Inhibition of enzymes responsible for endocannabinoid hydrolysis represents an invaluable emerging tool for the potential treatment of neurodegenerative disorders. Monoacylglycerol lipase (MAGL) is the enzyme responsible for degrading 2-arachydonoylglycerol (2-AG), the most abundant endocannabinoid in the central nervous system (CNS). Here, we tested the effects of the selective MAGL inhibitor JZL184 on the 3-nitropropinic acid (3-NP)-induced short-term loss of mitochondrial reductive capacity/viability and oxidative damage in rat brain synaptosomal/mitochondrial fractions and cortical slices. In synaptosomes, while 3-NP decreased mitochondrial function and increased lipid peroxidation, JZL184 attenuated both markers. The protective effects evoked by JZL184 on the 3-NP-induced mitochondrial dysfunction were primarily mediated by activation of cannabinoid receptor 2 (CB2R), as evidenced by their inhibition by the selective CB2R inverse agonist JTE907. The cannabinoid receptor 1 (CB1R) also participated in this effect in a lesser extent, as evidenced by the CB1R antagonist/inverse agonist AM281. In contrast, activation of CB1R, but not CB2R, was responsible for the protective effects of JZL184 on the 3-NP-iduced lipid peroxidation. Protective effects of JZL184 were confirmed in other toxic models involving excitotoxicity and oxidative damage as internal controls. In cortical slices, JZL184 ameliorated the 3-NP-induced loss of mitochondrial function, the increase in lipid peroxidation, and the inhibition of succinate dehydrogenase (mitochondrial complex II) activity, and these effects were independent on CB1R and CB2R, as evidenced by the lack of effects of AM281 and JTE907, respectively. Our novel results provide experimental evidence that the differential protective effects exerted by JZL184 on the early toxic effects induced by 3-NP in brain synaptosomes and cortical slices involve MAGL inhibition, and possibly the subsequent accumulation of 2-AG. These effects involve pro-energetic and redox modulatory mechanisms that may be either dependent or independent of cannabinoid receptors’ activation.

抑制负责内源性大麻素水解的酶是神经退行性疾病潜在治疗的宝贵新兴工具。单酰甘油脂肪酶 (MAGL) 是负责降解 2-花生四烯酰甘油 (2-AG) 的酶，2-AG 是中枢神经系统 (CNS) 中最丰富的内源性大麻素。在这里，我们测试了选择性 MAGL 抑制剂 JZL184 对 3-硝基丙酸 (3-NP) 诱导的大鼠脑突触体/线粒体部分和皮质切片中线粒体还原能力/活力的短期丧失和氧化损伤的影响。在突触体中，虽然 3-NP 降低了线粒体功能并增加了脂质过氧化，但 JZL184 却减弱了这两种标记。JZL184 对 3-NP 诱导的线粒体功能障碍产生的保护作用主要是通过激活大麻素受体 2 (CB2R) 介导的，选择性 CB2R 反向激动剂 JTE907 的抑制作用证明了这一点。大麻素受体 1 (CB1R) 也在较小程度上参与了这种效应，CB1R 拮抗剂/反向激动剂 AM281 证明了这一点。相反，JZL184 对 3-NP 诱导的脂质过氧化的保护作用是由 CB1R（而不是 CB2R）的激活负责的。JZL184 的保护作用在其他涉及兴奋性毒性和氧化损伤的毒性模型（作为内部对照）中得到了证实。在皮质切片中，JZL184 改善了 3-NP 诱导的线粒体功能丧失、脂质过氧化的增加以及琥珀酸脱氢酶（线粒体复合物 II）活性的抑制，并且这些作用独立于 CB1R 和 CB2R，如分别缺乏 AM281 和 JTE907 的效果。我们的新结果提供了实验证据，表明 JZL184 对脑突触体和皮质切片中 3-NP 诱导的早期毒性作用产生的差异保护作用涉及 MAGL 抑制，并可能涉及随后的 2-AG 积累。这些作用涉及促能量和氧化还原调节机制，可能依赖于或独立于大麻素受体的激活。