Protein kinase C modulates the protective ability of peptide growth factors during anoxia.
Neuronal degeneration following exposure to anoxia and nitric oxide (NO) may be modulated by peptide growth factors and the activity of signal transduction systems. Basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) are neuroprotective during anoxia and NO toxicity. Signal transduction systems that activate protein kinase C (PKC) can be detrimental to neurons and mediate the toxic effects of anoxia and NO. We therefore examined whether PKC was involved in the protective effects of bFGF and EGF during anoxia. After exposure to anoxia, approximately 20-30% of hippocampal neurons survive. In contrast, chronic down-regulation of PKC activity prior to anoxia increases hippocampal neuronal cell survival to approximately 75%. Yet, this protective effect of inhibition of PKC activity was not present with the application of peptide growth factors during anoxia. Combined inhibition of PKC activity and application of the peptide growth factors bFGF or EGF was detrimental to the hippocampal neurons during anoxia. Neuronal survival during anoxia was 68 +/- 2% with bFGF and 79 +/- 3% with EGF but decreased to 49 +/- 7% (bFGF) and 44 +/- 2% (EGF) with PKC down-regulation. Addition of the growth factors with the agent H-7, an inhibitor of PKC activity, also decreased neuronal survival during anoxia. In addition, the protective effects of the growth factors during anoxia were lessened to a greater degree with the activation of PKC, decreasing hippocampal neuronal survival for bFGF to 23 +/- 2% and for EGF to 31 +/- 3%.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Neurology and Neuroscience, Cornell University Medical College, New York, New York 10021.
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D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D002534:Hypoxia, Brain / Q000473:pathology*; D007546:Isoquinolines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D006133:Growth Substances; D007546:Isoquinolines; D010879:Piperazines; D016222:Fibroblast Growth Factor 2; D004815:Epidermal Growth Factor; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C