Abstract
The pentane extract of the Peruvian plant, Lepidium meyenii (Maca), has been demonstrated to possess neuroprotective activity in previous in vitro and in vivo studies (Pino-Figueroa et al. in Ann N Y Acad Sci 1199:77–85, 2010; Pino-Figueroa et al. in Am J Neuroprot Neuroregener 3:87–92, 2011). This extract contains a number of macamides that may act on the endocannabinoid system (Pino-Figueroa et al. in Ann N Y Acad Sci 1199:77–85, 2010; Pino-Figueroa et al., 2011; Dini et al. in Food Chem 49:347–349, 1994). The aim of this study was to characterize the inhibitory activity of four of these maccamides (N-benzylstearamide, N-benzyloleamide, N-benzyloctadeca-9Z,12Z-dienamide, and N-benzyloctadeca-9Z,12Z,15Z-trienamide) on fatty acid amide hydrolase (FAAH), an enzyme that is responsible for endocannabinoid degradation in the nervous system (Kumar et al. in Anaesthesia 56:1059–1068, 2001). The four compounds were tested at concentrations between 1 and 100 μM, utilizing an FAAH inhibitor screening assay. The results demonstrated concentration-dependent FAAH inhibitory activities for the four macamides tested. N-Benzyloctadeca-9Z,12Z-dienamide demonstrated the highest FAAH inhibitory activity whereas N-benzylstearamide had the lowest inhibitory activity. In addition, N-benzylstearamide, N-benzyloleamide, and N-benzyloctadeca-9Z,12Z-dienamide demonstrated time-dependent inhibition when tested after a pre-incubation period, indicating that the mechanism of inhibition for these compounds most likely is irreversible. Of interest, unsaturation in the fatty acid moiety resulted in greater FAAH inhibitory activity. LC/MS/MS analysis demonstrated that FAAH was able to hydrolyze N-benzyloctadeca-9Z,12Z-dienamide, suggesting that N-benzyloctadeca-9Z,12Z-dienamide is also a slow substrate for FAAH. These results provide useful information about the mechanism of action of Lepidium meyenii and may help with the development of new compounds with FAAH inhibitory or modulatory activity.
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This work was supported by grants from the College of Medicine, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Jeddah 22384, Saudi Arabia.
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Alasmari, M., Bӧhlke, M., Kelley, C. et al. Inhibition of Fatty Acid Amide Hydrolase (FAAH) by Macamides. Mol Neurobiol 56, 1770–1781 (2019). https://doi.org/10.1007/s12035-018-1115-8
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DOI: https://doi.org/10.1007/s12035-018-1115-8