DHM抑制海马JNK信号缓解内质网应激改善2型糖尿病大鼠认知功能障碍

doi:10.5246/jcps.2025.11.075

中国药学(英文版) ›› 2025, Vol. 34 ›› Issue (11): 1003-1023.DOI: 10.5246/jcps.2025.11.075

DHM抑制海马JNK信号缓解内质网应激改善2型糖尿病大鼠认知功能障碍

吕慧婕¹^,²^,^#, 彭俊¹^,²^,^#, 黄旭¹, 许拓³, 张天成²^,^*(), 凌宏艳⁴^,^*()

^1. 吉首大学第一附属医院, 湖南湘西 416000
^2. 吉首大学, 湖南吉首 416000
^3. 湖南交通职业技术学院, 湖南长沙 410000
^4. 南华大学, 湖南衡阳 421001

收稿日期:2025-07-18 修回日期:2025-08-24 接受日期:2025-09-17 出版日期:2025-12-02 发布日期:2025-12-02
通讯作者: 张天成, 凌宏艳

Dihydromyricetin reverses cognitive dysfunction in type 2 diabetic rats via inhibition of the JNK-ERS axis

Huijie Lv¹^,²^,^#, Jun Peng¹^,²^,^#, Xu Huang¹, Tuo Xu³, Tianchen Zhang²^,^*(), Hongyan Ling⁴^,^*()

¹ The First Affiliated Hospital of Jishou University, Xiangxi 416000, Hunan, China
² Jishou University, Jishou4 16000, Hunan, China
³ Hunan Vocational and Technical College of Transportation, Changsha 410000, Hunan, China
⁴ Nanhua University, Hengyang 421001, Hunan, China

Received:2025-07-18 Revised:2025-08-24 Accepted:2025-09-17 Online:2025-12-02 Published:2025-12-02
Contact: Tianchen Zhang, Hongyan Ling
About author:
^# Huijie Lv and Jun Peng contributed equally to this work.
Supported by:
This research was financially supported by the Humanities and Social Sciences Research Planning Fund of the Ministry of Education (Grant No. 22YJA880086), the Natural Science Foundation of Hunan Province (Grant No. 2025JJ70621), and the Hunan Provincial Natural Science and Technology Foundation (Grant No. 2021JJ30595). Additional support was provided by the Hunan Provincial Graduate Research Innovation Projects (Grant No. CX20211061 and CX20231065), as well as several grants from Jishou University, including campus-level research projects (Grant No. Jdzd21028, Jdzd21004, Jdzd2211, and Jdy22188), and the Graduate Base Opening Project (Grant No. TYBJD202303).

摘要/Abstract

摘要：

研究发现二氢杨梅素(Dihydromyricetin, DHM)对中枢神经系统损伤有明显的改善作用。因此, 本实验拟观察DHM是否可改善T2DM大鼠认知功能障碍, 及其机制是否通过抑制JNK信号从而下调ERS实现。本文采用4w高糖高脂饮食联合STZ一次性腹腔注射的方法构建T2DM模型。接着进行以下检测:尾静脉采血测定空腹血糖, 水迷宫(Morris water maze, MWM)和Y迷宫检测大鼠认知功能, 随后断颈处死大鼠, 取海马进行苏木精-伊红(Hematoxylin-eosin, HE)染色, 观察海马神经细胞损伤情况、WB检测海马组织凋亡蛋白Bax和抗凋亡蛋白Bcl-2的表达水平、Elisa检测海马p-tau, Aβ表达水平。随后分别用或不用DHM处理(250 mg/kg/d, 灌胃)12周后, 进行上述相关指标的检测, 观察DHM对大鼠认知功能、海马损伤的影响。各组剩余大鼠进行侧脑室置管给药(TUDCA, 衣霉素, SP600125, 茴香霉素)后, 在进行上述相关指标的检测的基础上使用WB检测海马组织JNK、p-JNK以及内质网特异性蛋白Bip、pPERK的表达水平。结果发现: 高糖高脂饮食4周联合低剂量STZ一次性腹腔注射SD大鼠成功复制T2DM大鼠模型。与Control组相比, T2DM组大鼠出现认知功能障碍, 海马神经细胞凋亡、p-tau和Aβ水平增加。DHM能逆转T2DM大鼠上述指标改变, 但DHM对Control组大鼠上述指标无显著改变; TUDCA以及SP600125能改善T2DM大鼠认知功能障碍、减少T2DM大鼠海马神经细胞凋亡、p-tau和Aβ蛋白水平。使用ERS激活剂(TUN)以及JNK激活剂(AMY)后SD大鼠的认知功能明显下降, 海马神经细胞凋亡、p-tau和Aβ蛋白水平显著增加。综上, 我们得出结论: DHM可改善T2DM大鼠认知功能障碍, 其机制可能与其抑制JNK缓解ERS, 抑制海马神经细胞凋亡、p-tau和Aβ水平有关。

