Abstract
The effect of palmitoylethanolamide (PEA), an endogenous fatty acid amide displaying neuroprotective actions, on glutamate release from rat cerebrocortical nerve terminals (synaptosomes) was investigated. PEA inhibited the Ca2+-dependent release of glutamate, which was triggered by exposing synaptosomes to the potassium channel blocker 4-aminopyridine. This release inhibition was concentration dependent, associated with a reduction in cytosolic Ca2+ concentration, and not due to a change in synaptosomal membrane potential. The glutamate release-inhibiting effect of PEA was prevented by the Cav2.1 (P/Q-type) channel blocker ω-agatoxin IVA or the protein kinase A inhibitor H89, not affected by the intracellular Ca2+ release inhibitors dantrolene and CGP37157, and partially antagonized by the cannabinoid CB1 receptor antagonist AM281. Based on these results, we suggest that PEA exerts its presynaptic inhibition, likely through a reduction in the Ca2+ influx mediated by Cav2.1 (P/Q-type) channels, thereby inhibiting the release of glutamate from rat cortical nerve terminals. This release inhibition might be linked to the activation of presynaptic cannabinoid CB1 receptors and the suppression of the protein kinase A pathway.
Highlights
Palmitoylethanolamide (PEA) is an endogenous lipid belonging to the family of fatty acid ethanolamides [1]
PEA is abundant in the central nervous system (CNS) and exerts neuroprotective effects [2,3,4]
Using an established method for examining endogenous glutamate release [25], we found that PEA greatly inhibited glutamate release from synaptosomes by suppressing Cav2.1 (P/Q-type) channels and protein kinase A activity
Summary
Palmitoylethanolamide (PEA) is an endogenous lipid belonging to the family of fatty acid ethanolamides [1]. PEA administration has been reported to reduce brain damage and improve behavioral dysfunctions in several experimental models of CNS injury and disease, including epilepsy, cerebral ischemia, stroke, Alzheimer’s disease, and Parkinson’s disease [8,9,10,11,12,13,14]. These findings suggest that PEA acts as an endogenous protective factor of the brain; the precise mechanisms involved in this role are unclear
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