Ahmad Mir Hilal, Fatima Mahino, Ali Mansoor, Rizvi Moshahid Alam, Mondal Amal Chandra
Laboratory of Cellular and Molecular Neurobiology, School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India; Genome Biology Lab, Department of Biosciences, Jamia Millia Islamia, New Delhi, 110025, India.
Laboratory of Cellular and Molecular Neurobiology, School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India.
Neuropharmacology. 2021 Dec 15;201:108831. doi: 10.1016/j.neuropharm.2021.108831. Epub 2021 Oct 13.
Parkinson's disease (PD), a common neurodegenerative disease is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. The cause of dopaminergic loss in PD remains unknown for a long time, however, recent reports suggest oxidative stress plays a key role in the pathogenesis of PD. Paraquat (PQ), a widely used herbicide is an oxidative stress inducer that has been implicated as a potential risk factor for the development of PD. Flavonoids are naturally occurring polyphenolic compounds that display a variety of therapeutic properties against oxidative stress. Naringenin (NAR), a natural flavonoid, exhibits neuroprotection against PD-related pathology. However, studies on its neuroprotective role and the underlying mechanisms are scarce, therefore the present study explored the potential neuroprotective role of NAR in PQ-induced parkinsonism in SH-SY5Y cells and rat model. The effect of NAR on PQ-induced cellular toxicity was determined by measuring cell viability, oxidative stress, ATP levels and the same effect was determined by assessing behavioral, biochemical, immunohistochemical, qRT-PCR and Western blot in rat model. NAR treatment in SH-SY5Y cells resulted in increased cell viability, reduced oxidative stress, elevated mitochondrial membrane potential, and higher cellular ATP levels. In rats, NAR treatment resulted in significant neuroprotection against PQ-induced behavioral deficits, oxidative stress, mitochondrial dysfunction, and astrocytosis. NAR treatment significantly modulated PQ-induced mRNA expressions of DRD2, DAT, LRRK2, SNCA, β-catenin, caspase-3, BDNF genes. NAR treatment increased TH protein expression and modulated its immunoreactivity in rat striatum. Also, GFAP decreased in response to NAR treatment. So, in the present study, NAR exhibits neuroprotection against PQ-induced neurotoxicity and neurodegeneration indicating its novel therapeutic potential against PD.
帕金森病（PD）是一种常见的神经退行性疾病，其特征是黑质中多巴胺能神经元逐渐丧失。长期以来，PD中多巴胺能神经元丧失的原因一直不明，然而，最近的报告表明氧化应激在PD的发病机制中起关键作用。百草枯（PQ）是一种广泛使用的除草剂，是一种氧化应激诱导剂，被认为是PD发生的潜在危险因素。黄酮类化合物是天然存在的多酚化合物，具有多种抗氧化应激的治疗特性。柚皮素（NAR）是一种天然黄酮类化合物，对PD相关病理具有神经保护作用。然而，关于其神经保护作用及其潜在机制的研究很少，因此本研究探讨了NAR在PQ诱导的SH-SY5Y细胞帕金森综合征和大鼠模型中的潜在神经保护作用。通过测量细胞活力、氧化应激、ATP水平来确定NAR对PQ诱导的细胞毒性的影响，并通过评估大鼠模型中的行为、生化、免疫组织化学、qRT-PCR和蛋白质印迹来确定相同的影响。在SH-SY5Y细胞中进行NAR处理导致细胞活力增加、氧化应激降低、线粒体膜电位升高和细胞ATP水平升高。在大鼠中，NAR处理对PQ诱导的行为缺陷、氧化应激、线粒体功能障碍和星形细胞增生具有显著的神经保护作用。NAR处理显著调节了PQ诱导的DRD2、DAT、LRRK2、SNCA、β-连环蛋白、半胱天冬酶-3、BDNF基因的mRNA表达。NAR处理增加了大鼠纹状体中TH蛋白的表达并调节了其免疫反应性。此外，GFAP在NAR处理后减少。因此，在本研究中，NAR对PQ诱导的神经毒性和神经退行性变具有神经保护作用，表明其对PD具有新的治疗潜力。
