Liraglutide ameliorates cerebral ischemic injury in diabetic rats by regulating microglia/macrophage polarization through inhibition of NOX2 expression

Jingfan GUAN; Lulu AN; Jiangquan HAN; Mingqiao TIAN; Wanmei HOU; Dongrong LIN; Yuanyu ZHAO; Juanzi ZHANG

doi:10.16016/j.2097-0927.202111090

您当前的位置：

首页 >

文章列表页 >

Liraglutide ameliorates cerebral ischemic injury in diabetic rats by regulating microglia/macrophage polarization through inhibition of NOX2 expression

Basic Medicine | 更新时间：2026-01-09

- Liraglutide ameliorates cerebral ischemic injury in diabetic rats by regulating microglia/macrophage polarization through inhibition of NOX2 expression
- Journal of Army Medical University Vol. 44, Issue 11, Pages: 1136-1142(2022)
- 作者机构：
  
  519100 广东珠海，遵义医科大学第五附属(珠海)医院神经内科
- 作者简介：
- 基金信息：
  
  the Project of Zunyi Science and Technology Plan(遵市科合社字(2018)20号);the "Fourteenth Five-Year Plan" of Clinical Key-Discipline Construction Program of Zhuhai, Guangdong Province(珠卫函〔2021〕115号)
- DOI：10.16016/j.2097-0927.202111090
  CLC： R587.2;R743.31;R977.15
- Received：12 November 2021，
  
  Revised：2021-12-14，
  
  Published：15 June 2022
- 稿件说明：
移动端阅览
Jingfan GUAN, Lulu AN, Jiangquan HAN, et al. Liraglutide ameliorates cerebral ischemic injury in diabetic rats by regulating microglia/macrophage polarization through inhibition of NOX2 expression[J]. Journal of Army Medical University, 2022, 44(11): 1136-1142.
DOI：

Jingfan GUAN, Lulu AN, Jiangquan HAN, et al. Liraglutide ameliorates cerebral ischemic injury in diabetic rats by regulating microglia/macrophage polarization through inhibition of NOX2 expression[J]. Journal of Army Medical University, 2022, 44(11): 1136-1142. DOI： 10.16016/j.2097-0927.202111090.

摘要

目的

观察利拉鲁肽(liraglutide)对局灶性脑缺血糖尿病大鼠缺血侧脑组织小胶质细胞/巨噬细胞极化及烟酰胺腺嘌呤二核苷酸磷酸氧化酶(nicotinamide adenine dinucleotide phosphate oxidase

NOX2)表达的影响。

方法

将75只大鼠按照随机数字表法分为脑缺血(CI)组、糖尿病脑缺血(DCI)组、胰岛素(Ins)组、利拉鲁肽(Lir)组和NOX2激动剂TBCA(tetrabromocinnamic acid)+利拉鲁肽(TBCA)组，每组15只。脑缺血后第3天行神经功能缺损评分; 2

5-氯化三苯四氮唑((TTC))染色测脑梗死体积; 免疫荧光双标染色检测小胶质细胞/巨噬细胞CD16/32、CD206与Iba1共标情况；Western blot检测NOX2、TNF-α、IL-1β、IL-10、TGF-β的蛋白表达。

结果

与DCI组相比，Lir组大鼠神经功能评分减少，脑梗死体积减小，同时M1型小胶质细胞/巨噬细胞Iba1

/CD16/32

细胞数减少，TNF-α、IL-1β、NOX2表达减少，而M2型小胶质细胞/巨噬细胞Iba1

/CD206

细胞数增多，IL-4、IL-10表达增多(

0.05)。上述效应可被NOX2激动剂TBCA所逆转(

0.05)。

结论

利拉鲁肽的神经保护作用可能与其抑制NOX2表达，同时促进小胶质细胞/巨噬细胞向M2型转换有关。

Abstract

Objective

To investigate the effects of liraglutide (Lir) on microglia/macrophage polarization and on the expression of nicotinamide adenine dinucleotide phosphate oxidase (NOX2) in the ischemic brain tissue of diabetic rats with focal cerebral ischemia.

