Neurotherapeutics Laboratory, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi, U.P., 221005, India.
Naunyn Schmiedebergs Arch Pharmacol. 2020 Mar;393(3):429-444. doi: 10.1007/s00210-019-01737-9. Epub 2019 Oct 25.
Disease-modifying agents are unmet medical need for Parkinson's disease (PD). Drugs are under clinical trial to halt its progression, such as ambroxol due to its glucocerebrosidase (GCase)-stimulating activity. However, the neurorestorative effect of ambroxol is not yet investigated in any of the well-established PD models in vivo. Ambroxol was administered as 400 mg/kg orally twice a day from D-28 to D-70 after the unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA) in male rats. Behavioral parameters were observed every week, and at last, tyrosine hydroxylase (TH), dopamine transporter (DAT), glucocerbrosidase (GCase) enzymatic and mitochondrial complex-I activity, α-synuclein levels, and Nissl's staining were performed. Behavioral functions were progressively recovered. Ambroxol restored TH and DAT levels on D-71 as the markers of dopaminergic cell and extracellular DA concentration respectively, indicating the recovery of dopaminergic system. Factors involved in PD pathogenesis such as GCase enzymatic and mitochondrial complex-I activity were restored, and α-synuclein pathology was decreased by ambroxol. GCase deficiency is involved in mitochondrial impairment and formation of oligomeric α-synuclein aggregates which negatively affect mitochondrial function. Nissl bodies were also normalized. Therefore, both the GCase-stimulating and α-synuclein pathology-diminishing effects of ambroxol may be responsible for increment in mitochondrial function and restoration of dopaminergic system. These may act as significant mechanisms for disease-modifying potential of ambroxol. The current study provides the preclinical evidence to support the neurorestorative potential of ambroxol in 6-OHDA-induced hemiparkinson's rat model and indicates its possible use as disease-modifying agent in PD.
疾病修饰剂是帕金森病（PD）未满足的医学需求。有一些药物正在临床试验中，以阻止其进展，例如氨溴索，因为它具有葡萄糖脑苷脂酶（GCase）刺激活性。然而，氨溴索在任何已建立的体内 PD 模型中的神经修复作用尚未被研究过。氨溴索以 400mg/kg 剂量每天口服两次，从单侧纹状体注射 6-羟基多巴胺（6-OHDA）后第 28 天开始，持续到第 70 天，在雄性大鼠中。每周观察行为参数，最后进行酪氨酸羟化酶（TH）、多巴胺转运蛋白（DAT）、葡萄糖脑苷脂酶（GCase）酶和线粒体复合物-I 活性、α-突触核蛋白水平和尼氏染色。行为功能逐渐恢复。氨溴索在第 71 天恢复了 TH 和 DAT 水平，分别作为多巴胺能细胞和细胞外 DA 浓度的标志物，表明多巴胺能系统的恢复。与 PD 发病机制相关的因素，如 GCase 酶和线粒体复合物-I 活性得到恢复，α-突触核蛋白病理学也被氨溴索减少。GCase 缺乏与线粒体损伤和寡聚体α-突触核蛋白聚集体的形成有关，这会对线粒体功能产生负面影响。尼氏小体也得到了正常化。因此，氨溴索的 GCase 刺激和α-突触核蛋白病理学减少作用可能是增加线粒体功能和恢复多巴胺能系统的原因。这些可能是氨溴索具有疾病修饰潜力的重要机制。本研究为氨溴索在 6-OHDA 诱导的半帕金森大鼠模型中的神经修复潜力提供了临床前证据，并表明其在 PD 中作为疾病修饰剂的可能用途。
