Effects and mechanism of short-acting exenatide on improving diabetic cognitive dysfunction

LING Xin; WANG Deming; LU Qi; HUANG Jinyue; ZHENG Xian; ZHU Xiaona

doi:10.6039/j.issn.1001-0408.2026.05.07

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Effects and mechanism of short-acting exenatide on improving diabetic cognitive dysfunction

更新时间：2026-03-10

- Effects and mechanism of short-acting exenatide on improving diabetic cognitive dysfunction
- ZHONGGUO YAOFANG Vol. 37, Issue 5, Pages: 589-594(2026)
- 作者机构：
  
  1.徐州市肿瘤医院药剂科，江苏徐州　221005
  2.昆山市第一人民医院药学部，江苏昆山　215300
  3.徐州市儿童医院药剂科，江苏徐州　221002
- 作者简介：
- 基金信息：
- DOI：10.6039/j.issn.1001-0408.2026.05.07
  CLC： R965
- Received：17 September 2025，
  
  Revised：2026-02-05，
  
  Accepted：05 February 2026，
  
  Published：15 March 2026
- 稿件说明：
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凌心,王德铭,鹿琦,等.短效艾塞那肽改善糖尿病认知功能障碍的作用及机制研究 ^Δ[J].中国药房,2026,37(05):589-594.

LING Xin,WANG Deming,LU Qi,et al.Effects and mechanism of short-acting exenatide on improving diabetic cognitive dysfunction[J].ZHONGGUO YAOFANG,2026,37(05):589-594.
凌心,王德铭,鹿琦,等.短效艾塞那肽改善糖尿病认知功能障碍的作用及机制研究 ^Δ[J].中国药房,2026,37(05):589-594. DOI： 10.6039/j.issn.1001-0408.2026.05.07.

LING Xin,WANG Deming,LU Qi,et al.Effects and mechanism of short-acting exenatide on improving diabetic cognitive dysfunction[J].ZHONGGUO YAOFANG,2026,37(05):589-594. DOI： 10.6039/j.issn.1001-0408.2026.05.07.

摘要

目的

研究短效艾塞那肽对糖尿病认知功能障碍的改善作用及机制。

方法

将自发性糖尿病

小鼠随机分为模型组（生理盐水）和艾塞那肽组（50 μg/kg），另将

小鼠作为正常对照组（生理盐水），每组8只。各组小鼠皮下注射相应药液/生理盐水，每天2次，连续8周。每周固定时间称量小鼠体重，并检测其空腹血糖；采用Morris水迷宫实验评估各组小鼠的认知功能；检测小鼠海马组织中氧化应激指标[丙二醛（MDA）、超氧化物歧化酶（SOD）和谷胱甘肽（GSH）

]

和环磷酸腺苷（cAMP）、蛋白激酶A（PKA）水平。另将小鼠海马神经元细胞HT22分为对照组（25 mmol/L葡萄糖）、高糖组（125 mmol/L葡萄糖）、高糖+艾塞那肽组（125 mmol/L葡萄糖+20 nmol/L艾塞那肽）、高糖+艾塞那肽+H89（PKA抑制剂）组（125 mmol/L葡萄糖+20 nmol/L艾塞那肽+10 μmol/L H89）、高糖+H89组（125 mmol/L葡萄糖+10 μmol/L H89），加入相应药液/培养基干预48 h后，检测细胞中氧化应激指标和cAMP、PKA水平，线粒体呼吸酶Ⅱ、Ⅳ活性，以及动力相关蛋白1（Drp1）的磷酸化水平。

