<italic style="font-style: italic">Zuogui Jiangtang Jieyu</italic> Formula regulates the CD300f/GLUT1 signaling pathway to improve the synaptic damage of hippocampal neurons in rats with diabetes-related depression

LIU Jian; TANG Lin; ZHAO Hongqing; JIANG Fan; LIU Lin; HU Chao

doi:10.3969/j.issn.1006-2157.2024.11.012

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Zuogui Jiangtang Jieyu Formula regulates the CD300f/GLUT1 signaling pathway to improve the synaptic damage of hippocampal neurons in rats with diabetes-related depression

Experimental Studies | 更新时间：2024-12-02

- Zuogui Jiangtang Jieyu Formula regulates the CD300f/GLUT1 signaling pathway to improve the synaptic damage of hippocampal neurons in rats with diabetes-related depression
- Journal of Beijing University of Traditional Chinese Medicine Vol. 47, Issue 11, Pages: 1573-1584(2024)
- 作者机构：
  
  1.湖南中医药大学第一附属医院，长沙　410007
  2.湖南中医药大学科技创新中心
- 作者简介：
  
  HU Chao, Chief Pharmacist. The First Hospital of Hunan University of Chinese Medicine, No.95, Shaoshan Road, Changsha 410007. E-mail: 348009051@qq.com
- 基金信息：
  
  National Natural Science Foundation of China(82104793)
- DOI：10.3969/j.issn.1006-2157.2024.11.012
  CLC： R285.5
- Received：31 May 2024，
  
  Published：30 November 2024
- 稿件说明：
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LIU Jian, TANG Lin, ZHAO Hongqing, et al. Zuogui Jiangtang Jieyu Formula regulates the CD300f/GLUT1 signaling pathway to improve the synaptic damage of hippocampal neurons in rats with diabetes-related depression[J]. Journal of beijing university of traditional chinese medicine, 2024, 47(11): 1573-1584.
DOI：

LIU Jian, TANG Lin, ZHAO Hongqing, et al. Zuogui Jiangtang Jieyu Formula regulates the CD300f/GLUT1 signaling pathway to improve the synaptic damage of hippocampal neurons in rats with diabetes-related depression[J]. Journal of beijing university of traditional chinese medicine, 2024, 47(11): 1573-1584. DOI： 10.3969/j.issn.1006-2157.2024.11.012.

摘要

目的

基于白细胞单免疫球蛋白样受体3(CD300f)/葡萄糖转运体1(GLUT1)信号通路介导小胶质细胞糖代谢，探讨左归降糖解郁方改善糖尿病并发抑郁症大鼠海马神经元突触损伤的作用机制。

方法

80只雄性SD大鼠按照随机数字表法选取10只大鼠作为正常组，其余70只高脂饲料喂养4周后单次尾静脉注射链脲佐菌素(38 mg/kg)复制大鼠糖尿病模型，筛选造模成功的大鼠60只，按随机数字表法分为模型组、CD300f阻断剂组、CD300f激动剂组、二甲双胍＋氟西汀组(二甲双胍0.18 g/kg＋氟西汀1.8 mg/kg)和左归降糖解郁方高、低剂量组(20.52、10.26 g/kg)。除正常组外，其余各组大鼠予28 d慢性不可预知温和应激加孤养复制糖尿病并发抑郁症大鼠模型。其中，二甲双胍＋氟西汀组与左归降糖解郁方高、低剂量组在造模第2周后连续灌胃相应药物，正常组、模型组灌胃等体积蒸馏水，连续14 d；CD300f阻断剂组、激动剂组则进行海马区微量注射给药，分别注射髓系细胞触发受体抑制因子(CLM1，2 μg/kg)和免疫球蛋白Fc段表面蛋白(Fcγ，5 μg/kg)，每周1次。干预结束后，采用旷场实验、强迫游泳实验检测大鼠抑郁样行为；生化分析检测大鼠海马组织葡萄糖、乳酸含量及腺苷二磷酸(ADP)/三磷酸腺苷(ATP)；采用酶联免疫吸附测定法检测大鼠海马组织胰岛素、5－羟色胺(5-HT)和多巴胺(DA)水平；采用免疫荧光检测海马组织CD300f、GLUT1、突触相关前膜蛋白3(RIMS3)、突触后膜相关蛋白102(SAP102)平均荧光强度；蛋白质印迹法检测大鼠海马组织CD300f、GLUT1、RIMS3、SAP102蛋白表达情况；采用尼氏染色和透射电镜观察大鼠海马组织病理改变。

结果

与正常组比较，模型组大鼠旷场总活动路程减少、强迫游泳不动时间增加，海马组织葡萄糖、乳酸含量及ADP/ATP升高、胰岛素水平降低、5-HT和DA水平下降，海马组织CD300f、GLUT1、RIMS3、SAP102平均荧光强度及蛋白相对表达量均降低(均

