoxic cell death using primary cultures of rat cortical neurons and whether the cell death is associated with changes in Bcl-2 and Bax expressions and activities of caspases. Hypoxic insult accelerates apoptosis, as shown by apoptotic nuclei and by chromatin degradation of internucleosomal fragments. This apoptotic process is accompanied by a rapid and sustained down-regulation of Bcl-2, whereas levels of Bax are unchanged. Furthermore, hypoxic insult activates sequentially caspase-1-like and caspase-3-like proteases, following down-regulation of Bcl-2 expression. Peptide inhibitors of either caspase-1 or caspase-3 protect against neuronal death, although they do not prevent hypoxia-induced down-regulation of Bcl-2. Furthermore, treatment of cortical neurons with either insulin-like growth factor-1 (IGF-1) or basic fibroblast growth factor (bFGF), growth factors which are implicated to prevent neuronal loss in ischemic brain, partly prevented neuronal death accompanied by inhibition of alterations in Bcl-2 protein levels and caspase-3-like activities. These results suggest that hypoxia induces neuronal death by down-regulation of Bcl-2 protein levels followed by sequential activation of the caspases, and the protection from neuronal cell death of these growth factors under hypoxic conditions derives at least partly from their capability to prevent down-regulation of the anti-apoptotic protein levels.
Department of Anatomy and Neuroscience, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565, Japan. tama@anat2.med.osaka-u.ac.jp
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Tamatani
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Ogawa
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Tohyama
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death; D015687:Cell Hypoxia; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D051028:bcl-2-Associated X Protein
C494828:Bax protein, rat; D015853:Cysteine Proteinase Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D016222:Fibroblast Growth Factor 2; D007334:Insulin-Like Growth Factor I; D003546:Cysteine Endopeptidases