Method

Seventy-five rats were randomly and equally divided into 5 groups: cerebral ischemia (CI) group

diabetes+cerebral ischemia (DCI) group

insulin treatment (Ins) group

Lir treatment (Lir) group

and NOX2 agonist tetrabromocinnamic acid (TBCA) + Lir group (TBCA). On the 3rd day after cerebral ischemia

the neurological deficit scores of the rats were evaluated

and 2

5-triphenyltetrazolium chloride (TTC) staining was adopted to measure the cerebral infarct volume in each group. The co-labeling of CD16/32 and CD206 with Iba1 on microglia/macrophages were detected by immunofluorescence double-label staining

and the protein expression of NOX2

TNF-α

IL-1β

IL-10 and TGF-β were determined using Western blotting.

Results

As co

mpared with the DCI group

the neurological deficit scores were decreased

and the cerebral infarction volume was reduced in the Lir group. The cell number of Iba1

/CD16/32

microglia/macrophage (M1 type) was declined

with down-regulated expression of TNF-α

IL-1β and NOX2 in the Lir group

while the number of Iba1

/CD206

microglia /macrophage (M2 type) was increased

with improved levels of IL-10 and TGF-β (all

0.05). However

the above effects were reversed by the treatment of NOX2 agonist TBCA (

0.05).

Conclusion

The neuroprotective effects of Lir on cerebral ischemic injury may be related to the inhibition of NOX2 expression and promotion of microglia/macrophages conversion to M2 type.

关键词

Keywords

references

JIANG Y H, LIU N, WANG Q Z, et al . Endocrine regulator rFGF21(recombinant human fibroblast growth factor 21) improves neurological outcomes following focal ischemic stroke of type 2 diabetes mellitus male mice[J ] . Stroke, 2018, 49(12): 3039-3049. DOI: 10.1161/STROKEAHA.118.022119.

BORGGREFE J, GLVCK B, MAUS V, et al . Clinical outcome after mechanical thrombectomy in patients with diabetes with major ischemic stroke of the anterior circulation[J ] . World Neurosurg, 2018, 120: e212-e220. DOI: 10.1016/j.wneu.2018.08.032.

BAI B, LI D F, XUE G F, et al . The novel GLP-1/GIP dual agonist DA3-CH is more effective than liraglutide in reducing endoplasmic Reticulum stress in diabetic rats with cerebral ischemia-reperfusion injury[J ] . Nutr Metab Cardiovasc Dis, 2021, 31(1): 333-343. DOI: 10.1016/j.numecd.2020.09.002.

何婧, 韩江全, 施宁华, 等. 利拉鲁肽通过激活过氧化物酶体增殖物激活受体改善合并糖尿病的局灶性脑缺血损伤[J]. 重庆医科大学学报, 2020, 45(3): 350-355. DOI: 10.13406/j.cnki.cyxb.001949.

HE J, HAN J Q, SHI N H, et al . Liraglutide protects against focal cerebral ischemic injury with diabetes mellitus by activating peroxisome proliferator-activated receptors[J ] . J Chongqing Med Univ, 2020, 45(3): 350-355. DOI: 10.13406/j.cnki.cyxb.001949.

SHI N H, HE J, GUO Q Q, et al . Liraglutide protects against diabetes mellitus complicated with focal cerebral ischemic injury by activating mitochondrial ATP-sensitive potassium channels[J ] . Neuroreport, 2019, 30(7): 479-484. DOI: 10.1097/WNR.0000000000001225.

MA S B, WANG J Y, WANG Y L, et al . Diabetes mellitus impairs white matter repair and long-term functional deficits after cerebral ischemia[J ] . Stroke, 2018, 49(10): 2453-2463. DOI: 10.1161/STROKEAHA.118.021452.

DARSALIA V, HUA S S, LARSSON M, et al . Exendin-4 reduces ischemic brain injury in normal and aged type 2 diabetic mice and promotes microglial M2 polarization[J ] . PLoS One, 2014, 9(8): e103114. DOI: 10.1371/journal.pone.0103114.

JACKSON-COWAN L, ELDAHSHAN W, DUMANLI S, et al . Delayed administration of angi otensin receptor(AT2R) agonist C21 improves survival and preserves sensorimotor outcomes in female diabetic rats post-stroke through modulation of microglial activation[J ] . Int J Mol Sci, 2021, 22(3): 1356. DOI: 10.3390/ijms22031356.

RUSSO M V, MCGAVERN D B. Inflammatory neuroprotection following traumatic brain injury[J]. Science, 2016, 353(6301): 783-785. DOI: 10.1126/science.aaf6260.