0.05)，海马神经元突触超微结构受损。与模型组比较，CD300f激动剂组及左归降糖解郁方高、低剂量组上述抑郁样行为学改变、糖代谢和单胺神经递质失衡得到改善(均

0.05)；CD300f激动剂组及左归降糖解郁方高剂量组海马CD300f、GLUT1、RIMS3、SAP102平均荧光强度和蛋白相对表达量均升高(均

0.05)，突触损伤减轻；CD300f阻断剂组葡萄糖、乳酸、ADP/ATP、5-HT异常及CD300f蛋白表达异常情况加重(均

0.05)，突触损伤加重。

结论

左归降糖解郁方能有效缓解糖尿病并发抑郁症大鼠海马小胶质细胞糖代谢异常与神经元突触损伤，其机制可能与调控CD300f/GLUT1信号通路有关。

Abstract

Objective

To explore the protective mechanism of

Zuogui Jiangtang Jieyu

Formula (ZGF) on synaptic damage of hippocampal neurons based on leukocyte mono-immunoglobulin-like receptor 3 (CD300f)/glucose transporter 1 (GLUT1) signal-mediated microglial glucose metabolism in rats with diabetes-related depression.

Methods

Eighty male SD rats were randomly selected using random number table method

with 10 rats serving as the normal group. The remaining 70 rats were fed a high-fat diet for 4 weeks and then injected once with 38 mg/kg of streptozotocin via the tail vein to replicate the diabetes rat model. Sixty rats were screened and successfully modeled

which were randomly divided into the model

CD300f blocker

CD300f agonist

metformin + fluoxetine (metformin 0.18 g/kg + fluoxetine 1.8 mg/kg)

and ZGF high- and low-dose (20.52 and 10.26 g/kg

respectively) groups using random number table method. In addition to the normal group

the rats in the other groups underwent chronic unpredictable mild stress combined with isolation feeding for 28 days to replicate the diabetes-related depression rat model. The metformin + fluoxetine and ZGF high- and low-dose groups were subjected to continuous intragastrial administration for 14 days after the second week of modeling. The normal and model groups were administered an equal amount of distilled water by gavage. The CD300f blocker group and agonist group received microinjection into the hippocampus

with injection of myeloid cell trigger receptor inhibitory factor (CLM1

2 μg/kg) and immunoglobulin Fc surface protein (Fcγ

5 μg/kg) once a week

respectively. Depression-like behavior in rats was evaluated using open-field and forced swimming tests after the intervention. Biochemical analysis was used to detect the glucose

lactic acid

and adenosine diphosphate (ADP)/adenosine triphosphate (ATP) ratio contents. The insulin

5-hydroxytryptamine (5-HT)

and dopamine (DA) levels in the hippocampus were detected using an enzyme-linked immunosorbent assay. Immunofluorescence was used to detect the average fluorescence intensity of CD300f

GLUT1

regulating synaptic membrane wxocytosis 3 (RIMS3)

and synapse-associated protein 102 (SAP102) in hippocampal tissue. Western blotting was used to detect the CD300f

GLUT1

RIMS3

and SAP102 protein expression levels in the hippocampus. The synaptic damage of hippocampal neurons was observed using Nissl staining and transmission electron microscope.

Results

Compared with the normal group

the model group showed a decrease in the total active distance in the open-field test and an increase in forced swimming immobility time

with an increase in glucose and lactic acid contents and ADP/ATP ratio

whereas a decrease in insulin

5-HT

and DA levels was observed in the hippocampus. The average fluorescence intensity and relative protein expression levels of CD300f

GLUT1

RIMS3

and SAP102 in hippocampal tissue decreased (

0.05)

and the synaptic ultrastructure of hippocampal neurons was damaged. Compared with the model group

depression-like behavioral changes

glucose metabolism

and monoamine neurotransmitter imbalance were alleviated in the CD300f agonist group and ZGF high- and low-dose group (

0.05). The average fluorescence intensity and relative protein expression levels of CD300f

GLUT1

RIMS3

and SAP102 in the hippocampus of the CD300f agonist group and the ZGF high-dose group were all increased (

0.05)

and synaptic damage was alleviated. The abnormal levels of glucose

lactate

ADP/ATP

5-HT

and CD300f protein expression were aggravated in the CD300f blocker group (

0.05)

and synaptic damage was aggravated.

Conclusion

ZGF can alleviate glucose metabolism disorders in hippocampal microglia and synaptic damage in hippocampal neurons in rats with diabetes-related depression. Its mechanism may be related to regulating the CD300f/GLUT1 signaling pathway.

关键词

Keywords

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Zuogui Jiangtang Jieyu Formula regulates the CD300f/GLUT1 signaling pathway to improve the synaptic damage of hippocampal neurons in rats with diabetes-related depression

DOI：10.3969/j.issn.1006-2157.2024.11.012

摘要

Abstract

关键词

Keywords

references