Formation ofN‐acyl‐phosphatidylethanolamine andN‐acylethanolamine (including anandamide) during glutamate‐induced neurotoxicity

N‐Acyl‐phosphatidylethanolamine (NAPE) is present in very small amounts in mammalian tissues (less than 0.1% of total phospholipids). However, NAPE as 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‐formingN‐acyl‐transferase using thesn‐1 acyl group of a donor phospholipid as substrate in the transfer reaction. This membrane‐bound enzyme seems to have no substrate specificity with respect to transfer of acyl groups; thus the fatty acids in theN‐acyl group of NAPE are mainly 16:0 and 18:1, corresponding to the fatty acids in thesn‐1 acyl group of the donor phospholipids. The NAPE‐hydrolyzing phospholipase D also seems not to be acyl‐group specific. In mouse neocortical neurons in primary culture, formation of NAPE and NAE is stimulated by glutamatevia activation of theN‐methyl‐d‐aspartate‐receptor. Both NAPE and, to a lesser extent, NAE accumulate in a linear fashion for many hours while at the same time the neurons are dying. Likewise, in neurons prelabeled with14C‐arachidonic acid,14C‐arachidonic acid‐labeled NAPE, and anandamide (=N‐arachi‐donoylethanolamine) are accumulating. The formation of NAPE and NAE may represent a cytoprotective response in relation to various forms of neurotoxicity.