Dendrobium nobile Lindl. alkaloid (DNLA) is effective against animal models of Alzheimer's disease. This study further examined its effect on anxiety and depression produced by chronic unpredictable stress (CUS). Rats were subjected to CUS for 42 days, followed by DNLA treatment (20 mg/kg/day, po) for 28 days. The behavioral tests, histopathology, neurotransmitters and RNA-Seq were examined. DNLA attenuated body weight loss and CUS-induced anxiety/depressive-like behaviors, as evidenced by the elevated-plus-maze test, open-field test and sucrose preference. DNLA alleviated neuronal damage and loss and increased Nissl bodies in the hippocampus CA2 region and cortex. DNLA decreased CUS-elevated 5-hydroxytryptamine, dopamine and monoamine oxidase and catechol-O-methyltransferase activities in the brain. DNLA attenuated HPA activation by decreasing adrenocorticotropic hormones and the expression of corticotropin-releasing hormone receptor-1, and increased the expression of glucocorticoid receptor in the brain. RNA-Seq revealed distinct gene expression patterns among groups. Gene ontology revealed the cell projection assembly, postsynapse and centrosome as top biological processes, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment showed the cAMP, cGMP-PKG, glutamatergic synapse and circadian as major pathways for DNLA effects. Using DESeq2, CUS modulated 1700 differentially expressed genes (DEGs), which were prevented or attenuated by DNLA. CUS-induced DEGs were highly correlated with the Gene Expression Omnibus (GEO) database for anxiety and depression and were ameliorated by DNLA. Taken together, DNLA attenuated anxiety/depression-like behavior and neuronal damage induced by CUS in rats. The mechanisms could be related to regulation of the monoamine neurotransmitters and the HPA axis, and modulation of gene expression in the hippocampus.

金钗石斛林德尔。生物碱 (DNLA) 对阿尔茨海默病动物模型有效。本研究进一步检验了其对慢性不可预测压力 (CUS) 产生的焦虑和抑郁的影响。对大鼠进行 CUS 42 天，然后进行 DNLA 治疗（20 mg/kg/天，口服）28 天。检查了行为测试、组织病理学、神经递质和 RNA-Seq。DNLA 减轻了体重减轻和 CUS 引起的焦虑/抑郁样行为，如高架加迷宫试验、旷场试验和蔗糖偏好所证明的。DNLA 减轻了海马 CA2 区和皮质中的神经元损伤和损失，并增加了 Nissl 小体。DNLA 降低了大脑中 CUS 升高的 5-羟色胺、多巴胺和单胺氧化酶以及儿茶酚-O-甲基转移酶的活性。DNLA 通过降低促肾上腺皮质激素和促肾上腺皮质激素释放激素受体 1 的表达来减弱 HPA 的活化，并增加大脑中糖皮质激素受体的表达。RNA-Seq 揭示了组间不同的基因表达模式。基因本体论揭示了细胞投射组装、突触后和中心体是顶级生物过程，京都基因和基因组百科全书 (KEGG) 富集显示 cAMP、cGMP-PKG、谷氨酸能突触和昼夜节律是 DNLA 效应的主要途径。使用 DESeq2，CUS 调节了 1700 个差异表达基因 (DEG)，这些基因被 DNLA 阻止或减弱。CUS 诱导的 DEG 与焦虑和抑郁的基因表达综合 (GEO) 数据库高度相关，并且通过 DNLA 得到改善。综合起来，DNLA 减轻了 CUS 引起的大鼠焦虑/抑郁样行为和神经元损伤。这些机制可能与单胺神经递质和 HPA 轴的调节以及海马中基因表达的调节有关。