Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates.
Department of Pharmacology, College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates.
Molecules. 2023 Jan 10;28(2):685. doi: 10.3390/molecules28020685.
Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, resulting in motor deficits. The exact etiology of PD is currently unknown; however, the pathological hallmarks of PD include excessive production of reactive oxygen species, enhanced neuroinflammation, and overproduction of α-synuclein. Under normal physiological conditions, aggregated α-synuclein is degraded via the autophagy lysosomal pathway. However, impairment of the autophagy lysosomal pathway results in α-synuclein accumulation, thereby facilitating the pathogenesis of PD. Current medications only manage the symptoms, but are unable to delay, prevent, or cure the disease. Collectively, oxidative stress, inflammation, apoptosis, and autophagy play crucial roles in PD; therefore, there is an enormous interest in exploring novel bioactive agents of natural origin for their protective roles in PD. The present study evaluated the role of myrcene, a monoterpene, in preventing the loss of dopaminergic neurons in a rotenone (ROT)-induced rodent model of PD, and elucidated the underlying mechanisms. Myrcene was administered at a dose of 50 mg/kg, 30 min prior to the intraperitoneal injections of ROT (2.5 mg/kg). Administration of ROT caused a considerable loss of dopaminergic neurons, subsequent to a significant reduction in the antioxidant defense systems, increased lipid peroxidation, and activation of microglia and astrocytes, along with the production of pro-inflammatory cytokines (IL-6, TNF-α, IL-1β) and matrix metalloproteinase-9. Rotenone also resulted in impairment of the autophagy lysosomal pathway, as evidenced by increased expression of LC3, p62, and beclin-1 with decreased expression in the phosphorylation of mTOR protein. Collectively, these factors result in the loss of dopaminergic neurons. However, myrcene treatment has been observed to restore antioxidant defenses and attenuate the increase in concentrations of lipid peroxidation products, pro-inflammatory cytokines, diminished microglia, and astrocyte activation. Myrcene treatment also enhanced the phosphorylation of mTOR, reinstated neuronal homeostasis, restored autophagy-lysosomal degradation, and prevented the increased expression of α-synuclein following the rescue of dopaminergic neurons. Taken together, our study clearly revealed the mitigating effect of myrcene on dopaminergic neuronal loss, attributed to its potent antioxidant, anti-inflammatory, and anti-apoptotic properties, and favorable modulation of autophagic flux. This study suggests that myrcene may be a potential candidate for therapeutic benefits in PD.
帕金森病（PD）的特征是黑质致密部多巴胺能神经元丧失，导致运动功能障碍。PD 的确切病因目前尚不清楚；然而，PD 的病理标志包括活性氧物种的过度产生、神经炎症的增强以及α-突触核蛋白的过度产生。在正常生理条件下，聚集的α-突触核蛋白通过自噬溶酶体途径降解。然而，自噬溶酶体途径的损伤导致α-突触核蛋白积累，从而促进 PD 的发病机制。目前的药物只能治疗症状，而不能延缓、预防或治愈这种疾病。总的来说，氧化应激、炎症、细胞凋亡和自噬在 PD 中起关键作用；因此，人们对探索天然来源的新型生物活性物质在 PD 中的保护作用非常感兴趣。本研究评估了单萜化合物月桂烯在预防鱼藤酮（ROT）诱导的 PD 啮齿动物模型中多巴胺能神经元丧失中的作用，并阐明了其潜在机制。在腹腔注射 ROT（2.5mg/kg）前 30 分钟，给予月桂烯 50mg/kg。ROT 的给药导致多巴胺能神经元大量丧失，随后抗氧化防御系统显著减少，脂质过氧化增加，小胶质细胞和星形胶质细胞激活，以及促炎细胞因子（IL-6、TNF-α、IL-1β）和基质金属蛋白酶-9 的产生。鱼藤酮还导致自噬溶酶体途径受损，表现为 LC3、p62 和 beclin-1 的表达增加，而 mTOR 蛋白磷酸化减少。综上所述，这些因素导致多巴胺能神经元丧失。然而，已经观察到月桂烯治疗可以恢复抗氧化防御，减轻脂质过氧化产物、促炎细胞因子、减少小胶质细胞和星形胶质细胞激活的浓度增加。月桂烯治疗还增强了 mTOR 的磷酸化，恢复了神经元的内稳态，恢复了自噬溶酶体降解，并防止了多巴胺能神经元挽救后α-突触核蛋白的表达增加。总之，我们的研究清楚地揭示了月桂烯对多巴胺能神经元丧失的缓解作用，这归因于其强大的抗氧化、抗炎和抗凋亡特性，以及对自噬流的有利调节。这项研究表明，月桂烯可能是治疗 PD 的潜在候选药物。
