Department of Applied Biology and Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500007, India.
Department of Applied Biology and Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500007, India.
Biochim Biophys Acta Bioenerg. 2020 Mar 1;1861(3):148157. doi: 10.1016/j.bbabio.2020.148157. Epub 2020 Jan 24.
Parkinson's disease (PD) is a chronic neurodegenerative disease characterized by the death of dopamine neurons of Substantia nigra pars compacta (SNpc) leading to motor deficits. Amongst the mechanisms proposed, mitochondrial dysfunction, reduced complex-I and PGC1α levels were found to correlate with the pathology of PD. As embelin is a natural product with structural resemblance to ubiquinone, exhibits mitochondrial uncoupling and antioxidant effects, in the present study, we sought to examine its role in the mechanisms mediating PD. Results indicate that embelin protects from MPP-induced oxidative stress and apoptosis in a time and dose-dependent manner in N27 dopaminergic cells. Cells treated with embelin exhibited increased levels of pAMPK, SIRT1 and PGC1α leading to enhanced mitochondrial biogenesis. Though treatment of cells with MPP also increased pAMPK levels, but, SIRT1 and PGC1α levels decreased substantially, possibly due to the block in the mitochondrial electron transport chain and reduced NAD/NADH levels. The mitochondrial uncoupling effects of embelin leading to increased NAD/NADH levels followed by enhanced SIRT1, PGC1α and mitochondrial biogenesis were found to confer embelin mediated protection as treatment of cells with SIRT1 inhibitor or siRNA nullified this effect. Embelin (10 mg/kg) also conferred protection in vivo in MPTP mouse model of PD, wherein, MPTP-induced loss of TH staining, reduced striatal dopamine and markers of mitochondrial biogenesis pathway were averted by embelin.
帕金森病（PD）是一种慢性神经退行性疾病，其特征是黑质致密部（SNpc）中的多巴胺神经元死亡，导致运动功能障碍。在提出的机制中，发现线粒体功能障碍、复合物-I 和 PGC1α 水平降低与 PD 的病理学相关。由于杨梅素具有与泛醌结构相似的天然产物，具有线粒体解偶联和抗氧化作用，因此在本研究中，我们试图研究其在介导 PD 的机制中的作用。结果表明，杨梅素以时间和剂量依赖的方式保护 N27 多巴胺能细胞免受 MPP 诱导的氧化应激和细胞凋亡。用杨梅素处理的细胞表现出 pAMPK、SIRT1 和 PGC1α 水平的增加，导致线粒体生物发生增强。尽管 MPP 处理也增加了 pAMPK 水平，但 SIRT1 和 PGC1α 水平大幅下降，可能是由于线粒体电子传递链受阻和 NAD/NADH 水平降低所致。杨梅素的线粒体解偶联作用导致 NAD/NADH 水平增加，随后 SIRT1、PGC1α 和线粒体生物发生增强，这被发现赋予了杨梅素介导的保护作用，因为用 SIRT1 抑制剂或 siRNA 处理细胞会消除这种作用。杨梅素（10mg/kg）在 MPTP 诱导的 PD 小鼠模型中也具有体内保护作用，其中，MPTP 诱导的 TH 染色丢失、纹状体多巴胺减少以及线粒体生物发生途径的标志物被杨梅素所避免。
