Tianma Gouteng granules decreases the susceptibility of Parkinson's disease by inhibiting ALOX15-mediated lipid peroxidation
Tianma Gouteng granules decreases the susceptibility of Parkinson's disease by inhibiting ALOX15-mediated lipid peroxidation
复制标题
天麻钩藤颗粒通过抑制ALOX15介导的脂质过氧化降低帕金森病的易感性
DOI：
10.1016/j.jep.2020.112824
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发表时间：
2020-06-28
影响因子：
5.4
通讯作者：
Yao, Xin-Sheng
中科院分区：
文献类型：
--
作者：
Jiang, Ying-Nan;Guo, Yong-Zhi;Yao, Xin-Sheng
民族药理学相关性：天麻钩藤颗粒（TG）是一种中药临床处方，已被中国药典（2015年版）收载，临床应用于与美多巴联合治疗帕金森病（PD）。TG具有降低PD易感性的潜力，但其作用机制尚需进一步研究。本研究的目的：探讨TG在多种PD模型中的药理作用及其可能的作用机制。材料和方法：采用6-OHDA处理的大鼠、MPTP处理的小鼠和α-synuclein A53 T过表达的小鼠作为PD动物模型。采用旋转棒、自发活动、斜面和牵引试验进行行为学评估。免疫组化法测定酪氨酸水解酶。Western blot检测4-HNE和15-脂氧合酶-1（ALOX 15）的表达。结果：6-OHDA诱导的大鼠多巴胺能神经元损伤与脂质过氧化反应有关。在MPTP治疗的小鼠中，脂质过氧化的抑制改善了PD的行为和病理症状。脂质过氧化相关蛋白ALOX 15被发现是多种PD模型（包括6-OHDA处理的大鼠、MPTP处理的小鼠和α-突触核蛋白A53 T过表达的小鼠）中PD过程的关键因素。TG治疗显著减轻MPTP诱导的PD小鼠模型的行为和病理症状，其潜在机制是减轻ALOX 15诱导的脂质过氧化。分子对接分析结果表明，TG中的化合物可能与ALOX 15存在相互作用。结论：TG能有效改善多种PD模型的行为学和多巴胺能神经元损伤。其作用机制可能与直接抑制ALOX 15和减轻脂质过氧化有关。
Ethnopharmacological relevance: Tianma Gouteng granules (TG), a clinical prescription of traditional Chinese medicine, has been clinically applied to treat Parkinson's disease (PD) in combination with Madopar, as included in the Chinese Pharmacopoeia (2015). TG has the potential to decrease the susceptibility of PD pharmacologically, however the mechanisms need detailed demonstration.Aim of the study: To evaluate the pharmacological activities, as well as the possible mechanism of TG in diverse models of PD.Materials and methods: 6-OHDA-treated rats, MPTP-treated mice, and alpha-synuclein A53T overexpressed mice, were utilized as PD animal models. Rotarod, locomotor activity, inclined plane and traction tests were used for behavioral assessment. Immunohistochemistry was used for tyrosine hydrolase determination. Western blot were conducted for detection of 4-HNE and 15-lipoxygenase-1 (ALOX15). The interactions of ALOX15 with the components in TG were predicted by molecular docking approach.Results: Lipid peroxidation was involved in dopaminergic neuron damage in 6-OHDA-induced rat models. In MPTP-treated mice, the inhibition of lipid peroxidation improved behavioral and pathological symptoms of PD. The lipid peroxidation-related protein, ALOX15 was found to be the key factor in PD process in diverse PD models including 6-OHDA-treated rats, MPTP-treated mice, and alpha-synuclein A53T overexpressed mice. TG treatment significantly relieved behavioral and pathological symptoms of MPTP-induced PD mouse models with a potential mechanism of alleviating ALOX15-induced lipid peroxidation. Moreover, the results of molecular docking analysis show that compounds in TG might have interactions with ALOX15.Conclusions: TG effectively improved the behavioral and dopaminergic neuron damage in diverse PD models. The mechanism of this action may be related to the direct inhibition of ALOX15 and the relief of lipid peroxidation.