基于β2AR/β-arrestin2/NF-κB通路探讨预电针“内关”“间使”对阿尔茨海默病样大鼠学习记忆及蓝斑核－海马神经环路的作用机制

何川; 王丽; 潘小丽; 余超超; 肖娟; 鲁镇坤; 李湘钰; 杜艳军; 沈峰

doi:10.3969/j.issn.1006-2157.2024.11.017

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基于β2AR/β-arrestin2/NF-κB通路探讨预电针“内关”“间使”对阿尔茨海默病样大鼠学习记忆及蓝斑核－海马神经环路的作用机制

针灸推拿 | 更新时间：2024-12-02

- 基于β2AR/β-arrestin2/NF-κB通路探讨预电针“内关”“间使”对阿尔茨海默病样大鼠学习记忆及蓝斑核－海马神经环路的作用机制
- Exploring the mechanism of pre-electroacupuncture at " Neiguan" (PC6) and " Jianshi" (PC5) acupoints on learning, memory, and locus coeruleus-hippocampal neural circuit in Alzheimer′s disease-like rats via the β2AR/β-arrestin2/NF-κB pathway
- 北京中医药大学学报 2024年47卷第11期页码：1612-1622
- 作者机构：
  
  1.湖北中医药大学针灸骨伤学院　武汉　430061
  2.湖北时珍实验室
  3.深圳市中医院
  4.广州中医药大学第四临床学院
  5.湖北省中医院
- 作者简介：
  
  何川，男，博士，讲师
  #沈峰，男，博士，教授，主任医师，博士生导师，主要研究方向：针灸作用机制，E-mail：40052958@qq.com
- 基金信息：
  
  国家自然科学基金项目(82374564);湖北省自然科学基金中医药联合资助重点项目(2023AFD113);湖北省中医药管理局科研项目(ZY2023F138);湖北中医药大学博士科研启动经费支持项目
- DOI：10.3969/j.issn.1006-2157.2024.11.017
  中图分类号： R245.9⁺7
- 收稿：2024-06-26，
  
  网络首发：2024-10-10，
  
  纸质出版：2024-11-30
- 稿件说明：
移动端阅览
何川, 王丽, 潘小丽, 等. 基于β2AR/β-arrestin2/NF-κB通路探讨预电针“内关”“间使”对阿尔茨海默病样大鼠学习记忆及蓝斑核－海马神经环路的作用机制[J]. 北京中医药大学学报, 2024,47(11):1612-1622.

HE Chuan, WANG Li, PAN Xiaoli, et al. Exploring the mechanism of pre-electroacupuncture at " Neiguan" (PC6) and " Jianshi" (PC5) acupoints on learning, memory, and locus coeruleus-hippocampal neural circuit in Alzheimer′s disease-like rats via the β2AR/β-arrestin2/NF-κB pathway[J]. Journal of Beijing University of Traditional Chinese Medicine, 2024, 47(11): 1612-1622.
何川, 王丽, 潘小丽, 等. 基于β2AR/β-arrestin2/NF-κB通路探讨预电针“内关”“间使”对阿尔茨海默病样大鼠学习记忆及蓝斑核－海马神经环路的作用机制[J]. 北京中医药大学学报, 2024,47(11):1612-1622. DOI： 10.3969/j.issn.1006-2157.2024.11.017.

HE Chuan, WANG Li, PAN Xiaoli, et al. Exploring the mechanism of pre-electroacupuncture at " Neiguan" (PC6) and " Jianshi" (PC5) acupoints on learning, memory, and locus coeruleus-hippocampal neural circuit in Alzheimer′s disease-like rats via the β2AR/β-arrestin2/NF-κB pathway[J]. Journal of Beijing University of Traditional Chinese Medicine, 2024, 47(11): 1612-1622. DOI： 10.3969/j.issn.1006-2157.2024.11.017.

摘要

目的

观察预电针对阿尔茨海默病(AD)样大鼠空间学习记忆能力、蓝斑核－海马神经环路及神经炎症的影响，探讨预电针防治AD的潜在作用机制。

方法

36只雄性SD大鼠按随机数字表法分为正常组、模型组、电针组、假电针组，每组9只。除正常组外，其余各组通过腹腔注射D－半乳糖[120 mg/(kg·d)，连续8周]制备AD样大鼠模型。每日腹腔注射后，电针组大鼠予电针刺激“内关”“间使”，连续波，频率50 Hz，电流1 mA，20 min/次，每日1次，共8周。假电针组仅于“内关”“间使”位置浅刺至皮下，不通电，其余操作均与电针组同。干预结束后，以Morris水迷宫实验评估大鼠空间学习记忆能力，免疫荧光标记法检测蓝斑核多巴胺β羟化酶和c-Fos共定位去甲肾上腺素能神经元表达数、海马CA1区胶质纤维酸性蛋白和肿瘤坏死因子－α(TNF-α)共定位星形胶质细胞数，蛋白质印迹法测定大鼠海马去甲肾上腺素(NE)、β2肾上腺素受体(β2AR)、β－抑制蛋白2(β-arrestin2)、核转录因子－κB(NF-κB)、NF-κB抑制蛋白α(IκBα)蛋白表达水平，酶联免疫吸附测定法检测海马组织TNF-α、白细胞介素－1β(IL-1β)及白细胞介素－6(IL-6)含量。