结果

动物实验结果显示，与正常对照组比较，模型组小鼠在实验周期内体重、空腹血糖水平和海马组织中MDA水平均显著升高（

＜0.05），逃避潜伏期显著延长（

＜0.05），游泳速度、目标象限停留时间、穿越目标平台次数和海马组织中SOD、GSH、cAMP、PKA水平均显著减慢/缩短/减少/降低（

＜0.05）；与模型组比较，艾塞那肽组小鼠上述指标（游泳速度除外）水平均显著逆转（

＜0.05）。细胞实验结果显示，与高糖组比较，高糖+艾塞那肽组细胞中MDA水平显著降低（

＜0.05），SOD、GSH、cAMP、PKA水平和线粒体呼吸酶Ⅱ、Ⅳ活性以及Drp1磷酸化水平均显著升高（

＜0.05）；与高糖+艾塞那肽组比较，高糖+艾塞那肽+H89组细胞中上述指标水平均显著逆转（

＜0.05）。

结论

短效艾塞那肽可通过激活cAMP/PKA通路、促进Drp1磷酸化、升高线粒体呼吸酶活性，维持线粒体稳定，减轻氧化应激损伤，从而发挥改善糖尿病认知功能障碍的作用。

Abstract

OBJECTIVE

To investigate the ameliorative effect and mechanism of short-acting exenatide on diabetic cognitive dysfunction.

METHODS

Spontaneously diabetic

mice were randomly divided into model group （normal saline） and exenatide group （50 μg/kg）， with

mice as the normal control group （normal saline）， with 8 mice in each group. Mice in each group were subcutaneously injected with corresponding drugs or normal saline twice daily for 8 consecutive weeks. Body weight and fasting blood glucose were measured at a fixed time every week. Cognitive function was evaluated by Morris water maze test. The levels of oxidative st

ress indicators [malondialdehyde （MDA）， superoxide dismutase （SOD）， glutathione （GSH）

]

， cyclic adenosine monophosphate （cAMP） and protein kinase A （PKA） were detected in hippocampus tissue of mice. The hippocampal neuronal HT22 cells of mice were divided into control group （25 mmol/L glucose）， high glucose group （125 mmol/L glucose）， high glucose+exenatide group （125 mmol/L glucose+20 nmol/L exenatide）， high glucose+exenatide+H89 （PKA inhibitor） group （125 mmol/L glucose+20 nmol/L exenatide+10 μmol/L H89）， and high glucose+H89 group （125 mmol/L glucose+10 μmol/L H89）. After 48 h of intervention with corresponding solutions/culture medium， the levels of oxidative stress indicators， cAMP and PKA， the activities of mitochondrial respiratory enzymes Ⅱ and Ⅳ， and the phosphorylation level of dynamin-related protein 1 （Drp1） were measured.

RESULTS

Animal experiments showed that compared with the normal control group， the model group exhibited significantly increased body weight， fasting blood glucose and MDA level in the hippocampus （

＜0.05）， as well as significantly prolonged escape latency （

＜0.05）； swimming speed significantly slowed down， the time spent in the target quadrant， the number of platform crossings， and the levels of SOD， GSH， cAMP and PKA in the hippocampus were significantly decreased （

＜0.05）. Compared with model group， all the above indicators （except for swimming speed） in the exenatide group were significantly reversed （

＜0.05）. Cell experiments showed that compared with high glucose group， the high glucose+exenatide group had significantly decreased MDA level （

＜0.05）， and significantly increased levels of SOD， GSH， cAMP and PKA， the activities of mitochondrial respiratory enzymes Ⅱ and Ⅳ， and phosphorylation level of Drp1 （

＜0.05）. Compared with high glucose+exenatide group， the above indicators in the high glucose+exenatide+H89 group were significantly reversed （

＜0.05）.

CONCLUSIONS

Short-acting exenatide can activate the cAMP/PKA pathway， promote Drp1 phosphorylation， and increase the activities of mitochondrial respiratory enzymes， thereby maintaining mitochondrial stability， reducing oxidative stress injury， and ultimately improving diabetic cognitive dysfunction.

关键词

Keywords

references

VAN SLOTEN T T ， SEDAGHAT S ， CARNETHON M R ， et al . Cerebral microvascular complications of type 2 diabetes：stroke，cognitive dysfunction，and depression [J ] . Lancet Diabetes Endocrinol ， 2020 ， 8 （ 4 ）： 325 - 336 .

DEL CAMPO-ROTA I M ， DELGADO-CASILLAS O M ， IBARRA A . Cognitive impairment induced by gestational diabetes：the role of oxidative stress [J ] . Arch Med Res ， 2024 ， 55 （ 5 ）： 103016 .

