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. 2023 May;48(5):1561-1579.
doi: 10.1007/s11064-022-03853-0. Epub 2022 Dec 26.

Dulaglutide Improves Gliosis and Suppresses Apoptosis/Autophagy Through the PI3K/Akt/mTOR Signaling Pathway in Vascular Dementia Rats

Tianyuan Guan  1   2 , Yining Xiao  1   2   3 , Xiaohua Xie  2 , Nan Meng  2 , Qianqian Qi  2 , Jing Xu  2 , Xin Jiang  2 , Zhe Zhang  4 , Zhenjie Teng  2   3 , Peiyuan Lv  5   6   7
Affiliations

Dulaglutide Improves Gliosis and Suppresses Apoptosis/Autophagy Through the PI3K/Akt/mTOR Signaling Pathway in Vascular Dementia Rats

Tianyuan Guan et al. Neurochem Res. 2023 May.

Abstract

Dulaglutide is a new type of hypoglycemic agent that agonizes glucagon-like peptide-1 receptor (GLP-1RA). It can be concluded from previous studies that a GLP-1RA can reduce apoptosis and regulate autophagy in the nervous system, while related research on dulaglutide in vascular dementia (VD) has not been reported. In our study, the VD rat model was established by bilateral carotid artery occlusion, and the results of the Morris water maze test (MWM) and open-field test showed that the application of dulaglutide could effectively reduce the cognitive decline of VD rats without changing the behavior in the open-field test, which was used to assess an anxiety-like phenotype. We applied HE staining and immunofluorescence labeling to show that dulaglutide treatment significantly alleviated neuronal damage in the hippocampal region of VD rats, and reduced microglial and astrocyte proliferation. Western blot results showed that dulaglutide reduced VD-induced neuronal apoptosis (BCL2/BAX, c-caspase3) and autophagy (P62, LC3B, Beclin-1), and upregulated phosphorylation of PI3K/Akt/mTOR signaling pathway. KEGG pathway analysis of RNA-Sequence results showed that the differentially expressed genes in the dulaglutide treatment group were significantly enriched in the mTOR signaling pathway, and the repressor of mTOR, Deptor, was down-regulated. In conclusion, this study suggested that dulaglutide may alleviate learning and memory impairment and neuron damage in VD rats by attenuating apoptosis, regulating autophagy, and activating the PI3K/Akt/mTOR signaling pathway in neurons, which may make it a promising candidate for the simultaneous treatment of VD and diabetes.

Keywords: Apoptosis; Autophagy; Dulaglutide; Gliosis; PI3K/Akt/mTOR signaling pathway; Vascular dementia.

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