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Dopamine, a key factor of mitochondrial damage and neuronal toxicity on rotenone exposure and also parkinsonic motor dysfunction – impact of asiaticoside with a probable vesicular involvement
Journal of Chemical Neuroanatomy ( IF 2.8 ) Pub Date : 2020-07-01 , DOI: 10.1016/j.jchemneu.2020.101788 Gopi Margabandhu 1 , Arambakkam Janardhanam Vanisree 1
Journal of Chemical Neuroanatomy ( IF 2.8 ) Pub Date : 2020-07-01 , DOI: 10.1016/j.jchemneu.2020.101788 Gopi Margabandhu 1 , Arambakkam Janardhanam Vanisree 1
Affiliation
Persuasive evidence propose that the toxicity of dopamine in parkinsonism and the loss of dopaminergic neurons are the earliest events during the pathogenesis of Parkinson's disease (PD). In our earlier study, Asiaticoside (AS), a triterpenoid saponin isolated from Centella asiatica was shown to exert a neuroprotective effect against hemiparkinsonism, purportedly due to phosphoinositides (PI)-assisted cytodynamics and synaptic function. Here, we evaluate AS in the modulation of dopamine (DA), mitochondrial integrity and neurite variations in vitro and motor dysfunctions in vivo. PC12 cells challenged with rotenone-(ROT) (0.1 μM/ml) were exposed to AS and L-DOPA (10 mM and 20 μM/ml respectively). The protein expressions of Bax and Bcl-2 that regulate cell death were assessed following neurite length assays. Rats were distributed into 6 groups (6 rats/group): Sham, Vehicle controls, ROT-infused (6 µg/µl/kg), AS- treated (50 mg/kg/day), Drug control, and ROT + L-DOPA-treated (6 mg/kg/day) groups. At the end of the experimental period, the rats were sacrificed after performing motor behavioral analysis, and the striatum was dissected out. The contents of synaptic vesicular and cytosolic DA were analyzed. Further, the levels of striatal PI were also measured. ROT had caused significant reduction in the neurite outgrowth in the exposed PC12 cells while the tested concentrations of AS and L-DOPA can exert their protective effect on the stunted neurite growth. The levels of Bax, Bcl-2, and cytochrome c which were significantly disturbed by ROT, could also be affected by AS thereby suggesting its effect on neurons. AS treatment caused an improved motor performance, vesicular and cytosolic DA, and striatal PI. These pre-clinical findings force us to speculate that AS could be a potential drug candidate in combating ROT-induced variations that are possibly precipitated by varied vesicular trafficking of DA.
中文翻译:
多巴胺,线粒体损伤和神经元毒性对鱼藤酮暴露以及帕金森运动功能障碍的关键因素——积雪草苷的影响可能与囊泡受累
有说服力的证据表明,多巴胺在帕金森病中的毒性和多巴胺能神经元的丧失是帕金森病 (PD) 发病机制中最早发生的事件。在我们早期的研究中,积雪草苷 (AS) 是一种从积雪草中分离出的三萜皂苷,据称对偏侧帕金森症具有神经保护作用,据称是由于磷酸肌醇 (PI) 辅助的细胞动力学和突触功能。在这里,我们评估 AS 在调节多巴胺 (DA)、体外线粒体完整性和神经突变异以及体内运动功能障碍方面的作用。用鱼藤酮-(ROT) (0.1 μM/ml) 攻击的 PC12 细胞暴露于 AS 和 L-DOPA(分别为 10 mM 和 20 μM/ml)。在神经突长度测定后评估了调节细胞死亡的 Bax 和 Bcl-2 的蛋白质表达。大鼠被分为 6 组(6 只大鼠/组):假手术、载体对照、ROT 输注(6 µg/µl/kg)、AS 治疗(50 mg/kg/天)、药物对照和 ROT + L-多巴治疗 (6 mg/kg/天) 组。实验结束时,进行运动行为分析后处死大鼠,解剖出纹状体。分析了突触小泡和胞质 DA 的含量。此外,还测量了纹状体 PI 的水平。ROT 导致暴露的 PC12 细胞中神经突生长显着减少,而测试浓度的 AS 和 L-DOPA 可以对发育不良的神经突生长发挥保护作用。受 ROT 显着干扰的 Bax、Bcl-2 和细胞色素 c 的水平也可能受到 AS 的影响,从而表明其对神经元的影响。AS 治疗导致运动表现、囊泡和细胞质 DA 以及纹状体 PI 的改善。这些临床前发现迫使我们推测 AS 可能是对抗 ROT 诱导的变异的潜在候选药物,这些变异可能是由 DA 的各种囊泡运输引起的。
更新日期:2020-07-01
中文翻译:
多巴胺,线粒体损伤和神经元毒性对鱼藤酮暴露以及帕金森运动功能障碍的关键因素——积雪草苷的影响可能与囊泡受累
有说服力的证据表明,多巴胺在帕金森病中的毒性和多巴胺能神经元的丧失是帕金森病 (PD) 发病机制中最早发生的事件。在我们早期的研究中,积雪草苷 (AS) 是一种从积雪草中分离出的三萜皂苷,据称对偏侧帕金森症具有神经保护作用,据称是由于磷酸肌醇 (PI) 辅助的细胞动力学和突触功能。在这里,我们评估 AS 在调节多巴胺 (DA)、体外线粒体完整性和神经突变异以及体内运动功能障碍方面的作用。用鱼藤酮-(ROT) (0.1 μM/ml) 攻击的 PC12 细胞暴露于 AS 和 L-DOPA(分别为 10 mM 和 20 μM/ml)。在神经突长度测定后评估了调节细胞死亡的 Bax 和 Bcl-2 的蛋白质表达。大鼠被分为 6 组(6 只大鼠/组):假手术、载体对照、ROT 输注(6 µg/µl/kg)、AS 治疗(50 mg/kg/天)、药物对照和 ROT + L-多巴治疗 (6 mg/kg/天) 组。实验结束时,进行运动行为分析后处死大鼠,解剖出纹状体。分析了突触小泡和胞质 DA 的含量。此外,还测量了纹状体 PI 的水平。ROT 导致暴露的 PC12 细胞中神经突生长显着减少,而测试浓度的 AS 和 L-DOPA 可以对发育不良的神经突生长发挥保护作用。受 ROT 显着干扰的 Bax、Bcl-2 和细胞色素 c 的水平也可能受到 AS 的影响,从而表明其对神经元的影响。AS 治疗导致运动表现、囊泡和细胞质 DA 以及纹状体 PI 的改善。这些临床前发现迫使我们推测 AS 可能是对抗 ROT 诱导的变异的潜在候选药物,这些变异可能是由 DA 的各种囊泡运输引起的。