Department of Pharmaceutical Sciences, MCPHS University, 179 Longwood Ave., Boston, MA, 02115, USA.
Mol Neurobiol. 2019 Mar;56(3):1770-1781. doi: 10.1007/s12035-018-1115-8. Epub 2018 Jun 20.
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.
秘鲁植物 Lepidium meyenii（玛卡）的正戊烷提取物已在先前的体外和体内研究中证明具有神经保护活性（Pino-Figueroa 等人，Ann N Y Acad Sci 1199：77-85，2010；Pino-Figueroa 等人，Am J Neuroprot Neuroregener 3：87-92，2011）。该提取物含有多种酰胺，可能作用于内源性大麻素系统（Pino-Figueroa 等人，Ann N Y Acad Sci 1199：77-85，2010；Pino-Figueroa 等人，2011；Dini 等人，Food Chem 49：347-349，1994）。本研究的目的是表征这四种酰胺（N-苯甲酰硬脂酰胺、N-苯甲酰油酸酰胺、N-苯甲酰十八碳-9Z,12Z-二烯酰胺和 N-苯甲酰十八碳-9Z,12Z,15Z-三烯酰胺）对脂肪酸酰胺水解酶（FAAH）的抑制活性，FAAH 是负责神经系统内源性大麻素降解的酶（Kumar 等人，Anaesthesia 56：1059-1068，2001）。四种化合物在 1 到 100μM 的浓度下进行测试，利用 FAAH 抑制剂筛选测定法。结果表明，四种测试的酰胺均表现出浓度依赖性 FAAH 抑制活性。N-苯甲酰十八碳-9Z,12Z-二烯酰胺表现出最高的 FAAH 抑制活性，而 N-苯甲酰硬脂酰胺的抑制活性最低。此外，当在预孵育期后进行测试时，N-苯甲酰硬脂酰胺、N-苯甲酰油酸酰胺和 N-苯甲酰十八碳-9Z,12Z-二烯酰胺表现出时间依赖性抑制，表明这些化合物的抑制机制很可能是不可逆的。有趣的是，脂肪酸部分的不饱和性导致 FAAH 抑制活性增强。LC/MS/MS 分析表明 FAAH 能够水解 N-苯甲酰十八碳-9Z,12Z-二烯酰胺，表明 N-苯甲酰十八碳-9Z,12Z-二烯酰胺也是 FAAH 的慢底物。这些结果提供了关于 Lepidium meyenii 作用机制的有用信息，并可能有助于开发具有 FAAH 抑制或调节活性的新化合物。