结果

与正常组比较，模型组大鼠平均逃避潜伏期延长，平台穿越次数和在目标象限探索时间减少(

0.01)；电针干预能缩短大鼠平均逃避潜伏期，增加平台穿越次数和在目标象限探索时间(

0.01)。与正常组比较，模型组大鼠共定位去甲肾上腺素能神经元数减少、共定位星形胶质细胞数增多(

0.01)，NE、β2AR、β-arrestin2及IκBα蛋白表达降低(

0.01)，NF-κB蛋白表达增加(

0.01)，TNF-α、IL-1β及IL-6含量增加(

0.01)；与模型组比较，电针组大鼠共定位去甲肾上腺素能神经元数增多、共定位星形胶质细胞减少(

0.01)，NE、β2AR、β-arrestin2及IκBα蛋白表达增加(

0.01)，NF-κB蛋白表达减少(

0.01)，TNF-α、IL-1β及IL-6含量减少(

0.01)。与模型组比较，假电针组大鼠上述各项指标差异均无统计学意义。

结论

预电针“内关”“间使”可缓解AD样大鼠学习记忆功能障碍，减轻蓝斑核去甲肾上腺素能神经元丢失，抑制星形胶质细胞激活，保护蓝斑核－海马神经环路，其作用机制可能与抑制了β2AR/β-arrestin2/NF-κB炎性通路的激活相关。

Abstract

Objective

To investigate the effects of pre-electroacupuncture (EA) on spatial learning and memory

the locus coeruleus-hippocampal neural circuit

and neuroinflammation in Alzheimer′s disease (AD)-like rats

and to explore the possible mechanism of pre-EA in preventing and treating AD.

Methods

Thirty-six male SD rats were divided into the normal

model

and sham EA groups using the random number table method

with nine rats per group. An AD-like rat model was prepared through intraperitoneal injection of 120 mg/(kg·d) D-galactose for eight consecutive weeks. After daily intraperitoneal injection

the rats in the EA group underwent EA stimulation at the " Neiguan" (PC6) and " Jianshi" (PC5) acupoints with a continuous wave

frequency of 50 Hz

and a current of 1 mA for 20 min once a day for 8 weeks. The sham EA group was only superficially punctured to the subcutaneous tissue at the " Neiguan" (PC6) and " Jianshi" (PC5) acupoints without electricity

and the rest of the operations were the same as those in the EA group. The Morris water maze experiment was then used to evaluate the spatial learning and memory of the rats. Immunofluorescence labeling was used to detect dopamine β hydroxylase and c-Fos co-localization in the locus coeruleus of noradrenergic neurons

as well as glial fibrillary acidic protein and tumor necrosis factor-α (TNF-α) co-localization in the CA1 area of the hippocampus of astrocytes. Western blotting was used to measure the protein expressions of norepinephrine (NE)

β2-adrenergic receptor (β2AR)

β-inhibitory protein 2 (β-arrestin2)

nuclear transcription factor-κB (NF-κB) inhibitory factor protein α (IκBα)

and NF-κB in the hippocampus of rats. An enzyme-linked immunosorbent assay was used to detect the TNF-α

interleukin-1β (IL-1β)

and interleukin-6 (IL-6) contents in hippocampal tissue.

Results

Compared with the normal group

the average escape latency of the model group rats was prolonged

and the times of crossing platform and exploration time in the target quadrant were reduced (

0.01)

while the EA intervention can shorten the average escape latency and increase the times of crossing platform and exploration time in the target quadrant (

0.01). Compared with the normal group

the expression of co-located noradrenergic neurons in the model group

decreased

co-located astrocytes increased (

0.01); NE

β2AR

β-arrestin2

and IκBα protein expression decreased(

0.01)

NF-κB protein expression increased (

0.01); the contents of TNF-α

IL-1β

and IL-6 increased (

0.01). Compared with the model group

the EA group showed an increase in the expression of co-located noradrenergic neurons

a decrease in co-located astrocytes (

0.01)

an increase in NE

β2AR

β-arrestin2

and IκBα protein expressions (

0.01)

a decrease in NF-κB protein expression (

0.01)

and a decrease in TNF-α

IL-1β

and IL-6 levels (

0.01). No significant difference was observed in the above indicators between the model and sham EA groups.

Conclusion

Pre-EA at " Neiguan" (PC6) and " Jianshi" (PC5) can alleviate learning and memory dysfunction

alleviate noradrenergic neuronal loss in the locus coeruleus

inhibit astrocyte activation

protect the locus coeruleus-hippocampal neural circuit

and may be associated with inhibiting β2AR/β-arrestin2/NF-κB inflammatory pathway activation.

关键词

Keywords

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