Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 17666, UAE.
Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 17666, UAE.
Biomolecules. 2020 Oct 8;10(10):1421. doi: 10.3390/biom10101421.
Rotenone (ROT), a plant-derived pesticide is a well-known environmental neurotoxin associated with causation of Parkinson's disease (PD). ROT impairs mitochondrial dysfunction being mitochondrial complex-I (MC-1) inhibitor and perturbs antioxidant-oxidant balance that contributes to the onset and development of neuroinflammation and neurodegeneration in PD. Due to the scarcity of agents to prevent the disease or to cure or halt the progression of symptoms of PD, the focus is on exploring agents from naturally occurring dietary phytochemicals. Among numerous phytochemicals, α-Bisabolol (BSB), natural monocyclic sesquiterpene alcohol found in many ornamental flowers and edible plants garnered attention due to its potent pharmacological properties and therapeutic potential. Therefore, the present study investigated the neuroprotective effects of BSB in a rat model of ROT-induced dopaminergic neurodegeneration, a pathogenic feature of PD and underlying mechanism targeting oxidative stress, inflammation and apoptosis. BSB treatment significantly prevented ROT-induced loss of dopaminergic neurons and fibers in the substantia nigra and striatum respectively. BSB treatment also attenuated ROT-induced oxidative stress evidenced by inhibition of MDA formation and GSH depletion as well as improvement in antioxidant enzymes, SOD and catalase. BSB treatment also attenuated ROT-induced activation of the glial cells as well as the induction and release of proinflammatory cytokines (IL-1β, IL-6 and TNF-α) and inflammatory mediators (iNOS and COX-2) in the striatum. In addition to countering oxidative stress and inflammation, BSB also attenuated apoptosis of dopaminergic neurons by attenuating downregulation of anti-apoptotic protein Bcl-2 and upregulation of pro-apoptotic proteins Bax, cleaved caspases-3 and 9. Further, BSB was observed to attenuate mitochondrial dysfunction by inhibiting mitochondrial lipid peroxidation, cytochrome-C release and reinstates the levels/activity of ATP and MC-I. The findings of the study demonstrate that BSB treatment salvaged dopaminergic neurons, attenuated microglia and astrocyte activation, induction of inflammatory mediators, proinflammatory cytokines and reduced the expression of pro-apoptotic markers. The in vitro study on ABTS radical revealed the antioxidant potential of BSB. The results of the present study are clearly suggestive of the neuroprotective effects of BSB through antioxidant, anti-inflammatory and anti-apoptotic properties in ROT-induced model of PD.
鱼藤酮（ROT）是一种植物源性杀虫剂，是一种与帕金森病（PD）发病有关的众所周知的环境神经毒素。ROT 可损害线粒体功能，作为线粒体复合物-I（MC-1）抑制剂，并扰乱抗氧化-氧化平衡，导致 PD 中的神经炎症和神经退行性变的发生和发展。由于缺乏预防疾病或治愈或阻止 PD 症状进展的药物，因此重点在于探索来自天然存在的膳食植物化学物质的药物。在众多植物化学物质中，α- 姜黄烯（BSB），一种天然单环倍半萜醇，存在于许多观赏花卉和食用植物中，由于其强大的药理学特性和治疗潜力而受到关注。因此，本研究调查了 BSB 在 ROT 诱导的多巴胺能神经退行性变大鼠模型中的神经保护作用，ROT 诱导的多巴胺能神经退行性变是 PD 的一种发病特征，其作用机制针对氧化应激、炎症和细胞凋亡。BSB 治疗可显著预防 ROT 诱导的黑质和纹状体中多巴胺能神经元和纤维的丢失。BSB 治疗还可减轻 ROT 诱导的氧化应激，表现为抑制 MDA 形成和 GSH 耗竭以及改善抗氧化酶、SOD 和过氧化氢酶。BSB 治疗还可减轻 ROT 诱导的神经胶质细胞激活以及纹状体中促炎细胞因子（IL-1β、IL-6 和 TNF-α）和炎症介质（iNOS 和 COX-2）的诱导和释放。除了对抗氧化应激和炎症外，BSB 还通过减轻抗凋亡蛋白 Bcl-2 的下调和促凋亡蛋白 Bax、裂解 caspase-3 和 9 的上调来减轻多巴胺能神经元的凋亡。此外，BSB 通过抑制线粒体脂质过氧化、细胞色素 C 释放并恢复 ATP 和 MC-I 的水平/活性来减轻线粒体功能障碍。研究结果表明，BSB 治疗挽救了多巴胺能神经元，减轻了小胶质细胞和星形胶质细胞的激活、诱导炎症介质、促炎细胞因子的表达，并降低了促凋亡标志物的表达。ABTS 自由基体外研究揭示了 BSB 的抗氧化潜力。本研究结果清楚地表明，BSB 通过抗氧化、抗炎和抗细胞凋亡特性在 ROT 诱导的 PD 模型中具有神经保护作用。
