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左归降糖解郁方调控小胶质细胞TREM2/C1q信号改善糖尿病并发抑郁症海马神经元突触丢失的机制研究

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中草药 | 药理与临床 2026,57(7): 2602-2613

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中草药 |药理与临床 2026 , 57 (7) : 2602 -2613

左归降糖解郁方调控小胶质细胞TREM2/C1q信号改善糖尿病并发抑郁症海马神经元突触丢失的机制研究

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李中¹, 蔺晓源¹, 姜帆¹, 姚淑霞¹, 王宇红^2,3, 谭琥¹, 刘检¹

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通讯作者:

谭琥

作者简介:

李中: 李中,主治医师,医学博士,从事中医药防治脑病及精神情志类研究。E-mail:983695421@qq.com

Mechanism of Zuogui Jiangtang Jieyu Formula in improving synaptic loss of hippocampal neurons via regulating microglial TREM2/C1q signaling in diabetes-related depression rats

LI Zhong, LIN Xiaoyuan, JIANG Fan, YAO Shuxia, WANG Yuhong, TAN Hu, LIU Jian

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doi: 10.7501/j.issn.0253-2670.2026.07.015

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目的探讨左归降糖解郁方调控髓系细胞触发受体2（triggering receptor expressed on myeloid cells 2，TREM2）/补体1q（complement component 1q，C1q）信号介导的小胶质细胞突触修剪改善糖尿病并发抑郁症（diabetes-related depression，DD）海马神经元突触丢失的保护作用及机制。方法复制DD大鼠模型，设置对照组、模型组、TREM2抑制剂（IN1，1.5 μg/kg）组、TREM激动剂（AL002，2 μg/kg）组、阳性药（二甲双胍0.18 g/kg＋氟西汀1.8 mg/kg）组和左归降糖解郁方（10.26 g/kg）组。分别培养SD大鼠原代小胶质细胞和海马神经元，采用150 mmol/L高糖联合200 μmol/L皮质酮干预构建模拟DD环境下的体外共培养细胞模型，设置对照组、模型组、TREM2抑制剂（IN1，2 μmol/L）组、TREM2激动剂（AL002，5 μmol/L）组、阳性药（10%阳性药含药血清）组和左归降糖解郁方（10%左归降糖解郁方含药血清）组。采用旷场、强迫游泳和糖水偏好实验评估大鼠抑郁样行为；高尔基染色观察大鼠海马神经元突触丢失情况；细胞成像分析观察体外小胶质细胞和海马神经元形态学情况；尼氏染色观察体外海马神经元突触损伤情况；免疫荧光检测大鼠海马小胶质细胞或体外小胶质细胞中TREM2、C1q以及大鼠海马神经元或体外海马神经元中突触后密度蛋白95（postsynaptic density protein 95，PSD95）蛋白表达；Western blotting检测海马组织或体外小胶质细胞中TREM2蛋白表达。结果动物实验结果表明，左归降糖解郁方显著增加大鼠旷场实验总活动路程与糖水偏好率（P＜0.01），减少强迫游泳不动时间（P＜0.01），上调海马小胶质细胞中TREM2表达（P＜0.01），并抑制C1q/PSD95信号介导的小胶质细胞突触过度修剪继而改善大鼠海马神经元突触丢失（P＜0.05、0.01）。细胞实验结果表明，左归降糖解郁方含药血清可显著上调TREM2表达并抑制C1q/PSD95信号介导的小胶质细胞突触过度修剪继而逆转海马神经元突触丢失（P＜0.05、0.01）。结论左归降糖解郁方能有效改善DD海马神经元突触丢失，进而缓解大鼠抑郁样行为，其机制可能与调控TREM2/C1q信号介导的小胶质细胞突触过度修剪有关。

