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 microM; 3 h)-induced cell death (maximal effect, 26.3 +/- 7.5% in comparison with t-BOOH-untreated cells at 30 microM), whereas it was ineffective against the L-glutamate (1 mM; 24 h)-induced excitotoxicity at all concentrations tested (0.01-30 microM). 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 microM). 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.
Lombardi
Grazia
G
Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche, e Farmacologiche, University of Piemonte Orientale Amedeo Avogadro, Via Bovio, 6, 28100 Novara, Italy. lombardi@pharm.unipmn.it
Miglio
Gianluca
G
Varsaldi
Federica
F
Minassi
Alberto
A
Appendino
Giovanni
G
D000577:Amides; D000975:Antioxidants / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D063387:Cannabinoid Receptor Antagonists; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000494:pharmacology; D063388:Endocannabinoids; D004983:Ethanolamines; D018698:Glutamic Acid / Q000494:pharmacology; D006801:Humans; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress; D010169:Palmitic Acids / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D013329:Structure-Activity Relationship
D000577:Amides; D000975:Antioxidants; D063387:Cannabinoid Receptor Antagonists; D002614:Chelating Agents; D063388:Endocannabinoids; D004983:Ethanolamines; D018696:Neuroprotective Agents; D010169:Palmitic Acids; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; C005958:palmidrol; D002118:Calcium