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Neuroprotective effect of salidroside on hippocampal neurons in diabetic mice via PI3K/Akt/GSK-3β signaling pathway

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Abstract

Background

Diabetic encephalopathy is manifested by cognitive dysfunction. Salidroside, a nature compound isolated from Rhodiola rosea L, has the effects of anti-inflammatory and antioxidant, hypoglycemic and lipid-lowering, improving insulin resistance, inhibiting cell apoptosis, and protecting neurons. However, the mechanism by which salidroside alleviates neuronal degeneration and improves learning and memory impairment in diabetic mice remains unclear.

Objective

To investigate the effects and mechanisms of salidroside on hippocampal neurons in streptozotocin-induced diabetic mice.

Materials and methods

C57BL/6 mice were randomly divided into 4 groups to receive either sham (control group (CON)), diabetes mellitus (diabetes group (DM)), diabetes mellitus + salidroside (salidroside group (DM + SAL)), and diabetes mellitus + salidroside + phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 (diabetes mellitus + salidroside + LY294002 group (DM + SAL + LY294002)). After 12 weeks of diabetes onset, the cognitive behaviors were tested using Morris water maze. The number of hippocampal neurons was detected by Nissl staining. The expressions of PI3K, p-PI3K, Akt, p-Akt, GSK-3β, p-GSK-3β, cleaved caspase-3, caspase-3, Bax, Bcl-2, MAP2, and SYN in the hippocampus were detected by Western blot. Moreover, the expression of MAP2 and SYN in the hippocampus was further confirmed by immunofluorescence staining.

Results

Salidroside increased the time of diabetic mice in the platform quadrant and reduced the escape latency of diabetic mice. Salidroside also increased the expression of p-PI3K, p-Akt, p-GSK-3β, MAP2, SYN, Bcl-2, while suppressed the expression of cleaved caspase-3, caspase3, and Bax in the DM + SAL group compared with the DM group (P < 0.05). The Nissl staining showed that the number of hippocampus neurons in the DM + SAL group was increased with the intact, compact, and regular arrangement, compared with the DM groups (P < 0.05). Interestingly, the protective effects of salidroside on diabetic cognitive dysfunction, hippocampal morphological alterations, and protein expressions were abolished by inhibition of PI3K with LY294002.

Conclusions

Salidroside exerts neuroprotective properties in diabetic cognitive dysfunction partly via activating the PI3K/Akt/GSK-3β signaling pathway.

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Acknowledgements

We acknowledge and appreciate our teachers and classmates for their valuable efforts and comments on this paper.

Funding

This study was supported by China Postdoctoral Science Foundation (No. 2017M612870) and Natural Science Foundation of Liaoning Province (No. 2019-ZD-0807).

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Author notes

  1. Xue-Hua Wang and Zhong-Fu Zuo contributed equally to this work.

Authors and Affiliations

  1. Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China

    Xue-Hua Wang, Zhong-Fu Zuo, Lu Meng, Qi Yang, Pan Lv, Li-Pan Zhao, Xiao-Bai Wang, Yu-Fei Wang, Ying Huang, Cong Fu, Wen-Qiang Liu, Xue-Zheng Liu & De-Yu Zheng

  2. Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Histology and Embryology, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China

    Zhong-Fu Zuo & Xue-Zheng Liu

  3. Department of Anatomy, Histology and Embryology, Postdoctoral Research Station, Guangxi Medical University, Nanning, 530021, Guangxi, China

    Zhong-Fu Zuo

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Correspondence to Xue-Zheng Liu or De-Yu Zheng.

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All experiments were performed according to the NIH guidelines and approved by the Animal Ethics Committee of the Department of Jinzhou Medical University.

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Wang, XH., Zuo, ZF., Meng, L. et al. Neuroprotective effect of salidroside on hippocampal neurons in diabetic mice via PI3K/Akt/GSK-3β signaling pathway. Psychopharmacology 240, 1865–1876 (2023). https://doi.org/10.1007/s00213-023-06373-z

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