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IF 4.8 2区医学 Q1 CHEMISTRY, MEDICINAL

Journal of ethnopharmacology Pub Date : 2024-12-14 DOI:10.1016/j.jep.2024.119252

Yue Qu, Jingna Gu, Lanxin Li, Yuqi Yan, Can Yan, Tiange Zhang

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引用次数: 0

摘要

民族药理学意义：桂枝二仙焦（GLEXJ）是一种著名的传统中药配方，用于补肾。它可用于治疗精神疾病，缓解记忆损伤、认知功能障碍和行为障碍。现代药理学研究表明，葛根素史克能够显著抑制创伤后应激障碍（PTSD）患者的恐惧反应，并促进恐惧记忆的消退。然而，其潜在的药理机制仍然难以捉摸：恐惧记忆泛化是创伤后应激障碍的一个基本特征，但人们对其了解甚少，也缺乏最佳的药物治疗方法。本研究旨在探讨 GLEXJ 对 PTSD 大鼠恐惧记忆泛化的抑制作用，并阐明其潜在机制：采用单次长时间应激和电刺激（SPS&S）方案诱导创伤后应激障碍大鼠，并用 GLEXJ 或帕罗西汀（PRX）治疗。使用情境恐惧记忆测试评估恐惧记忆泛化。海马树突棘形态采用高尔基-考克斯染色法进行分析。使用超高效液相色谱-串联质谱（UHPLC-MS/MS）测定了GLEXJ的化学成分。利用网络药理学预测了GLEXJ治疗创伤后应激障碍的机制。研究人员利用Western印迹法和免疫荧光法测定了瞬态受体电位通道6（TRPC6）介导的钙/钙调蛋白依赖性蛋白激酶IV-CAMP反应元件结合蛋白（CaMKIV-CREB）信号通路的指标。在体外，利用慢病毒载体抑制了大鼠肾上腺嗜铬细胞瘤（PC12）细胞中的TRPC6，并利用类胶体素染色法检测了纤维肌动蛋白（F-actin）的变化，从而阐明了含GLEXJ血清的机理作用：结果：GLEXJ能明显减轻创伤后应激障碍大鼠的恐惧记忆泛化，即使反复暴露于应激中也是如此。它还改善了异常海马树突棘形态。网络药理学分析证实，GLEXJ与治疗创伤后应激障碍的Ca2+信号通路密切相关。创伤后应激障碍大鼠表现出TRPC6介导的CaMKIV-CREB信号传导中断，突触可塑性受损。GLEXJ 可上调 TRPC6 的表达，重新激活 CaMKIV-CREB 通路，促进突触重塑。体外研究证实，TRPC6的抑制降低了F-肌动蛋白的水平，而含GLEXJ的血清则增加了TRPC6的表达和F-肌动蛋白的含量：结论：GLEXJ通过上调创伤后应激障碍大鼠海马中的TRPC6来激活CaMKIV-CREB信号，从而改善树突棘动态和突触重塑。这一机制有助于减轻恐惧记忆的泛化。鉴于目前创伤后应激障碍治疗方法的局限性，这些发现为开发更有效的治疗策略提供了潜在的途径。

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Guilu Erxian Jiao remodels dendritic spine morphology through activation of the hippocampal TRPC6-CaMKIV-CREB signaling pathway and suppresses fear memory generalization in rats with post-traumatic stress disorder.

Ethnopharmacological relevance: Guilu Erxian Jiao (GLEXJ) is a renowned traditional Chinese herbal formula used to tonify the kidney. It is employed to treat psychiatric disorders, and alleviate memory impairment, cognitive dysfunction, and behavioral disorders. Modern pharmacological studies have demonstrated GLEXJ's ability to significantly inhibit the fear response in post-traumatic stress disorder (PTSD) and facilitate the extinction of fear memory. However, the underlying pharmacological mechanisms remain elusive.

Aim of the study: Fear memory generalization, a fundamental characteristic of PTSD, remains poorly understood, and optimal pharmacological treatments are lacking. This study aimed to investigate GLEXJ's inhibitory effects on fear memory generalization in PTSD rats and elucidate its underlying mechanisms.

Materials and methods: PTSD rats were induced using the single prolonged stress and electrical stimulation (SPS&S) protocol and treated with GLEXJ or paroxetine (PRX). Fear memory generalization was assessed using a contextual fear memory test. Hippocampal dendritic spine morphology was analyzed using Golgi-Cox staining. The chemical composition of GLEXJ was determined using ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Network pharmacology was employed to predict GLEXJ's therapeutic mechanism in PTSD treatment. Western blotting and immunofluorescence were used to measure indicators of the transient receptor potential channel 6 (TRPC6)-mediated calcium/calmodulin-dependent protein kinase IV-cAMP response element-binding protein (CaMKIV-CREB) signaling pathway. In vitro, TRPC6 was suppressed in rat adrenal pheochromocytoma (PC12) cells using lentiviral vectors, and phalloidin staining was employed to examine changes in Fibros actin (F-actin), elucidating the mechanistic effects of GLEXJ-containing serum.

Results: GLEXJ significantly mitigated fear memory generalization in PTSD rats, even with repeated stress exposure. It also improved abnormal hippocampal dendritic spine morphology. Network pharmacology analysis confirmed that GLEXJ was closely related to the Ca²⁺ signaling pathway in PTSD treatment. PTSD rats exhibited disrupted TRPC6-mediated CaMKIV-CREB signaling and impaired synaptic plasticity. GLEXJ upregulated TRPC6 expression, reactivated the CaMKIV-CREB pathway, and promoted synaptic remodeling. In vitro studies confirmed that TRPC6 suppression reduced F-actin levels while GLEXJ-containing serum increased TRPC6 expression and F-actin content.

Conclusions: GLEXJ activates CaMKIV-CREB signaling by upregulating TRPC6 in the hippocampus of PTSD rats, leading to improved dendritic spine dynamics and synaptic remodeling. This mechanism contributes to the attenuation of fear memory generalization. Given the limitations of current PTSD treatments, these findings offer potential avenues for developing more effective therapeutic strategies.

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来源期刊

Journal of ethnopharmacology 医学-全科医学与补充医学

CiteScore

10.30

自引率

5.60%

发文量

967

审稿时长

77 days

期刊介绍： The Journal of Ethnopharmacology is dedicated to the exchange of information and understandings about people''s use of plants, fungi, animals, microorganisms and minerals and their biological and pharmacological effects based on the principles established through international conventions. Early people confronted with illness and disease, discovered a wealth of useful therapeutic agents in the plant and animal kingdoms. The empirical knowledge of these medicinal substances and their toxic potential was passed on by oral tradition and sometimes recorded in herbals and other texts on materia medica. Many valuable drugs of today (e.g., atropine, ephedrine, tubocurarine, digoxin, reserpine) came into use through the study of indigenous remedies. Chemists continue to use plant-derived drugs (e.g., morphine, taxol, physostigmine, quinidine, emetine) as prototypes in their attempts to develop more effective and less toxic medicinals.