SONG X Q ， FAN S W ， GAO Y T ， et al . Swietenolide inhibits the TXNIP/NLRP3 pathways via Nrf2 activation to ameliorate cognitive dysfunction in diabetic mice [J ] . Neuropharmacology ， 2025 ， 267 ： 110312 .

HAHN A ， ZURYN S . Mitochondrial genome （mtDNA） mutations that generate reactive oxygen species [J ] . Antioxidants ， 2019 ， 8 （ 9 ）： 392 .

GARCÍA-CASARES N ， GONZÁLEZ-GONZÁLEZ G ， DE LA CRUZ-COSME C ， et al . Effects of GLP-1 receptor agonists on neurological complications of diabetes [J ] . Rev Endocr Metab Disord ， 2023 ， 24 （ 4 ）： 655 - 672 .

DEI CAS A ， MICHELI M M ， ALDIGERI R ， et al . Long-acting exenatide does not prevent cognitive decline in mild cognitive impairment：a proof-of-concept clinical trial [J ] . J Endocrinol Invest ， 2024 ， 47 （ 9 ）： 2339 - 2349 .

KANG X N ， WANG D ， ZHANG L ， et al . Exendin-4 ameliorates tau hyperphosphorylation and cognitive impairment in type 2 diabetes through acting on Wnt/β-catenin/NeuroD1 pathway [J ] . Mol Med ， 2023 ， 29 （ 1 ）： 118 .

XIE Y Z ， ZHENG J P ， LI S Q ， et al . GLP-1 improves the neuronal supportive ability of astrocytes in Alzheimer’s disease by regulating mitochondrial dysfunction via the cAMP/PKA pathway [J ] . Biochem Pharmacol ， 2021 ， 188 ： 114578 .

秦亚玮，李娜，黄钰涵，等 . 艾塞那肽改善T2DM患者和 db / db 小鼠肝脏胰岛素抵抗的作用 [J ] . 药学与临床研究， 2024 ， 32 （ 2 ）： 103 - 108 .

RACHMANY L ， TWEEDIE D ， RUBOVITCH V ， et al . Exendin-4 attenuates blast traumatic brain injury induced cognitive impairments，losses of synaptophysin and in vitro TBI-induced hippocampal cellular degeneration [J ] . Sci Rep ， 2017 ， 7 ： 3735 .

MENG L L ， LU Y ， WANG X L ， et al . NPRC deletion attenuates cardiac fibrosis in diabetic mice by activating PKA/PKG and inhibiting TGF-β 1 /Smad pathways [J ] . Sci Adv ， 2023 ， 9 （ 31 ）： eadd4222 .

KOEKKOEK P S ， KAPPELLE L J ， VAN DEN BERG E ， et al . Cognitive function in patients with diabetes mellitus：guidance for daily care [J ] . Lancet Neurol ， 2015 ， 14 （ 3 ）： 329 - 340 .

CAO Y J ， SUN W ， LIU C ， et al . Resveratrol ameliorates diabetic encephalopathy through PDE4D/PKA/Drp1 signaling [J ] . Brain Res Bull ， 2023 ， 203 ： 110763 .

WEI W ， DONG Q Y ， JIANG W B ， et al . Dichloroacetic acid-induced dysfunction in rat hippocampus and the protective effect of curcumin [J ] . Metab Brain Dis ， 2021 ， 36 （ 4 ）： 545 - 556 .

TANG W X ， YAN C Y ， HE S X ， et al . Neuron-targeted overexpression of caveolin-1 alleviates diabetes-associated cognitive dysfunction via regulating mitochondrial fission-mitophagy axis [J ] . Cell Commun Signal ， 2023 ， 21 （ 1 ）： 357 .

SOUSA J S ， D’IMPRIMA E ， VONCK J . Mitochondrial respiratory chain complexes [J ] . Subcell Biochem ， 2018 ， 87 ： 167 - 227 .

CHANG C R ， BLACKSTONE C . Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology [J ] . J Biol Chem ， 2007 ， 282 （ 30 ）： 21583 - 21587 .

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