Paeoniflorin Alleviates Anxiety and Visceral Hypersensitivity via HPA Axis and BDNF/TrkB/PLCγ1 Pathway in Maternal Separation-induced IBS-like Rats.

Ruifeng Liang, Wenjing Ge, Xianmei Song, Huisen Wang, Weifeng Cui, Xuexia Zhang, Zheng Wei, Gengsheng Li
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Abstract

Background: Irritable Bowel Syndrome (IBS) is a prevalent gastrointestinal disorder that significantly diminishes the quality of life for affected individuals. The pathophysiology of IBS remains poorly understood, and available therapeutic options for IBS are limited. The crucial roles of brain-gut interaction, which is mediated by the Hypothalamic-Pituitary-Adrenocortical (HPA) axis and the autonomic nervous system in IBS, have attracted increasing attention.

Objective: The objective of this study was to examine the impact of paeoniflorin (PF) on anxiety and visceral hypersensitivity in maternal separation-induced IBS-like rats.

Methods: The IBS-like rat model was established through the implementation of Maternal Separation (MS) and subsequently subjected to various doses of PF administered via oral gavage for 14 days. Anxiety-like behavior was evaluated using the Open Field Test (OFT) and Elevated Plus Maze (EPM) test. The assessment of visceral sensitivity involved the utilization of the Abdominal Withdrawal Reflex (AWR) score and electromyographic (EMG) responses of the external oblique muscle in response to colorectal distention. The levels of adrenocorticotropic hormone (ACTH), corticosterone (CORT), and corticotrophin-releasing hormone (CRH) were examined by ELISA. Quantitative real-time PCR (qRT-PCR) and immunofluorescence were employed to detect the expressions of CRH receptors 1 (CRHR1) and 2 (CRHR2). Glucocorticoid receptors (GR), mineralocorticoid receptor (MR), brain-derived neurotrophic factor (BDNF), tyrosine receptor kinase B (TrkB), and phospholipase C γ1 (PLCγ1) were examined by Western blot.

Results and discussion: The results showed that MS induced anxiety-like behavior and visceral hypersensitivity, while PF treatment attenuated these changes. Furthermore, the HPA axis hyperactivity in MS rats was attenuated by PF treatment, indicated by reduced serum ACTH, CORT, and CRH levels and recovered hippocampal CRHR1 and GR expressions. In addition, PF inhibited BDNF/TrkB signaling by downregulating the protein levels of BDNF, TrkB, and phospho-PLCγ1 in the colon.

Conclusion: These findings suggest that PF alleviated anxiety and visceral hypersensitivity in MS-induced IBS-like rats, which may be the modulation of HPA axis activity and BDNF/TrkB/PLCγ1 signaling pathway.

芍药苷通过HPA轴和BDNF/TrkB/PLCγ1通路缓解母鼠分离诱发的肠易激综合征样大鼠的焦虑和内脏超敏反应
背景:肠易激综合征(IBS肠易激综合征(IBS)是一种常见的胃肠道疾病,严重影响患者的生活质量。人们对肠易激综合征的病理生理学仍然知之甚少,现有的治疗方法也很有限。由下丘脑-垂体-肾上腺皮质轴(HPA)和自主神经系统介导的脑-肠相互作用在肠易激综合征中的关键作用已引起越来越多的关注:本研究的目的是探讨芍药苷(PF)对母体分离诱导的IBS样大鼠焦虑和内脏超敏性的影响:方法:通过实施母体分离(MS)建立肠易激综合征样大鼠模型,然后通过口服给药的方式给大鼠注射不同剂量的芍药苷(PF),持续14天。焦虑样行为的评估采用开阔地试验(OFT)和高架迷宫试验(EPM)。对内脏敏感性的评估包括腹部回缩反射(AWR)评分和腹外斜肌对大肠胀气的肌电图(EMG)反应。通过 ELISA 检测了促肾上腺皮质激素(ACTH)、皮质酮(CORT)和促肾上腺皮质激素释放激素(CRH)的水平。采用定量实时 PCR(qRT-PCR)和免疫荧光法检测 CRH 受体 1(CRHR1)和 2(CRHR2)的表达。糖皮质激素受体(GR)、矿皮质激素受体(MR)、脑源性神经营养因子(BDNF)、酪氨酸受体激酶B(TrkB)和磷脂酶Cγ1(PLCγ1)通过Western印迹进行检测:结果表明,MS可诱导焦虑样行为和内脏过敏,而PF治疗可减轻这些变化。此外,血清促肾上腺皮质激素(ACTH)、促肾上腺皮质激素(CORT)和促肾上腺皮质激素(CRH)水平的降低以及海马 CRHR1 和 GR 表达的恢复表明,PF 治疗可减轻 MS 大鼠 HPA 轴的过度活跃。此外,PF 通过下调结肠中 BDNF、TrkB 和 phospho-PLCγ1 的蛋白水平,抑制了 BDNF/TrkB 信号转导:这些研究结果表明,PF 可减轻 MS 诱导的肠易激综合征样大鼠的焦虑和内脏超敏反应,这可能是 HPA 轴活性和 BDNF/TrkB/PLCγ1 信号通路的调节作用。
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