关键词: 二氢杨梅素, 2型糖尿病, 认知功能障碍, JNK信号, 内质网应激

Abstract:

Recent studies have demonstrated that dihydromyricetin (DHM) exerts a protective effect against central nervous system injury. Building on these findings, the present study aimed to investigate whether DHM could ameliorate cognitive deficits in a type 2 diabetes mellitus (T2DM) rat model, and to explore whether this effect involved inhibition of the JNK signaling pathway and suppression of endoplasmic reticulum stress (ERS). To establish the T2DM model, Sprague Dawley (SD) rats were fed a high-fat, high-sugar diet in combination with a single intraperitoneal injection of streptozotocin (STZ). Fasting blood glucose levels were measured from tail vein samples, and cognitive performance was evaluated using the Morris water maze (MWM) and Y-maze tests. Following behavioral assessments, the animals were sacrificed by cervical dislocation, and hippocampal tissues were collected for further analysis. Histological examination using hematoxylin-eosin (H&E) staining was performed to assess hippocampal neuronal damage. Western blotting (WB) analysis was employed to quantify the expression of pro-apoptotic protein Bax and anti-apoptotic protein Bcl-2, while ELISA was conducted to measure levels of phosphorylated tau (p-tau) and amyloid-β (Aβ) in the hippocampus. After 12 weeks of oral administration of DHM (250 mg/kg/d), relevant biomarkers were re-evaluated to determine the compound's impact on cognitive function and hippocampal integrity. Additionally, rats from each group received intracerebroventricular injections of various pharmacological agents, namely, TUDCA (an ERS inhibitor), STZ, SP600125 (a JNK inhibitor), and anisomycin (AMY, a JNK activator). WB analysis was further conducted to assess the expression of JNK, phosphorylated JNK (p-JNK), and ERS-associated proteins Bip and p-PERK in hippocampal tissue. The results confirmed that combining a high-fat, high-sugar diet with low-dose STZ injection for 4 weeks effectively established a T2DM model. Compared with the control group, T2DM rats exhibited significant cognitive deficits, increased neuronal apoptosis in the hippocampus, and elevated hippocampal levels of p-tau and Aβ. Notably, DHM treatment markedly reversed these pathological changes in T2DM rats, whereas it had no significant effects on control animals. Moreover, administration of TUDCA and SP600125 similarly mitigated cognitive impairment, neuronal apoptosis, and the accumulation of p-tau and Aβ in diabetic rats. Conversely, activation of ERS and JNK signaling using tunicamycin (TUN) and AMY, respectively, resulted in exacerbated cognitive decline, increased neuronal apoptosis, and higher levels of p-tau and Aβ. In conclusion, these findings suggested that DHM effectively alleviated cognitive dysfunction in T2DM rats, potentially through the inhibition of JNK signaling and subsequent attenuation of ERS, thereby reducing neuronal apoptosis and the pathological accumulation of p-tau and Aβ in the hippocampus.

Key words: Dihydromyricetin, Type 2 diabetes, Cognitive dysfunction, JNK signaling, Endoplasmic reticulum stress

Supporting:

吕慧婕, 彭俊, 黄旭, 许拓, 张天成, 凌宏艳. DHM抑制海马JNK信号缓解内质网应激改善2型糖尿病大鼠认知功能障碍[J]. 中国药学(英文版), 2025, 34(11): 1003-1023.

Huijie Lv, Jun Peng, Xu Huang, Tuo Xu, Tianchen Zhang, Hongyan Ling. Dihydromyricetin reverses cognitive dysfunction in type 2 diabetic rats via inhibition of the JNK-ERS axis[J]. Journal of Chinese Pharmaceutical Sciences, 2025, 34(11): 1003-1023.

图/表 10

Figure 1. The MWM and Y-maze tests were used to examine changes in spatial learning and memory abilities in rats (x ± s, n = 8). (A) The representative swimming route of rats on the 1st day and the 5th day in the acquisition phase. (B) The escape periods of rats in 1−5 d in the acquisition phase. After completing the acquisition phase, the rats were subjected to the probe trial. The times of crossing the platform. (C) The proportionality of swimming time in the target quadrant (D) was analyzed. After completing the probe test, the rats were subjected to the visible platform test. The latency to visible platform (E) and the average swimming speed (F) were recorded. (G) Alternation behavior. (H) Number of arm entries. Values are the mean ± SEM, *P < 0.05, **P < 0.01, vs. control group. #P < 0.05, vs. T2DM group.

