Laboratory of Neurochemistry and Cell Biology, Department of Biochemistry and Biophysics, Institute of Health Sciences, Federal University of Bahia, Salvador, Brazil.
Clinical & Experimental Neuroscience (NiCE). Institute for Bio-Health Research of Murcia (IMIB), Institute for Aging Research (IUIE), School of Medicine, Campus Mare Nostrum, University of Murcia, Murcia, Spain.
Neurotox Res. 2023 Jun;41(3):224-241. doi: 10.1007/s12640-022-00616-1. Epub 2023 Feb 1.
Causes of dopaminergic neuronal loss in Parkinson's disease (PD) are subject of investigation and the common use of models of acute neurodegeneration induced by neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine, and rotenone contributed to advances in the study of PD. However, the use of study models more similar to the pathophysiology of PD is required for advances in early diagnosis and translational pharmacology. Aminochrome (AMI), a compound derived from dopamine oxidation and a precursor of neuromelanin, is able to induce all the mechanisms associated with neurodegeneration. Previously, we showed AMI is cytotoxic in primary culture of mesencephalic cells (PCMC) and induces in vitro and in vivo neuroinflammation. On the other hand, the effect of rutin in central nervous system cells has revealed anti-inflammatory, antioxidative, and neuroprotective potential. However, there have been no data studies on the effect of rutin against aminochrome neurotoxicity. Here, we show that rutin prevents lysosomal dysfunction and aminochrome-induced cell death in SHSY-5Y cells, protects PCMC against aminochrome cytotoxicity, and prevents in vivo loss of dopaminergic neurons in substantia nigra pars compacta (SNPc), as well as microgliosis and astrogliosis. Additionally, we show that rutin decreases levels of interleukin-1β (IL-1β) mRNA and increases levels of glia-derived neurotrophic factor (GDNF) and nerve-derived neurotrophic factor (NGF) mRNA. We evidence for the first time the protective effect of rutin on PD aminochrome-induced models and suggest the potential role of the anti-inflammatory activity and upregulation of NGF and GDNF in the mechanism of rutin action against aminochrome neurotoxicity.
帕金森病（PD）中多巴胺能神经元丧失的原因是研究的主题，神经毒素 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）、6-羟多巴胺和鱼藤酮诱导的急性神经退行性变模型的广泛应用促进了 PD 的研究进展。然而，为了在早期诊断和转化药理学方面取得进展，需要使用更类似于 PD 病理生理学的研究模型。氨基chrome（AMI）是一种源自多巴胺氧化的化合物，也是神经黑色素的前体，能够诱导与神经退行性变相关的所有机制。先前，我们发现 AMI 在中脑细胞（PCMC）原代培养物中具有细胞毒性，并在体外和体内诱导神经炎症。另一方面，芦丁对中枢神经系统细胞的作用揭示了其抗炎、抗氧化和神经保护潜力。然而，目前还没有芦丁对氨基chrome 神经毒性作用的研究数据。在这里，我们表明芦丁可防止溶酶体功能障碍和 AMI 诱导的 SHSY-5Y 细胞死亡，保护 PCMC 免受 AMI 的细胞毒性作用，并防止体内黑质致密部（SNPc）中多巴胺能神经元的丢失，以及小胶质细胞和星形胶质细胞的增生。此外，我们发现芦丁降低白细胞介素-1β（IL-1β）mRNA 的水平，并增加胶质衍生神经营养因子（GDNF）和神经源性神经营养因子（NGF）mRNA 的水平。我们首次证明了芦丁对 PD 氨基chrome 诱导模型的保护作用，并提出了芦丁抗炎活性以及上调 NGF 和 GDNF 在芦丁对抗氨基chrome 神经毒性作用机制中的潜在作用。
