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. 2023 Apr 19:14:1185022.
doi: 10.3389/fendo.2023.1185022. eCollection 2023.

"Adjust Zang and arouse spirit" electroacupuncture ameliorates cognitive impairment by reducing endoplasmic reticulum stress in db/db mice

Mengyuan Li  1 , Lin Yao  1 , Min He  1 , Haipeng Huang  2 , Haizhu Zheng  3 , Shiqi Ma  3 , Zhen Zhong  3 , Shuo Yu  3 , Mengmeng Sun  1 , Hongfeng Wang  2
Affiliations

"Adjust Zang and arouse spirit" electroacupuncture ameliorates cognitive impairment by reducing endoplasmic reticulum stress in db/db mice

Mengyuan Li et al. Front Endocrinol (Lausanne). .

Abstract

Introduction: Diabetic cognitive impairment (DCI) is a chronic complication of the central nervous system (CNS) caused by diabetes that affects learning and memory capacities over time. Recently, acupuncture has been shown to improve cognitive impairment in streptozotocin-induced diabetic rats. However, the effects of electroacupuncture on DCI and its underlying mechanism have not yet been elucidated in detail.

Methods: In this study, we used db/db mice as DCI animal models which showed low cognitive, learning and memory functions. Electroacupuncture significantly ameliorated DCI, which is reflected by better spatial learning and memory function using behavioral tests. The db/db mice with cognitive impairment were randomly divided into a model group (Mod) and an electroacupuncture treatment group (Acup), while db/m mice were used as a normal control group (Con). First, the mice were subjected to behavioural tests using the Morris water maze (MWM), and body weight, blood glucose, insulin, triglycerides (TG) and total cholesterol (TC) were observed; HE, Nissl, and TUNEL staining were used to observe the morphological changes and neuronal apoptosis in the mice hippocampus; Finally, Western blot and rt-PCR were applied to detect the essential proteins and mRNA of ERS and insulin signalling pathway, as well as the expression levels of Tau and Aβ.

Results: Electroacupuncture significantly ameliorated DCI, which is reflected by better spatial learning and memory function using behavioral tests. Moreover, electroacupuncture attenuated diabetes-induced morphological structure change, neuronal apoptosis in the hippocampus of db/db mice. Our results revealed that electroacupuncture could regulate the expression levels of Tau and Aβ by improving hippocampal ERS levels in db/db mice, inhibiting JNK activation, attenuating IRS1 serine phosphorylation, and restoring normal transduction of the insulin signaling pathway.

Discussion: In summary, ERS and insulin signaling pathway paly causal roles in DCI development. Electroacupuncture can significantly alleviate the pathogenesis of DCI, improve mice's learning and memory ability, and improve cognitive dysfunction. This study adds to our understanding of the effect of acupuncture on DCI and opens the door to further research on DCI.

Keywords: diabetic cognitive impairment (DCI); endoplasmic reticulum stress (ERS); hippocampus; insulin signaling pathway; neuronal apoptosis.