Figure 2. DHM decreases neuronal apoptosis in the hippocampus of T2DM rats (x ± s). H&E staining in hippocampal CA1 area (n = 3). The expression of Bax (B) and Bcl-2 (C) protein in rats (n = 5). Values are the mean ± SEM, *P < 0.01, **P < 0.001, vs. control group. #P < 0.05, ##P < 0.01, vs. T2DM group.

Figure 3. The expression of p-tau and Aβ protein in rats (x ± s, n = 5). (A) Aβ OD value; (B) p-tau OD value. Values are the mean ± SEM, *P < 0.0001, vs. control group. #P < 0.0001, vs. T2DM group.

Figure 4. The MWM and Y-maze tests were used to examine changes in spatial learning and memory abilities in rats (x ± s, n = 8). (A) The representative swimming route of rats on the 1st day and the 5th day in the acquisition phase. (B) The escape periods of rats in 1−5 d in the acquisition phase. After completing the acquisition phase, the rats were subjected to the probe trial. The times of crossing platform (C) and the proportionality of swimming time in the target quadrant (D) were analyzed. After finishing the probe test, rats were subjected to the visible platform test. The latency to visible platform (E) and the average swimming speed (F) were recorded. (G) Alternation behavior. (H) Number of arm entries. Values are the mean ± SEM, *P < 0.05, **P < 0.01, ***P < 0.001, vs. control group. #P < 0.05, ##P < 0.01, vs. T2DM group. &P < 0.05, &&P < 0.01, vs. T2DM + DHM group.

Figure 5. TUN can abolish the improvement effect of DHM on hippocampal neuronal apoptosis in T2DM rats (x ± s). (A) H&E staining in the hippocampal CA1 area (n = 3). The expression of Bax (B) and Bcl-2 (C) protein in rats (n = 5). Values are the mean ± SEM, *P < 0.01, **P < 0.001, vs. control group. #P < 0.01, ##P < 0.001, vs. T2DM group. &P < 0.05, vs. T2DM + DHM group.

Figure 6. The expression of p-tau and Aβ protein in rats (x ± s, n = 5). (A) Aβ OD value. (B) p-tau OD value. Values are the mean ± SEM, *P < 0.001, **P < 0.0001, vs. control group. #P < 0.0001, vs. T2DM group. &P < 0.05, &&P < 0.001, vs. T2DM + DHM group.

Figure 7. The MWM and Y-maze tests were used to examine changes in spatial learning and memory abilities in rats (x ± s, n = 8). (A) The representative swimming route of rats on the 1st d and 5th d in the acquisition phase. (B) The escape periods of rats in 1−5 d in the acquisition phase. After completing the acquisition phase, the rats were subjected to the probe trial. The times of crossing platform (C) and the proportionality of swimming time in the target quadrant (D) were analyzed. After completing the probe test, the rats were subjected to the visible platform test. The latency to visible platform (E) and the average swimming speed (F) were recorded. (G) Alternation behavior. (H) Number of arm entries. Values are the mean ± SEM, #P < 0.05, ##P < 0.01, vs. T2DM group. &P < 0.05, &&P < 0.01, vs. T2DM + DHM group.

Figure 8. AMY can abolish the improvement effect of DHM on hippocampal neuronal apoptosis in T2DM rats (x ± s, n = 5). (A) H&E staining in the hippocampal CA1 area (n = 3). The expression of Bax (B) and Bcl-2 (C) protein in rats (n = 5). Values are the mean ± SEM, *P < 0.01, **P < 0.001, vs. control group. #P < 0.01, ##P < 0.001, vs. T2DM group. &P < 0.05, &&P < 0.01, vs. T2DM + DHM group.

Figure 9. The expression of p-tau and Aβ protein in rats (x ± s, n = 5). (A) Aβ OD value. (B) p-tau OD value. Values are the mean ± SEM, *P < 0.001, **P < 0.0001, vs. control group. #P < 0.0001, vs. T2DM group. &P < 0.01, &&P < 0.0001, vs. T2DM + DHM group.

Figure 10. The expression of Bip and p-PERK protein in rats (x ± s, n = 5). (A) Bip protein expression. (B) p-PERK protein expression. Values are the mean ± SEM, *P < 0.01, **P < 0.0001, vs. control group. #P < 0.05, ##P < 0.001, vs. T2DM group. &P < 0.01, vs. T2DM + DHM group.

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DHM抑制海马JNK信号缓解内质网应激改善2型糖尿病大鼠认知功能障碍

Dihydromyricetin reverses cognitive dysfunction in type 2 diabetic rats via inhibition of the JNK-ERS axis

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