DING M, FANG Q H, CUI Y T, et al . Liraglutide prevents β-cell apoptosis via inactivation of NOX2 and its related signaling pathway[J ] . J Diabetes Complications, 2019, 33(4): 267-277. DOI: 10.1016/j.jdiacomp.2018.12.013.

KUROKI T, TANAKA R, SHIMADA Y, et al . Exendin-4 inhibits matrix metalloproteinase-9 activation and reduces infarct growth after focal cerebral ischemia in hyperglycemic mice[J ] . Stroke, 2016, 47(5): 1328-1335. DOI: 10.1161/strokeaha.116.012934.

CERECEDO-LOPEZ C D, CANTU-ALDANA A, PATEL N J, et al . Insulin in the management of acute ischemic stroke: a systematic review and meta-analysis[J ] . World Neurosurg, 2020, 136: e514-e534. DOI: 10.1016/j.wneu.2020.01.056.

MA Y Y, WANG J X, WANG Y T, et al . The biphasic function of microglia in ischemic stroke[J ] . Prog Neurobiol, 2017, 157: 247-272. DOI: 10.1016/j.pneurobio.2016.01.005.

HU X M, LEAK R K, SHI Y J, et al . Microglial and macrophage polarization—new prospects for brain repair[J ] . Nat Rev Neurol, 2015, 11(1): 56-64. DOI: 10.1038/nrneurol.2014.207.

MCCLEAN P L, PARTHSARATHY V, FAIVRE E, et al . The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease[J ] . J Neurosci, 2011, 31(17): 6587-6594. DOI: 10.1523/JNEUROSCI.0529-11.2011.

PARTHSARATHY V, HÖLSCHER C. The type 2 diabetes drug liraglutide reduces chronic inflammation induced by irradiation in the mouse brain[J]. Eur J Pharmacol, 2013, 700(1/2/3): 42-50. DOI: 10.1016/j.ejphar.2012.12.012.

BARRETO-VIANNA A R C, AGUILA M B, MANDARIM-DE-LACERDA C A. Beneficial effects of liraglutide(GLP1 analog) in the hippocampal inflammation[J]. Metab Brain Dis, 2017, 32(5): 1735-1745. DOI: 10.1007/s11011-017-0059-4.

ZENG X Z, REN H L, ZHU Y N, et al . Gp91phox(NOX2) in activated microgl ia exacerbates neuronal damage induced by oxygen glucose deprivation and hyperglycemia in an in vitro model[J ] . Cell Physiol Biochem, 2018, 50(2): 783-797. DOI: 10.1159/000494243.

NAYERNIA Z, JAQUET V, KRAUSE K H. New insights on NOX enzymes in the central nervous system[J]. Antioxid Redox Signal, 2014, 20(17): 2815-2837. DOI: 10.1089/ars.2013.5703.

KUMAR A, ALVAREZ-CRODA D M, STOICA B A, et al . Microglial/macrophage polarization dynamics following traumatic brain injury[J ] . J Neurotrauma, 2016, 33(19): 1732-1750. DOI:10.1089/neu.2015.4268.

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

Phosphorylation of extracellular signalregulated protein kinase induced neuronal death under brain ischemia in diabetic rats

Early identification of delayed cerebral ischemia following aneurysmal subarachnoid hemorrhage: development and validation of a multifactorial clinical prediction model

Regulation and mechanism of Gm49394 on islet-β cell apoptosis

Efficacy and safety of drug-eluting balloon dilatation for coronary bifurcation disease in diabetic patients

Iron ion polarizes macrophages to M1 subtype through ROS-acetyl-P53

Related Author

张建忠

景丽

郭风英

马轶

王一理

ZHENG Hui

TAO Yihao

JI Xiang

Related Institution

Department of Neurosurgery， the Second Affiliated Hospital of Chongqing Medical University

Department of Immunology, Faculty of Pharmacy and Laboratory Medicine， Army Medical University （Third Military Medical University）

Department of Laboratory Animal Science， College of Basic Medical Sciences, Faculty of Pharmacy and Laboratory Medicine， Army Medical University （Third Military Medical University）

Department of Pharmaceutical Analysis, Faculty of Pharmacy and Laboratory Medicine， Army Medical University （Third Military Medical University）

Department of Cardiology, Second Affiliated Hospital of Army Medical University (Third Military Medical University)

⁰