Neuroprotection by peptide growth factors against anoxia and nitric oxide toxicity requires modulation of protein kinase C.
Basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) are neuroprotective during anoxia and nitric oxide (NO) toxicity. Signal transduction systems that modulate protein kinase C (PKC) also can modulate the toxic effects of anoxia and NO. We therefore examined whether PKC was involved in the protective effects of bFGF and EGF during anoxia and NO toxicity. Down-regulation or inhibition of PKC activity before anoxia or NO exposure prevented hippocampal neuronal degeneration. Yet, this protective effect of inhibition of PKC activity was not present with the coadministration of growth factors. Combined inhibition of PKC activity and application of bFGF or EGF lessened the protective mechanisms of the growth factors. In addition, the protective ability of the growth factors was lost during anoxia and NO exposure with the activation of PKC, suggesting that at least a minimal degree of PKC activation is necessary for growth factor protection. Although modulation of PKC activity may be a necessary prerequisite for protection against anoxia and NO toxicity by bFGF and EGF, only inhibition of PKC activity, rather than application of the growth factors, was protective following exposure to NO. These results suggest that the mechanism of protection by bFGF and EGF during anoxia and NO toxicity appears initially to be dependent on a minimum degree of PKC activation, but that other signal transduction pathways independent of PKC also may mediate protection by peptide growth factors.
Maiese
K
K
Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Boccone
L
L
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000818:Animals; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000494:pharmacology / Q000627:therapeutic use*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology / Q000627:therapeutic use*; D002534:Hypoxia, Brain / Q000150:complications / Q000188:drug therapy*; D007546:Isoquinolines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000633:toxicity*; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
D007546:Isoquinolines; D018696:Neuroprotective Agents; D010879:Piperazines; D016222:Fibroblast Growth Factor 2; D009569:Nitric Oxide; D004815:Epidermal Growth Factor; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C