Formation of N-acyl-phosphatidylethanolamine and N-acylethanolamine (including anandamide) during glutamate-induced neurotoxicity

N-Acyl-phosphalidylethanolamine (NAPE) is present in very small amounts in mammalian tissues (less than 0.1% of total phospholipids). However, NAPE la s well as its degradation product, N-acylethanolamine (NAE), can be formed in certain neuronal tissues in response to increased [Ca2+](i). A high [Ca2 +](i) will activate the NAPE-forming N-acyl-transferase using the sn-l acyl group of a donor phospholipid as substrate in the transfer reaction. This membrane-bound enzyme seems to have no substrate specificity with respect t o transfer of acyl groups; thus the fatty acids in the N-acyl group of NAPE are mainly 16:0 and 18:1, corresponding to the fatty acids in the sn-1 acy l group of the donor phospholipids. The NAPE-hydrolyzing phospholipase D al so seems not to be acyl-group specific. In mouse neocortical neurons in pri mary culture, formation of NAPE and NAE is stimulated by glutamate via acti vation of the N-methyl-D-aspartate-receptor. Both NAPE and, to a lesser ext ent, NAE accumulate in a linear fashion for many hours while at the same ti me the neurons are dying. Likewise, in neurons prelabeled with C-14-arachid onic acid, C-14-arachidonic acid-labeled NAPE, and anandamide (= N-arachido noylethanolamine) are accumulating. The formation of NAPE and NAE may-repre sent a cytoprotective response in relation to various forms of neurotoxicit y.