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. 2023 Aug 28:14:1146960.
doi: 10.3389/fphar.2023.1146960. eCollection 2023.

Tirzepatide ameliorates spatial learning and memory impairment through modulation of aberrant insulin resistance and inflammation response in diabetic rats

Xiying Guo #  1 , Min Lei #  1 , Jiangyan Zhao #  1 , Min Wu  1 , Zhanhong Ren  1 , Xiaosong Yang  1 , Changhan Ouyang  2 , Xiufen Liu  1 , Chao Liu  1 , Qingjie Chen  1
Affiliations

Tirzepatide ameliorates spatial learning and memory impairment through modulation of aberrant insulin resistance and inflammation response in diabetic rats

Xiying Guo et al. Front Pharmacol. .

Abstract

Background: One of the typical symptoms of diabetes mellitus patients was memory impairment, which was followed by gradual cognitive deterioration and for which there is no efficient treatment. The anti-diabetic incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were demonstrated to have highly neuroprotective benefits in animal models of AD. We wanted to find out how the GLP-1/GIP dual agonist tirzepatide affected diabetes's impairment of spatial learning memory. Methods: High fat diet and streptozotocin injection-induced diabetic rats were injected intraperitoneally with Tirzepatide (1.35 mg/kg) once a week. The protective effects were assessed using the Morris water maze test, immunofluorescence, and Western blot analysis. Golgi staining was adopted for quantified dendritic spines. Results: Tirzepatide significantly improved impaired glucose tolerance, fasting blood glucose level, and insulin level in diabetic rats. Then, tirzepatide dramatically alleviated spatial learning and memory impairment, inhibited Aβ accumulation, prevented structural damage, boosted the synthesis of synaptic proteins and increased dendritic spines formation in diabetic hippocampus. Furthermore, some aberrant changes in signal molecules concerning inflammation signaling pathways were normalized after tirzepatide treatment in diabetic rats. Finally, PI3K/Akt/GSK3β signaling pathway was restored by tirzepatide. Conclusion: Tirzepatide obviously exerts a protective effect against spatial learning and memory impairment, potentially through regulating abnormal insulin resistance and inflammatory responses.

Keywords: Aβ; diabetes mellitus; inflammation; insulin; spatial learning and memory; synaptic plasticity; tirzepatide.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Tirzepatide ameliorated hyperglycemia and insulin resistance in diabetic rats. (A) Flow chart of animal experiment design. (B) Body weight and (C) Fasting plasma glucose levels variation, n = 8/group. (D) The glucose tolerance test at the 13th week, n = 8/group. (E) The AUC of blood glucose curves in OGTT. (F) The plasma insulin levels were measured using ELISA kits, n = 9/group. The data represent the mean ± SD. ** p < 0.01 DM vs Con; *** p < 0.001 DM vs Con; **** p < 0.0001 DM vs Con; ## p < 0.01 DM + Tirzepatide vs DM; ### p < 0.001 DM + Tirzepatide vs DM; #### p < 0.0001 DM + Tirzepatide vs DM.
FIGURE 2
FIGURE 2
Tirzepatide ameliorated DM-induced Spatial learning memory impairment. (A) MWM schematic. (B) The trajectory of rats in MWM. (C) The time spent to find the platform (latency) in the 5-days consecutive training trials and the memory retention trial. (D) The swimming speed analysis (E) the time spent in four quadrants and (F) the platform crossing during the memory retention trial. n = 10/group. The data represent the mean ± SD. * p < 0.05 DM vs Con; *** p < 0.001 DM vs Con; # p < 0.05 DM + Tirzepatide vs DM; ## p < 0.01 DM + Tirzepatide vs DM; $$$$ p < 0.0001 NE vs SW.
FIGURE 3
FIGURE 3
Tirzepatide improved APP misprocessing in the hippocampus. (A) APP and (B) BACE-1 expressions were assessed by Western-blot, n = 3/group. (C) Aβ40 levels were detected by ELISA, n = 6. (D) Representative immunofluorescence staining images of the CA1 neuron (NeuN) in the hippocampus. Scale bar, 20 μm. (E) Bar plots showing the neuron density in the hippocampus, n = 3/group. The data represent the mean ± SD. * p < 0.05 DM vs Con; ** p < 0.01 DM vs Con; **** p < 0.0001 DM vs Con; # p < 0.05 DM + Tirzepatide vs DM; ## p < 0.01 DM + Tirzepatide vs DM; #### p < 0.0001 DM + Tirzepatide vs DM.
FIGURE 4
FIGURE 4
Tirzepatide affected synaptophysin proteins and dendritic spines in diabetic rats. (A–C) PSD95 and SYT1 levels were detected by Western blot, n = 3/group. (D) Representative images of neurons in the CA1 region; scale bar, 200 μm. (E) Representative images of dendritic spines; scale bar, 5 μm. Statistics of (F) Stubby spine, (G) Mushroom-like spine (H) Long spine and (I) Filopodia-like spine, n = 3/group. The data represent the mean ± SD. * p < 0.05 DM vs Con; ** p < 0.01 DM vs Con; *** p < 0.001 DM vs Con; **** p < 0.0001 DM vs Con; $ p < 0.05 con + Tirzepatide vs DM; $$ p < 0.01 con + Tirzepatide vs DM; # p < 0.05 DM + Tirzepatide vs DM; ## p < 0.01 DM + Tirzepatide vs DM; #### p < 0.0001 DM + Tirzepatide vs DM.
FIGURE 5
FIGURE 5
Tirzepatide inhibited inflammatory response in diabetic rats. The mRNA expression of (A) TNF-α, (B) IL-6 and (C) IL-1β were reduced by tirzepatide, n = 6/group. (D) Representative immunofluorescence images showing p-NFκB in the CA1 region of hippocampus. Scale bar, 20 μm. (E) The % of cells with p-NFκB immunoreactivity was inhibited after tirzepatide, n = 3/group. (F) Tirzepatide prevented the phosphorylation of IKKα, n = 3/group. The data represent the mean ± SD. * p < 0.05 DM vs Con; *** p < 0.001 DM vs Con; **** p < 0.0001 DM vs Con; # p < 0.05 DM + Tirzepatide vs DM; ## p < 0.01 DM + Tirzepatide vs DM; ### p < 0.001 DM + Tirzepatide vs DM; #### p < 0.0001 DM + Tirzepatide vs DM.
FIGURE 6
FIGURE 6
Tirzepatide improved insulin signaling pathway in diabetic rats. (A)The protein expression levels of IR were similar in four groups, n = 3/group. The phosphorylation of (B) IRS-1 ser307, (C) PI3K (D) AKT, (E) GSK3β were improved in diabetic rats after tirzepatide treatment, n = 3/group. (F) The protein expression levels of GSK3β in hippocampus were increased by tirzepatide in diabetic rats, n = 3/group. The data represent the mean ± SD. * p < 0.05 vs Con; ** p < 0.01 DM vs Con; *** p < 0.001 DM vs Con; # p < 0.05 DM + Tirzepatide vs DM; ## p < 0.01 DM + Tirzepatide vs DM.
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Grants and funding

This work was supported by the National Natural Science Foundation of China (82073852 and 82270892), the Innovation team Funds of Hubei University of Science and Technology (2022T01), the Provincial Science and Technology Plan Project Funds of Hubei Province (2021DFE025), the Natural Science Foundation of Hubei Province (2022CFB843 and 2021CFB439), the Hubei University of Science and Technology School-level Fund (BK202027, 2020TNB12, and 2022 TNB01).

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