Aging Biology Lab, Microbial Technology and Nematology Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India.
Department of Molecular and Structural Biology, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India.
Bioorg Chem. 2021 Mar;108:104655. doi: 10.1016/j.bioorg.2021.104655. Epub 2021 Jan 27.
The elusive targets and the multifactorial etiology of Parkinson's disease (PD) have hampered the discovery of a potent drug for PD. Furthermore, the presently available medications provide only symptomatic relief and have failed to mitigate the pathogenesis associated with PD. Therefore, the current study was aimed to evaluate the prospective of swertiamarin (SW), a secoiridoid glycoside isolated from a traditional medicinal plant, Enicostemma littorale Blume to ameliorate the characteristic features of PD in Caenorhabditis elegans. SW (25 μM) administration decreased the α-synuclein (α-syn) deposition, inhibited apoptosis and increased dopamine level mediated through upregulating the expression of genes linked to ceramide synthesis, mitochondrial morphology and function regulation, fatty acid desaturase genes along with stress responsive MAPK (mitogen-activated protein kinase) pathway genes. The neuroprotective effect of SW was evident from the robust reduction of 6-hydroxydopamine (6-OHDA) induced dopaminergic neurodegeneration independent of dopamine transporter (dat-1). SW mediated translational regulation of MAPK pathway genes was observed through increase expression of SKN-1 and GST-4. Further, in-silico molecular docking analysis of SW with C. elegans MEK-1 showed a promising binding affinity affirming the in-vivo results. Overall, these novel finding supports that SW is a possible lead for drug development against the multi- factorial PD pathologies.
帕金森病（PD）的难以捉摸的靶点和多因素病因学阻碍了 PD 强效药物的发现。此外，目前可用的药物仅提供对症缓解，未能减轻与 PD 相关的发病机制。因此，本研究旨在评估从传统药用植物肾茶（Enicostemma littorale Blume）中分离出的裂环烯醚萜苷类化合物 swertiamarin（SW）改善秀丽隐杆线虫 PD 特征的潜力。SW（25 μM）给药可减少α-突触核蛋白（α-syn）沉积，通过上调与神经酰胺合成、线粒体形态和功能调节、脂肪酸去饱和酶基因以及应激响应 MAPK（丝裂原激活蛋白激酶）途径基因相关的基因表达来抑制凋亡并增加多巴胺水平。SW 的神经保护作用是通过明显减少 6-羟基多巴胺（6-OHDA）诱导的多巴胺能神经退行性变来证明的，与多巴胺转运蛋白（dat-1）无关。SW 通过增加 SKN-1 和 GST-4 的表达来调节 MAPK 途径基因的翻译。此外，SW 与秀丽隐杆线虫 MEK-1 的计算机分子对接分析显示出有希望的结合亲和力，证实了体内结果。总的来说，这些新发现支持 SW 是针对多因素 PD 病理的药物开发的潜在先导化合物。