关键词

糖尿病并发抑郁症 / TREM2/C1q信号 / 突触修剪 / 突触丢失 / 左归降糖解郁方 / 马钱苷 / 芍药苷 / 丹酚酸B / 毛蕊异黄酮苷 / 梓醇

Abstract

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Objective To reveal the mechanism of Zuogui Jiangtang Jieyu Formula (左归降糖解郁方, ZGF) to improve synaptic loss of hippocampal neuron based on triggering receptor expressed on myeloid cells 2 (TREM2)/complement component 1q (C1q) signaling-mediated microglial cell synaptic pruning in diabetes-related depression (DD) rats. Methods The model of DD rats was established and rats were randomly divided into control group, model group, TREM2 inhibitor (IN1, 1.5 μg/kg) group, TREM2 agonist (AL002, 2 μg/kg) group, positive drug (metformin 0.18 g/kg+ fluoxetine 1.8 mg/kg) group and ZGF (10.26 g/kg) group. Primary microglia and hippocampal neurons from SD rats were cultured separately. An in vitro co-culture cell model simulating the DD environment was constructed by treating with 150 mmol/L high glucose combined with 200 μmol/L corticosterone, control group, model group, TREM2 inhibitor (IN1, 2 μmol/L) group, TREM2 agonist (AL002, 5 μmol/L) group, positive drug (10% positive drug-containing serum) group and ZGF (10% ZGF-containing serum) group were set up. Depression-like behavior was evaluated by open field, forced swimming and sucrose preference test. Synaptic loss of hippocampal neuron was observed by Golgi staining. Morphology and structure of microglia and hippocampal neuron was observed by cell imaging analysis. Nissl’s staining was used to observe synaptic loss of hippocampal neuron. The protein expressions of TREM2 and C1q in rat hippocampal microglia or in vitro microglia, and ostsynaptic density protein 95 (PSD95) in rat hippocampal neurons or in vitro hippocampal neurons were detected by immunofluorescence. The expressions of TREM2 protein in hippocampal tissue or in vitro microglia were detected by Western blotting. Results The animal experiment results showed that ZGF significantly increased the total activity distance and sugar water preference rate of rats in open field experiment (P < 0.01), reduced forced swimming immobility time (P < 0.01), up-regulated TREM2 expression in hippocampal microglia (P < 0.01), and inhibited C1q/PSD95 signal mediated excessive pruning of microglial synapses, thereby improving synaptic loss in rat hippocampal neurons (P < 0.05, 0.01). The results of cell experiments showed that the serum containing ZGF could significantly up-regulate TREM2 expression and inhibit C1q/PSD95 signal mediated synaptic pruning in microglia, thereby reversing synaptic loss in hippocampal neurons (P < 0.05, 0.01). Conclusion ZGF effectively mitigate the synaptic loss of hippocampal neuron and thereby alleviate depressive behavior in rats, the mechanism of which might be related to the regulation of excessive synaptic pruning of microglia mediated by TREM2/C1q signaling.

Key words

diabetes-related depression / TREM2/C1q signaling / synaptic pruning / synaptic loss / Zuogui Jiangtang Jieyu Formula / loganin / paeoniflorin / salvianolic acid B / calycosin-7-O-β-D-glucoside / catalpol

引用本文

李中, 蔺晓源, 姜帆, 姚淑霞, 王宇红, 谭琥, 刘检. 左归降糖解郁方调控小胶质细胞TREM2/C1q信号改善糖尿病并发抑郁症海马神经元突触丢失的机制研究. 中草药, 2026 , 57 (7) : 2602 -2613 . DOI: 10.7501/j.issn.0253-2670.2026.07.015

LI Zhong, LIN Xiaoyuan, JIANG Fan, YAO Shuxia, WANG Yuhong, TAN Hu, LIU Jian. Mechanism of Zuogui Jiangtang Jieyu Formula in improving synaptic loss of hippocampal neurons via regulating microglial TREM2/C1q signaling in diabetes-related depression rats[J]. Chinese Traditional and Herbal Drugs, 2026 , 57 (7) : 2602 -2613 . DOI: 10.7501/j.issn.0253-2670.2026.07.015

基金

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国家自然科学基金资助项目 (82104793); 湖南省自然科学基金资助项目 (2025JJ80936,2025JJ80965,2024JJ6358); 湖南省教育厅科研项目 (24B0374,24A0284); 湖南省卫健委科研项目 (W20243182,20255684)

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2026年第57卷第7期

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doi: 10.7501/j.issn.0253-2670.2026.07.015

接收时间：2025-12-09
首发时间：2026-09-09

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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