Neurotherapeutics Laboratory, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, UP, 221005, India.
Neurotox Res. 2019 Apr;35(3):542-562. doi: 10.1007/s12640-018-9983-2. Epub 2019 Jan 4.
Parkinson's disease (PD) is one of the widely reported neurodegenerative disorders affecting more than ten million people worldwide. Due to therapeutic limitations and several adverse effects associated with currently used drugs, it is crucial to search for safe and effective options for treatment of PD. Oxidative stress, mitochondrial dysfunction, α-synuclein oligomeric aggregates, and glucocerebrosidase (GCase) deficiency are involved in PD pathogenesis. Rebamipide, an anti-ulcer drug, is a proven free-radical scavenger and antioxidant. The drug has shown neuroprotective effects in cultured SH-SY5Y cells. Therefore, we investigated the pharmacological effect of rebamipide in 6-hydroxydopamine (6-OHDA)-induced experimental PD model. Rebamipide was given to adult male albino rats of Charles-Foster strain in 20, 40, and 80 mg/kg (R-20, R-40, and R-80) oral dose twice daily for 24 days (day 4 to day 27) after 6-OHDA intrastriatal injection. The drug inhibited 6-OHDA-induced motor deficits and nigral α-synuclein aggregates in dose-dependent manner. R-40 and R-80 dose dependently increased striatal mitochondrial complex I, II, IV, and V activities; mitochondrial bioenergetics; and nigral GCase activity. 6-OHDA-induced lipid peroxidation was decreased. Highest dose (R-80) also decreased apoptotic proteins and upregulated striatal dopamine concentration in 6-OHDA-induced hemiparkinson's rat model. Therefore, the anti-PD effect of rebamipide may involve stabilization of mitochondrial bioenergetics, enhancement of GCase enzymatic activity as well as decreased oxidative stress with α-synuclein pathology, and apoptosis in 6-OHDA-induced hemiparkinson's rat model. Hence, preclinical evidence indicates rebamipide to be a potential drug for management of PD.
帕金森病（PD）是一种广泛报道的神经退行性疾病，影响着全球超过 1000 万人。由于治疗的局限性和目前使用的药物的多种不良反应，寻找治疗 PD 的安全有效的方法至关重要。氧化应激、线粒体功能障碍、α-突触核蛋白寡聚体和β-葡萄糖脑苷脂酶（GCase）缺乏与 PD 的发病机制有关。瑞巴派特是一种抗溃疡药物，是一种已被证实的自由基清除剂和抗氧化剂。该药物在培养的 SH-SY5Y 细胞中显示出神经保护作用。因此，我们研究了瑞巴派特在 6-羟多巴胺（6-OHDA）诱导的实验性 PD 模型中的药理作用。瑞巴派特以 20、40 和 80mg/kg（R-20、R-40 和 R-80）的口服剂量，每天两次，共 24 天（第 4 天至第 27 天），在 6-OHDA 纹状体注射后给予成年雄性白化大鼠。该药物以剂量依赖性方式抑制 6-OHDA 诱导的运动功能障碍和黑质α-突触核蛋白聚集。R-40 和 R-80 剂量依赖性地增加纹状体线粒体复合物 I、II、IV 和 V 的活性、线粒体生物能学和黑质 GCase 活性。6-OHDA 诱导的脂质过氧化作用降低。最高剂量（R-80）还降低了凋亡蛋白，并上调了 6-OHDA 诱导的半帕金森大鼠模型中的纹状体多巴胺浓度。因此，瑞巴派特的抗 PD 作用可能涉及稳定线粒体生物能学、增强 GCase 酶活性以及降低氧化应激和α-突触核蛋白病理学中的细胞凋亡，在 6-OHDA 诱导的半帕金森大鼠模型中。因此，临床前证据表明瑞巴派特可能是一种治疗 PD 的潜在药物。