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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
Electroacupuncture improves db/db mice’s learning and memory abilities of the MWM test, respectively. (A) Timeline of experimental procedures. (B, C) A comparison of escape latency in each group from day 1 to day 5 before treatment. (D) A comparison of escape latency in each group from day 1 to day 5 after treatment. (E) A comparison of passing times in each group through the platform quadrant on the sixth day. (F) A comparison of percentage of swimming distance in each group through the platform quadrant (SW) on the sixth day. (G) A comparison of percentage of swimming time in each group through the platform quadrant (SW) on the sixth day. (H) A comparison of percentage of swimming distance in each group through the entry quadrant (NE) on the sixth day. (I) A comparison of percentage of swimming time in each group through the entry quadrant (NE) on the sixth day. (J) The swimming track in each group on the sixth day in 60 s. Non-Mod represents db/db mice model without cognitive impairment. Data are expressed as means ± SEM. Mod vs Con, # p < 0.05, ## p < 0.01; Acup vs Mod, * p < 0.05, ** p < 0.01.
Figure 2
Figure 2
Effects of electroacupuncture on general indicators in db/db mice. (A) Food intake, (B) Water intake, (C) Weight and (D) Blood glucose changes before and after electroacupuncture treatment. (E) INS, (F) TC and (G) TG levels in mice serum were analyzed using Elisa kit. Data are expressed as means ± SEM. Mod vs Con, # p < 0.05, ## p < 0.01; Acup vs Mod, * p < 0.05, ** p < 0.01.
Figure 3
Figure 3
Electroacupuncture regulates morphological changes in the hippocampus of db/db mice. (A) The representative images of H&E stained mouse hippocampal sections in the three groups (20×/200×/400×). (B) The representative images of Nissl staining of the mouse hippocampal sections in the three groups (20×/200×/400×). (C) (1) Percentage of positive cells in the CA1 region of the mouse hippocampus; (2) Number of neurons per unit area in the CA1 region of the db/db mice’s hippocampus. Data are expressed as means ± SEM. Mod vs Con, ## p < 0.01; Acup vs Mod, * p < 0.05, ** p < 0.01.
Figure 4
Figure 4
Electroacupuncture regulates db/db mice’s neuronal apoptosis in the hippocampus. (A) (1) The representative image of TUNEL assay showing apoptotic cells (green signal) in the CA1 regionof the db/db mice’s hippocampus. (2) The proportion of apoptotic neurons in the CA1 region of the hippocampus in three groups. (B) Western blotting and quantitative analysis of Bax, Bcl-2, and caspase-3 expression in the hippocampus of mice in three groups. Data are expressed as means ± SEM. Mod vs Con, ## p < 0.01; Acup vs Mod, ** p < 0.01.
Figure 5
Figure 5
Electroacupuncture regulates the expression of key proteins in the ERS. (A) (1) Western blotting and quantitative analysis of GRP78, IRE1α, TRAF2 andASK1 expression in the hippocampus of mice in three groups; (2) RT-PCR analysis of GRP78, IRE1α, TRAF2 and ASK1 mRNA expression in the hippocampus of mice in three groups. (B) (1) Western blotting and quantitative analysis of JNK and p-JNK expression in the hippocampus of mice in three groups; (2) RT-PCR analysis of JNK mRNA expression in the hippocampus of mice in three groups. Data are expressed as means ± SEM. Mod vs Con, ## p < 0.01; Acup vs Mod, * p < 0.05, ** p < 0.01.
Figure 6
Figure 6
Electroacupuncture regulates the expression of key proteins of the insulin signaling pathway. (A) (1) Western blotting and quantitative analysis of IRS1, p-IRS1, PI3K, p-PI3K, AKT, and p-AKT expression in the hippocampus of mice in the three groups; (2) RT-PCR analysis of IRS1, PI3K and AKT mRNA expression in the hippocampus of mice in the three groups. (B) (1) Western blotting and quantitative analysis of GSK3β, p-GSK3β, Aβ and Tau expression in the hippocampus of mice in the three groups; (2) RT-PCR analysis of GSK3β mRNA expression in the hippocampus of mice in the three groups. Data are expressed as means ± SEM. Mod vs Con, ## p < 0.01; Acup vs Mod, * p < 0.05, ** p < 0.01.
Figure 7
Figure 7
Potential regulatory mechanisms of DCI by acupuncture. (A) ERS induces an unfolded protein response that dissociates GRP78 from IRE1α and activates JNK, leading to abnormal insulin signalling pathway transduction, increasing the expression of p-tau and Aβ; (B) Electroacupuncture improves cognitive impairment by regulating hippocampal ERS levels in db/db mice, inhibiting JNK activation, restoring normal insulin signalling pathway transduction, and causing a reduction in p-Tau and Aβ expression.
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Grants and funding

This work was supported by National Natural Science Foundation of China (Grant No.82074548) and Natural Science Foundation of Jilin Province (Joint Funds) (Permit Number: YDZJ202101ZYTS103).
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