Antidepressant potential of Uncaria rhynchophylla and its active flavanol, catechin, targeting melatonin receptors
Antidepressant potential of Uncaria rhynchophylla and its active flavanol, catechin, targeting melatonin receptors
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钩藤及其活性黄烷醇、儿茶素的抗抑郁潜力，针对褪黑激素受体。
DOI：
10.1016/j.jep.2018.12.013
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发表时间：
2019-03-25
影响因子：
5.4
通讯作者：
Chen, Ji-Jun
中科院分区：
文献类型：
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作者：
Geng, Chang-An;Yang, Tong-Hua;Chen, Ji-Jun
民族药理学相关性：传统中药（TCM）是天然候选药物的迷人来源。钩藤（Uncaria rhynchophylla，Gouteng）是治疗中枢神经系统疾病的著名中药，其抗抑郁活性成分至今仍存在争议。材料与方法：对钩藤总提取物及各部位进行化学成分分析，并对与中枢神经系统疾病密切相关的褪黑素受体活性成分进行结构鉴定。Rhynchophylla在体外广泛评估了它们对褪黑激素受体的激动活性。随后的生物测定指导的分级分离产生活性成分，其活性通过剂量依赖性生物测定和对HEK 293细胞的拮抗实验证实。采用小鼠强迫游泳实验（FST）、悬尾实验（TST）和旷场实验（OFT）评价其抗抑郁作用。采用LCMS-IT-TOF法分析了它们在小鼠血浆中的代谢情况。Rhynchophylla对褪黑激素受体（MT 1和MT 2）具有激动活性。在生物活性测定的指导下，分离得到两种黄烷醇类化合物，儿茶素和表儿茶素，对MT_1（EC_（50）= 25.8和156.1 μ M）和MT_2（EC_（50）= 47.3和208.8 μ M）受体具有明显的激动活性。儿茶素对褪黑激素受体的激动活性可被浓度为1.57-100 μ M的luzindole拮抗。儿茶素在80和40 mg/kg剂量下均能显著缩短FST和TST模型小鼠的不动时间，而对OFT模型小鼠的自主活动无明显影响。灌胃（i）后，小鼠血浆中检测到五种儿茶素II相（M1-M5）和一种I相（M6）代谢物结论：儿茶素是一种有效的抗抑郁药物。rhynchophylla通过靶向褪黑激素受体。小鼠血浆中儿茶素的主要代谢途径是葡萄糖醛酸化（M3）和甲基化葡萄糖醛酸化（M4和M5）。本研究为深入了解钩藤及其有效成分的抗抑郁作用提供了有价值的信息。
Ethnopharmacological relevance: Traditional Chinese medicines (TCMs) are fascinating sources for natural drug candidates. Uncaria rhynchophylla (Gouteng) is a famous TCM used for alleviating central nervous system (CNS) disorders, while its antidepressant constituents are still disputed.Aim of the study: The present study was designed to assess the antidepressant property of U. rhynchophylla and characterize the active constituents targeting melatonin receptors which are closely related to CNS diseases.Materials and methods: The total extract and each fraction of U. rhynchophylla were extensively assessed for their agonistic activity on melatonin receptors in vitro. The following bioassay-guided fractionation yielded the active constituents, whose activity was confirmed by dose-dependent bioassay and antagonistic experiment on HEK293 cells. Their antidepressant effects were evaluated on forced swimming test (FST), tail suspension test (TST) and open-field test (OFT) mice models in vivo. Their metabolic profiles in mice plasma were analyzed by LCMS-IT-TOF.Results: The stems and hooks of U. rhynchophylla were revealed with agonistic activity on melatonin receptors (MT1 and MT2). Under the guidance of bioassay, two flavanols, catechin and epicatechin were obtained and showed obviously activity agitating MT1 (EC50 = 25.8 and 156.1 mu M) and MT2 (EC50 = 47.3 and 208.8 mu M) receptors. The agonistic activity of catechin on melatonin receptors can be antagonized by luzindole at the concentrations of 1.57-100 mu M. Catechin could significantly reduce the immobility time in both FST and TST mice models at doses of 80 and 40 mg/kg, without obvious effect on locomotor activity in OFT mice model. Five phase II (M1-M5) and one phase I (M6) metabolites of catechin were detected in mice plasma after intragastric (i.g.) administration.Conclusion: Catechin is a potent antidepressant candidate from U. rhynchophylla by targeting melatonin receptors. The main metabolic pathways of catechin in mice plasma are glucuronidation (M3) and methylated glucuronidation (M4 and M5). This study provides valuable information for understanding the antidepressant potency of Gouteng and its active constituents.