Comparative study of survival signal withdrawal- and 4-hydroxynonenal-induced cell death in cerebellar granule cells

The lipid peroxidation product, 4-hydroxynonenal (HNE), has been shown to i nduce apoptosis in PC12 cells and hippocampal neurons. We compared the degr ee of cell heath induced by survival signal withdrawal (K+ and serum depriv ation) with that induced by HNE. and investigated whether agents that block survival signal withdrawal-induced apoptosis could also prevent HNE-induce d cell death in cultured cerebellar granule cells. Cell death induced by K and serum deprivation was inhibited by cycloheximide, a CPP 32-like protea se inhibitor (Ac-DEVD-CHO) and a pituitary adenylate cyclase-activating pol ypeptide (PACAP)-38. In addition, nuclear cyclic AMP responsive element (CR E)- and activator protein 1 (AP-1) DNA-binding activities were increased 2 h after K+ and serum withdrawal, and these increases were inhibited by cycl oheximide. Ac-DEVD-CHO and PACAP 38. Although these agents also blocked HNE -induced cell death, consistent with their efficacy in preventing survival signal withdrawal-induced cells death, CRE and AP-1 DNA-binding activities were decreased in a time-dependent manner during HNE-induced cell death. Th ese results suggest that mechanistic differences exist between apoptosis in duced by HNE and that induced by withdrawal of survival signals in cerebell ar granule neurons. (C) 1999 Elsevier Science Ireland Ltd. All rights reser ved.