Oxyhomologation of the amide bond potentiates neuroprotective effects of the endolipid N-palmitoylethanolamine

The endolipid N-palmitoylethanolamine (PEA) shows a pleiotropic pattern of bioactivities, whose mechanistic characterization is still unclear and whose pharmacological potential is substantially limited by rapid metabolization by the amido hydrolyzing enzymes fatty acid amide hydrolases and N-acylethanolaminehydrolyzing acid amidase. To overcome this problem, we have synthesized a new series of PEA homologs and characterized their activity on two in vitro models of neurodegeneration (oxidative stress, excitotoxicity). PEA partially prevented tert-butylhydroperoxide (t-BOOH; 100 μM; 3 h)-induced cell death (maximal effect, 26.3 ± 7.5% in comparison with t-BOOH-untreated cells at 30 μM), whereas it was ineffective against the L-glutamate (1 mM; 24 h)-induced excitotoxicity at all concentrations tested (0.01-30 μM). Oxyhomologation of the amide bond, although leading to an increased enzymatic stability, also potentiated neuroprotective activity, especially for N-palmitoyl-N-(2-hydroxyethyl)hydroxylamine (EC₅₀ = 2.1 μM). These effects were not mediated by cannabinoid/vanilloid-dependent mechanisms but rather linked to a decreased t-BOOH-induced lipoperoxidation and reactive oxygen species formation and L-glutamate-induced intracellular Ca ²⁺ overload. The presence of the hydroxamic group and the absence of either redox active or radical scavenger moieties suggest that the improved neuroprotection is the result of increased metal-chelating properties that boost the antioxidant activity of these compounds.