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. Si gnal transduction systems that modulate protein kinase C (PKC) also ca n modulate the toxic effects of anoxia and NO. We therefore examined w hether PKC was involved in the protective effects of bFGF and EGF duri ng anoxia and NO toxicity. Down-regulation or inhibition of PKC activi ty before anoxia or NO exposure prevented hippocampal neuronal degener ation. Yet, this protective effect of inhibition of PKC activity was n ot present with the coadministration of growth factors. Combined inhib ition of PKC activity and application of bFGF or EGF lessened the prot ective mechanisms of the growth factors. In addition, the protective a bility of the growth factors was lost during anoxia and NO exposure wi th the activation of PKC, suggesting that at least a minimal degree of PKC activation is necessary for growth factor protection. Although mo dulation of PKC activity may be a necessary prerequisite for protectio n against anoxia and NO toxicity by bFGF and EGF, only inhibition of P KC activity, rather than application of the growth factors, was protec tive following exposure to NO. These results suggest that the mechanis m of protection by bFGF and EGF during anoxia and NO toxicity appears initially to be dependent on a minimum degree of PKC activation, but t hat other signal transduction pathways independent of PKC also may med iate protection by peptide growth factors.