Ursolic acid improves cognitive impairment in type 2 diabetic mice by preventing complement 3 secretion and neuropathy

IF 3.7 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin Pub Date : 2025-09-24 DOI:10.1016/j.brainresbull.2025.111562

Yaojun Suo , Yuan Fu , Chunfang Wang , Yi Wu , Peichu Tian

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引用次数: 0

Abstract

Background

Type 2 diabetes mellitus (T2DM) and cognitive impairment are high incidence epidemics worldwide and are recognized as comorbidities. Ursolic acid (UA) is considered as a potential therapy for diabetic cognitive impairment due to its neuroprotective effect. This study focused on the therapeutic efficacy and possible mechanisms of UA in restoring cognitive function in T2DM mice.

Methods

C57BL/6 male mice were fed with high-fat diet combined with intraperitoneal injection of streptozotocin to establish a T2DM model, and then were treated with UA or vehicle by oral administration for 21 days. The cognitive performance was determined using the T-maze test and novel object recognition test. The levels of complement C3, C3aR, GSK3β, neuronal damage, GFAP, Iba-1, pathological tau and proinflammatory cytokines such as IL-1β and TNF-α in prefrontal cortex of the T2DM mice were evaluated by western blot, tissue staining, or ELISA. The effect of UA on high glucose-induced cytotoxicity was assessed by MTT assay, and the effects of UA on proinflammatory cytokines and C3 were detected by ELISA and western blot.

Results

We showed that administration of UA prevented neuronal damage, neuroinflammation and tau hyperphosphorylation by suppressing C3-C3aR-GSK3β axis, resulting in a significant improvement of cognition in T2DM mice. UA inhibited C3 expression and lowered the production of proinflammatory cytokines to resist high glucose induced cytotoxicity in vitro.

Conclusion

Our results suggest that UA supplements have cognitive protective effects on the T2DM mouse model and may be a promising candidate drug for cognitive impairment.

查看原文本刊更多论文

熊果酸通过防止补体3分泌和神经病变改善2型糖尿病小鼠的认知障碍。

背景：2型糖尿病（T2DM）和认知功能障碍是世界范围内的高发流行病，是公认的合并症。熊果酸（UA）具有神经保护作用，被认为是治疗糖尿病认知障碍的潜在药物。本研究主要探讨UA对T2DM小鼠认知功能恢复的治疗效果及可能机制。方法：C57BL/6雄性小鼠以高脂饲料联合腹腔注射链脲佐菌素建立T2DM模型，然后口服UA或载药21 d。采用t -迷宫测验和新物体识别测验测定受试者的认知能力。采用western blot、组织染色或ELISA检测T2DM小鼠前额叶皮层补体C3、C3aR、GSK3β、神经元损伤、GFAP、Iba-1、病理性tau及促炎因子IL-1β、TNF-α水平。MTT法观察UA对高糖诱导的细胞毒性的影响，ELISA法和western blot法检测UA对促炎细胞因子和C3的影响。结果：我们发现，UA通过抑制C3-C3aR-GSK3β轴来预防神经元损伤、神经炎症和tau过度磷酸化，从而显著改善T2DM小鼠的认知能力。在体外实验中，UA抑制C3表达，降低促炎细胞因子的产生，抵抗高糖诱导的细胞毒性。结论：我们的研究结果表明，UA补充剂对T2DM小鼠模型具有认知保护作用，可能是一种有希望的认知障碍候选药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Brain Research Bulletin 医学-神经科学

CiteScore

6.90

自引率

2.60%

发文量

253

审稿时长

67 days

期刊介绍： The Brain Research Bulletin (BRB) aims to publish novel work that advances our knowledge of molecular and cellular mechanisms that underlie neural network properties associated with behavior, cognition and other brain functions during neurodevelopment and in the adult. Although clinical research is out of the Journal''s scope, the BRB also aims to publish translation research that provides insight into biological mechanisms and processes associated with neurodegeneration mechanisms, neurological diseases and neuropsychiatric disorders. The Journal is especially interested in research using novel methodologies, such as optogenetics, multielectrode array recordings and life imaging in wild-type and genetically-modified animal models, with the goal to advance our understanding of how neurons, glia and networks function in vivo.