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抑郁症是一种使人衰弱的精神障碍,其特征是持续情绪低落,对几乎所有活动都失去兴趣或愉悦感,并与疲劳、睡眠障碍、焦虑和神经认知障碍症状有关[1],是全球残疾的第三大原因。抑郁症患者工作低下、具有较高的自杀倾向,严重影响患者的生活,造成沉重的社会经济负担[2]。由于疫情的影响,社会心理健康问题正在急剧增加[3,4]。目前,临床上使用的大多数抗抑郁药都具有耐药性,并伴有各种不良反应。因此,寻找安全性更高、不良反应更少的抑郁症治疗方法具有重要意义。既往研究表明,炎症反应在抑郁症中起着至关重要的作用[5]。抑郁症患者血液及额叶皮层中的促炎细胞因子增加[6,7]。抗炎治疗可以产生抗抑郁作用,而抗抑郁药可以减弱抑郁症中促炎细胞因子的表达[8,9]。因此,抑制神经炎症是治疗抑郁症的重要方向。
百合知母汤是中国东汉张仲景医典《金匮要略》中记载的一种经典中药方剂,用于治疗“百合病”[10]。中医“百合病”被认为与现代抑郁症的表现具有较高的相似性[11]。目前,百合知母汤在中医临床上被广泛用于治疗抑郁症[12]。药理学研究表明,百合知母汤在动物模型中具有显著的抗抑郁作用[13]。然而,百合知母汤治疗抑郁症的作用机制并未完全明了。前期研究发现百合知母汤能够通过抑制CUMS抑郁模型小鼠的神经炎症,降低海马IL-1β、 IL-6和TNF-α等促炎细胞因子的表达,来发挥抗抑郁作用[14]。鉴于NLRP1炎症小体在炎症反应过程中的重要的作用[15],且最近研究发现NLRP1炎症小体在抑郁症的发展过程中扮演重用角色[16]。该研究基于NLRP1炎症小体的活化,对百合知母汤的抗抑郁作用进行进一步的探索。
Exploration of the antidepressant mechanism of Baihe Zhimu decoction based on NLRP1 inflammasome
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摘要:
目的 基于NLRP1炎症小体研究百合知母汤抗抑郁的作用机制。 方法 构建慢性不可预测轻度应激(CUMS)诱导的抑郁症小鼠模型,将C57BL/6J小鼠随机分为对照组、模型组、百合知母汤低剂量组、百合知母汤高剂量组以及MDP组(NLRP1激活剂)。连续给药4周,考察小鼠行为学特征。ELISA检测小鼠海马炎症因子IL-1β、IL-6、TNF-α和神经递质5-HT、NE 、DA的水平。Western blot检测炎症小体相关蛋白NLRP1、ASC和caspase-1的表达,以及BDNF/TrkB和ERK/AKT/mTOR信号通路相关蛋白的变化,免疫荧光检测小鼠海马BDNF表达的变化。 结果 百合知母汤能抑制CUMS 小鼠海马NLRP1炎症小体的活化,改善小鼠行为特征,提高小鼠海马神经递质水平,降低炎症反应。 NLRP1激活剂MDP能逆转百合知母汤的上述作用。百合知母汤能上调下游分子BDNF、TrkB的表达水平,提高ERK、AKT和mTOR蛋白磷酸化水平,而MDP能逆转上述作用。 结论 百合知母汤通过抑制NLRP1炎症小体活化,抑制CUMS抑郁症小鼠海马神经炎症反应,进而激活BDNF/TrkB信号通路和ERK/AKT/mTOR信号通路来改善CUMS小鼠的抑郁样行为。 -
关键词:
- 百合知母汤 /
- 抑郁症 /
- 炎症反应 /
- NLRP1炎症小体 /
- BDNF/TrkB信号通路
Abstract:Objective To study the mechanism of antidepressant effect of Baihe Zhimu decoction based on NLRP1 inflammasome. Methods A chronic unpredictable mild stress(CUMS)induced depression mouse model was constructed. C57BL/6J mice were randomly divided into a control group, CUMS group, low-dose Baihe Zhimu decoction group, high-dose Baihe Zhimu decoction group, and MDP group(NLRP1 activator). After continuous administration for 4 weeks, the behavioral characteristic of mice was investigated. The levels of mice hippocampal inflammatory factors IL-1β、IL-6,TNF-α, and neurotransmitters 5-HT, NE, and DA were detected by ELISA. The expression of inflammasome related proteins NLRP1, ASC, and caspase-1, as well as related proteins in BDNF/TrkB and ERK/AKT/mTOR signaling pathway were detected by Western blot. Immunofluorescence was used to detect changes in BDNF expression in the hippocampus of mice. Results Baihe Zhimu decoction inhibited the activation of NLRP1 inflammasomes in the hippocampus of CUMS mice, improved their behavioral characteristics, increased the level of neurotransmitters in the hippocampus, and reduced the inflammatory response. The NLRP1 activator MDP reversed the above effects of Baihe Zhimu decoction. Baihe Zhimu decoction increased BDNF, TrkB expression, and phosphorylation levels of ERK, AKT, and mTOR proteins, which could be reversed by MDP. Conclusion Baihe Zhimu decoction improved depression like behavior in CUMS mice by inhibiting NLRP1 inflammasome activation and hippocampal neuroinflammatory response, and thereby activating BDNF/TrkB and ERK/AKT/mTOR signaling pathway. -
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