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Background: Depression is a pervasive or persistent mental disorder that causes mood, cognitive and memory deficits. Uncaria rhynchophylla has been widely used to treat central nervous system diseases for a long history, although its efficacy and potential mechanism are still uncertain., Purpose: The present study aimed to investigate anti-depression effect and potential mechanism of U. rhynchophylla extract (URE)., Study Design and Methods: A mouse depression model was established using unpredictable chronic mild stress (UCMS). Effects of URE on depression-like behaviours, neurotransmitters, and neuroendocrine hormones were investigated in UCMS-induced mice. The potential target of URE was analyzed by transcriptomics and bioinformatics methods and validated by RT-PCR and Western blot. The agonistic effect on 5-HT 1A receptor was assayed by dual-luciferase reporter system., Results: URE ameliorated depression-like behaviours, and modulated levels of neurotransmitters and neuroendocrine hormones, including 5-hydroxytryptamine (5-HT), 5-hydroxyindole acetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), corticosterone (CORT), corticotropin-releasing hormone (CRH), and adrenocorticotropic hormone (ACTH), in UCMS-induced mice. Transcriptomics and bioinformatics results indicated that URE could regulate glutamatergic, cholinergic, serotonergic, and GABAergic systems, especially neuroactive ligand-receptor and cAMP signaling pathways, revealing that Htr1a encoding 5-HT 1A receptor was a potential target of URE. The expression levels of downstream proteins of 5-HT 1A signaling pathway 5-HT 1A , CREB, BDNF, and PKA were increased in UCMS-induced mice after URE administration, and URE also displayed an agonistic effect against 5-HT 1A receptor with an EC 50 value of 17.42 μg/ml., Conclusion: U. rhynchophylla ameliorated depression-like behaviours in UCMS-induced mice through activating 5-HT 1A receptor., (Copyright © 2020. Published by Elsevier GmbH.)

Main observation and conclusion: Uncaria rhynchophylla has been widely used to treat central nervous system diseases for a long history. After investigation of U. rhynchophylla, eleven monoterpene indole alkaloids, including four new compounds uncarialins J—M (1—4) and seven known analogues (5—11), were isolated and identified. Their structural characterization was conducted using HRESIMS, 1D and 2D NMR, electronic circular dichroism (ECD) spectra, and quantum chemical computations. Compounds 1, 2, 7, and 9—11 displayed significant agonistic effects towards 5‐HT1A receptor, and their EC50 values were 7.86, 7.32, 2.24, 1.18, 1.52, and 3.75 μmol/L, respectively. Furthermore, in vivo experimental results fully revealed that hirsuteine (7) displayed a significant antidepression effect in unpredictable chronic mild stress (UCMS)‐induced depression mice mainly via regulating 5‐HT1A signaling pathway. Molecular docking and site‐directed amino acid mutation verified that amino acid residues Asp116 and Asn386 were the binding sites of hirsuteine (7) with 5‐HT1A receptor. In addition, pre‐treatment of mice with WAY 100635 also blocked the anti‐depression effect of hirsuteine (7), which further demonstrated that 5‐HT1A receptor was a potential target of hirsuteine (7) to effectively treat depression. These findings indicated the therapeutic material basis of U. rhynchophylla and the anti‐depression underlying mechanism of hirsuteine (7), and further provided the useful guidance for the development of hirsuteine (7) as a potential antidepressant candidate. [ABSTRACT FROM AUTHOR]

Background: Depression is a pervasive or persistent mental disorder that causes mood, cognitive and memory deficits. Uncaria rhynchophylla has been widely used to treat central nervous system diseases for a long history, although its efficacy and potential mechanism are still uncertain.Purpose: The present study aimed to investigate anti-depression effect and potential mechanism of U. rhynchophylla extract (URE).Study Design and Methods: A mouse depression model was established using unpredictable chronic mild stress (UCMS). Effects of URE on depression-like behaviours, neurotransmitters, and neuroendocrine hormones were investigated in UCMS-induced mice. The potential target of URE was analyzed by transcriptomics and bioinformatics methods and validated by RT-PCR and Western blot. The agonistic effect on 5-HT1A receptor was assayed by dual-luciferase reporter system.Results: URE ameliorated depression-like behaviours, and modulated levels of neurotransmitters and neuroendocrine hormones, including 5-hydroxytryptamine (5-HT), 5-hydroxyindole acetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), corticosterone (CORT), corticotropin-releasing hormone (CRH), and adrenocorticotropic hormone (ACTH), in UCMS-induced mice. Transcriptomics and bioinformatics results indicated that URE could regulate glutamatergic, cholinergic, serotonergic, and GABAergic systems, especially neuroactive ligand-receptor and cAMP signaling pathways, revealing that Htr1a encoding 5-HT1A receptor was a potential target of URE. The expression levels of downstream proteins of 5-HT1A signaling pathway 5-HT1A, CREB, BDNF, and PKA were increased in UCMS-induced mice after URE administration, and URE also displayed an agonistic effect against 5-HT1A receptor with an EC50 value of 17.42 μg/ml.Conclusion: U. rhynchophylla ameliorated depression-like behaviours in UCMS-induced mice through activating 5-HT1A receptor. [ABSTRACT FROM AUTHOR]