THE ALIAMIDE PALMITOYLETHANOLAMIDE AND CANNABINOIDS, BUT NOT ANANDAMIDE, ARE PROTECTIVE IN A DELAYED POSTGLUTAMATE PARADIGM OF EXCITOTOXIC DEATH IN CEREBELLAR GRANULE NEURONS

The amino acid L-glutamate is a neurotransmitter that mediates fast ne uronal excitation in a majority of synapses in the central nervous sys tem. Glutamate stimulates both N-methyl-D-aspartate (NMDA) and non-NMD A receptors. While activation of NMDA receptors has been implicated in a variety of neurophysiologic processes, excessive NMDA receptor stim ulation (excitotoxicity) is thought to be primarily responsible for ne uronal injury in a wide variety of acute neurological disorders includ ing hypoxia-ischemia, seizures, and trauma. Very little is known about endogenous molecules and mechanisms capable of modulating excitotoxic neuronal death. Saturated N-acylethanolamides like palmitoylethanolam ide accumulate in ischemic tissues and are synthesized by neurons upon excitatory amino acid receptor activation. Here we report that palmit oylethanolamide, but not the cognate N-acylamide anandamide (the ethan olamide of arachidonic acid), protects cultured mouse cerebellar granu le cells against glutamate toxicity in a delayed postagonist paradigm. Palmitoylethanolamide reduced this injury in a concentration-dependen t manner and was maximally effective when added 15-min postglutamate. Cannabinoids, which like palmitoylethanolamide are functionally active at the peripheral cannabinoid receptor CB2 on mast cells, also preven ted neuron loss in this delayed postglutamate model. Furthermore, the neuroprotective effects of palmitoylethanolamide, as well as that of t he active cannabinoids, were efficiently antagonized by the candidate central cannabinoid receptor (CB1) agonist anandamide. Analogous pharm acological behaviors have been observed for palmitoylethanolamide (ALI -Amides) in downmodulating mast cell activation. Cerebellar granule ce lls expressed mRNA for CB1 and CB2 by in situ hybridization, while two cannabinoid binding sites were detected in cerebellar membranes. The results suggest that (i) non-CB1 cannabinoid receptors control, upon a gonist binding, the downstream consequences of an excitotoxic stimulus ; (ii) palmitoylethanolamide, unlike anandamide, behaves as an endogen ous agonist for CBZ-like receptors on granule cells; and (iii) activat ion of such receptors may serve to downmodulate deleterious cellular p rocesses following pathological events or noxious stimuli in both the nervous and immune systems.