Neurotherapeutics Laboratory, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi 221005, U.P., India.
Biochemistry Section, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi 221005, U.P., India.
Biochem Pharmacol. 2018 Sep;155:479-493. doi: 10.1016/j.bcp.2018.07.028. Epub 2018 Jul 21.
Reduced glucocerebrosidase (GCase) enzymatic activity is found in sporadic cases of Parkinson's disease making GCase a serious risk factor for PD. GCase gene mutations constitute a major risk factor in early-onset PD but only account for 5-10% cases. Having enough evidence for construct and face validity, 6-OHDA-induced hemiparkinson's model may be useful to assess the GCase-targeting drugs in order to have new leads for treatment of PD. Ambroxol (AMB) is reported to increase GCase activity in different brain-regions. Therefore, we investigated anti-PD like effects of AMB as well as GCase activity in striatal and nigral tissues of rats in hemiparkinson's model. AMB was given a dose of 400 mg/kg per oral twice daily and SEL used as positive control was given in the dose of 10 mg/kg per oral daily from D-4 to D-27 after 6-OHDA administration. 6-OHDA reduced GCase activity in striatal and in a progressive manner in nigral tissues. AMB and SEL attenuated 6-OHDA-induced motor impairments, dopamine (DA) depletion and GCase deficiency. AMB and SEL also ameliorated 6-OHDA-induced mitochondrial dysfunction in terms of MTT reduction, α-synuclein pathology, loss of nigral cells, and intrinsic pathway of apoptosis by modulating cytochrome-C, caspase-9, and caspase-3 expressions. The results suggest that AMB attenuated 6-OHDA-induced GCase deficiency and PD symptoms. Therefore, the regenerative effects of AMB in dopamine toxicity may be due to its effects on GCase activity and mitochondrial function. Results indicate that SEL also has regenerative effect in the 6-OHDA model. Thus, GCase enzymatic activity is likely to be involved in the development of PD symptoms, and 6-OHDA-induced hemiparkinson's model may be used to evaluate compounds targeting GCase activity for management of PD symptoms.
研究发现，在散发性帕金森病患者中，葡萄糖脑苷脂酶（GCase）的酶活性降低，这使得 GCase 成为帕金森病的一个严重风险因素。GCase 基因突变是早发性帕金森病的一个主要危险因素，但仅占病例的 5-10%。6-OHDA 诱导的偏侧帕金森病模型具有结构和内容效度，可用于评估针对 GCase 的药物，为治疗帕金森病提供新的线索。氨溴索（AMB）被报道能增加不同脑区的 GCase 活性。因此，我们研究了 AMB 对帕金森病的类似作用以及其对 6-OHDA 诱导的偏侧帕金森病大鼠纹状体和黑质组织中 GCase 活性的影响。AMB 以 400mg/kg 的剂量每天口服 2 次，SEL 以 10mg/kg 的剂量每天口服，从 6-OHDA 给药后的第 4 天到第 27 天给药。6-OHDA 降低了纹状体和黑质组织中 GCase 的活性，并呈进行性降低。AMB 和 SEL 减轻了 6-OHDA 诱导的运动障碍、多巴胺（DA）耗竭和 GCase 缺乏。AMB 和 SEL 还通过调节细胞色素-C、半胱天冬酶-9 和半胱天冬酶-3 的表达，改善了 6-OHDA 诱导的线粒体功能障碍，表现为 MTT 减少、α-突触核蛋白病理学、黑质细胞丢失和细胞凋亡的内在途径。结果表明，AMB 减轻了 6-OHDA 诱导的 GCase 缺乏和帕金森病症状。因此，AMB 在多巴胺毒性中的再生作用可能与其对 GCase 活性和线粒体功能的影响有关。结果表明，SEL 在 6-OHDA 模型中也具有再生作用。因此，GCase 酶活性可能参与了帕金森病症状的发展，6-OHDA 诱导的偏侧帕金森病模型可用于评估针对 GCase 活性的化合物，以管理帕金森病症状。
