Department of Pharmaceutical Sciences, MCPHS University, 179 Longwood Avenue, Boston, MA, USA.
School of Pharmacy, MCPHS University, 179 Longwood Avenue, Boston, MA, USA.
Toxicol Appl Pharmacol. 2018 Feb 1;340:67-76. doi: 10.1016/j.taap.2017.12.014. Epub 2017 Dec 27.
Macamides are a distinct class of secondary metabolites, benzylamides of long chain fatty acids, which were isolated from the Peruvian plant Lepidium meyenii (Maca). As structural analogues of the endocannabinoid anandamide (AEA), they have demonstrated neuroprotective effects in vitro and in vivo. The purpose of this study was to demonstrate the neuroprotective activity of the macamides: N-(3-methoxybenzyl)oleamide (MAC 18:1), N-(3-methoxybenzyl)linoleamide (MAC 18:2) and N-(3-methoxybenzyl)linolenamide (MAC 18:3) in a neurotoxic environment caused by exposure of U-87 MG glioblastoma cells to manganese chloride (MnCl). The neuroprotective effects of these macamides were reversed by the CB antagonist AM251. The mechanism by which manganese (Mn) induces cell damage was investigated by studying its effects on mitochondria. Reactive oxygen species (ROS) increase intracellular calcium and enhance the opening of mitochondrial permeability transition pores (MPTP), which leads to decreased mitochondrial membrane potential (MMP), to disruption of mitochondria and to neuron death in neurodegenerative disorders. In this study, MnCl at 50μM was responsible for mitochondrial disruption, which was attenuated by all three of the macamides tested. Human peroxisome proliferator-activated receptor gamma (PPARγ) has been proposed to be a cannabinoid target, and PPARγ has also been demonstrated to mediate some of the longer-term vascular effects of the plant cannabinoid, ∆9-tetrahydrocannabinol. PPARγ activation was observed in response to exposures of cells to MAC 18:2 and MAC 18:3. These findings suggest that macamides achieve their neuroprotective effects by binding to CB receptors to protect against Mn-induced toxicity in U-87 MG glioblastoma cells. Additionally these macamides, in a manner similar to the analogous endocannabinoid AEA, interact with other targets such as PPARγ to regulate metabolism and energy homeostasis, cell differentiation and inflammation.
马卡酰胺是一类独特的次生代谢产物，是长链脂肪酸的苄基酰胺，从秘鲁植物 Lepidium meyenii（玛卡）中分离得到。作为内源性大麻素大麻素（AEA）的结构类似物，它们在体外和体内都表现出神经保护作用。本研究旨在证明马卡酰胺的神经保护活性：N-(3-甲氧基苄基）-油酸酰胺（MAC 18:1）、N-(3-甲氧基苄基）-亚油酸酰胺（MAC 18:2）和 N-(3-甲氧基苄基）-亚麻酸酰胺（MAC 18:3）在 U-87 MG 神经胶质瘤细胞暴露于氯化锰（MnCl）引起的神经毒性环境中的作用。这些马卡酰胺的神经保护作用被 CB 拮抗剂 AM251 逆转。通过研究锰（Mn）对线粒体的影响，研究了锰诱导细胞损伤的机制。活性氧（ROS）增加细胞内钙并增强线粒体通透性转换孔（MPTP）的开放，导致线粒体膜电位（MMP）降低、线粒体破坏和神经退行性疾病中神经元死亡。在这项研究中，50μM 的 MnCl 负责线粒体破坏，而测试的三种马卡酰胺都能减轻这种破坏。人类过氧化物酶体增殖物激活受体γ（PPARγ）已被提议为大麻素的靶点，并且已经证明 PPARγ 介导了植物大麻素 ∆9-四氢大麻酚的一些长期血管作用。在细胞暴露于 MAC 18:2 和 MAC 18:3 时观察到 PPARγ 激活。这些发现表明，马卡酰胺通过与 CB 受体结合来保护 U-87 MG 神经胶质瘤细胞免受 Mn 诱导的毒性，从而发挥其神经保护作用。此外，这些马卡酰胺以类似于类似的内源性大麻素 AEA 的方式与其他靶点相互作用，例如 PPARγ，以调节代谢和能量稳态、细胞分化和炎症。
