College of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China; Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou, 510632, China; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, Guangzhou, 510632, China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research College of Pharmacy, Jinan University, Guangzhou, 510632, China.
Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou, 510632, China; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, Guangzhou, 510632, China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research College of Pharmacy, Jinan University, Guangzhou, 510632, China.
J Ethnopharmacol. 2020 Jun 28;256:112824. doi: 10.1016/j.jep.2020.112824. Epub 2020 Apr 4.
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 α-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 α-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.
民族药理学相关性：天马痛风颗粒（TG）是一种中药临床处方，已在临床上与美多巴联合应用于治疗帕金森病（PD），并收录于《中国药典》（2015 年版）中。TG 具有降低 PD 易感性的药理学潜力，但需要详细证明其机制。
研究目的：评价 TG 在不同 PD 模型中的药理活性及可能机制。
材料与方法：采用 6-OHDA 处理的大鼠、MPTP 处理的小鼠和α-突触核蛋白 A53T 过表达的小鼠作为 PD 动物模型。利用转棒试验、运动活性试验、斜面试验和牵引试验进行行为评估。采用免疫组织化学法测定酪氨酸羟化酶。采用 Western blot 法检测 4-HNE 和 15-脂氧合酶-1（ALOX15）。采用分子对接方法预测 ALOX15 与 TG 成分的相互作用。
结果：多巴胺能神经元损伤与 6-OHDA 诱导的大鼠模型中的脂质过氧化有关。在 MPTP 处理的小鼠中，抑制脂质过氧化可改善 PD 的行为和病理症状。在包括 6-OHDA 处理的大鼠、MPTP 处理的小鼠和α-突触核蛋白 A53T 过表达的小鼠在内的不同 PD 模型中，发现脂质过氧化相关蛋白 ALOX15 是 PD 发生的关键因素。TG 治疗可显著缓解 MPTP 诱导的 PD 小鼠模型的行为和病理症状，其潜在机制可能是通过减轻 ALOX15 诱导的脂质过氧化。此外，分子对接分析的结果表明，TG 中的化合物可能与 ALOX15 相互作用。
结论：TG 可有效改善不同 PD 模型的行为和多巴胺能神经元损伤。其作用机制可能与直接抑制 ALOX15 和缓解脂质过氧化有关。
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