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-acylethanolamine-hydrolyzing 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 muM; 3 h)-induced cell death (maximal effect, 26.3 +/- 7.5% in comparison with t-BOOH-untreated cells at 30 muM), whereas it was ineffective against the l-glutamate (1 mM; 24 h)-induced excitotoxicity at all concentrations tested (0.01-30 muM). Oxyhomologation of the amide bond, although leading to an increased enzymatic stability, also potentiated neuroprotective activity, especially for N-palmitoyl-N-(2-hydroxyethyl)hydroxylamine (EC(50) = 2.1 muM). 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.[1]References
- Oxyhomologation of the amide bond potentiates neuroprotective effects of the endolipid N-palmitoylethanolamine. Lombardi, G., Miglio, G., Varsaldi, F., Minassi, A., Appendino, G. J. Pharmacol. Exp. Ther. (2007) [Pubmed]
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