Doctorado en Ciencias Biológicas y de La Salud, Universidad Autónoma Metropolitana, 09310, Mexico City, Mexico.
Facultad de Ciencias, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico.
Mol Neurobiol. 2024 Sep;61(9):6435-6452. doi: 10.1007/s12035-024-03967-2. Epub 2024 Feb 3.
Mitochondrial dysfunction plays a key role in the development of neurodegenerative disorders. In contrast, the regulation of the endocannabinoid system has been shown to promote neuroprotection in different neurotoxic paradigms. The existence of an active form of the cannabinoid receptor 1 (CB1R) in mitochondrial membranes (mitCB1R), which might exert its effects through the same signaling mechanisms as the cell membrane CB1R, has been shown to regulate mitochondrial activity. Although there is evidence suggesting that some cannabinoids may induce protective effects on isolated mitochondria, substantial evidence on the role of cannabinoids in mitochondria remains to be explored. In this work, we developed a toxic model of mitochondrial dysfunction induced by exposure of brain mitochondria to the succinate dehydrogenase inhibitor 3-nitropropionic acid (3-NP). Mitochondria were also pre-incubated with the endogenous agonist anandamide (AEA) and the synthetic CB1R agonist WIN 55212-2 to evaluate their protective effects. Mitochondrial reduction capacity, reactive oxygen species (ROS) formation, and mitochondrial swelling were assessed as toxic markers. While 3-NP decreased the mitochondrial reduction capacity and augmented mitochondrial ROS formation and swelling, both AEA and WIN 55212-2 ameliorated these toxic effects. To explore the possible involvement of mitCB1R activation on the protective effects of AEA and WIN 55212-2, mitochondria were also pre-incubated in the presence of the selective CB1R antagonist AM281, which completely reverted the protective effects of the cannabinoids to levels similar to those evoked by 3-NP. These results show partial protective effects of cannabinoids, suggesting that mitCB1R activation may be involved in the recovery of compromised mitochondrial activity, related to reduction of ROS formation and further prevention of mitochondrial swelling.
线粒体功能障碍在神经退行性疾病的发展中起着关键作用。相比之下，内源性大麻素系统的调节已被证明在不同的神经毒性模型中促进神经保护。已经表明，在线粒体膜（mitCB1R）中存在一种活性形式的大麻素受体 1（CB1R），它可能通过与细胞膜 CB1R 相同的信号机制发挥作用，调节线粒体活性。尽管有证据表明一些大麻素可能对分离的线粒体产生保护作用，但大麻素在线粒体中的作用仍有大量证据需要探索。在这项工作中，我们开发了一种由琥珀酸脱氢酶抑制剂 3-硝基丙酸（3-NP）暴露于脑线粒体引起的线粒体功能障碍的毒性模型。线粒体也预先用内源性激动剂花生四烯酸酰胺（AEA）和合成的 CB1R 激动剂 WIN 55212-2 孵育，以评估它们的保护作用。线粒体还原能力、活性氧（ROS）形成和线粒体肿胀被评估为毒性标志物。虽然 3-NP 降低了线粒体还原能力，增加了线粒体 ROS 形成和肿胀，但 AEA 和 WIN 55212-2 均改善了这些毒性作用。为了探讨 AEA 和 WIN 55212-2 的保护作用可能涉及 mitCB1R 激活，线粒体也在用选择性 CB1R 拮抗剂 AM281 孵育，这完全使大麻素的保护作用恢复到类似于 3-NP 引起的水平。这些结果表明大麻素具有部分保护作用，表明 mitCB1R 激活可能参与恢复受损的线粒体活性，与减少 ROS 形成和进一步防止线粒体肿胀有关。
