Abstract
Neurodegenerative diseases and postoperative cognitive dysfunction involve the accumulation of β-amyloid peptide (Aβ). High glucose can inhibit autophagy, which facilitates intracellular Aβ clearance. The α2-adrenoreceptor agonist dexmedetomidine (DEX) can provide neuroprotection against several neurological diseases; however, the mechanism remains unclear. This study investigated whether DEX regulated autophagy via the AMPK/mTOR pathway to improve high glucose-induced neurotoxicity in SH-SY5Y/APP695 cells. SH-SY5Y/APP695 cells were cultured with high glucose with/without DEX. To examine the role of autophagy, the autophagy activator rapamycin (RAPA) and autophagy inhibitor 3-methyladenine (3-MA) were used. The selective AMPK inhibitor compound C was used to investigate the involvement of the AMPK pathway. Cell viability and apoptosis were examined by CCK-8 and annexin V-FITC/PI flow cytometric assays, respectively. Autophagy was analyzed by monodansylcadaverine staining of autophagic vacuoles. Autophagy- and apoptosis-related protein expression and the phosphorylation levels of AMPK/mTOR pathway molecules were quantified by western blotting. DEX pretreatment significantly suppressed high glucose-induced neurotoxicity in SH-SY5Y/APP695 cells, as evidenced by the enhanced viability, restoration of cellular morphology, and reduction in apoptotic cells. Furthermore, RAPA had a protective effect similar to that of DEX, but 3-MA eliminated the protective effect of DEX by promoting mTOR activation. Moreover, the AMPK/mTOR pathway was involved in DEX-mediated autophagy. Compound C significantly suppressed autophagy and reversed the protective effect of DEX against high glucose in SH-SY5Y/APP695 cells. Our findings demonstrated that DEX protected SH-SY5Y/APP695 cells against high glucose-induced neurotoxicity by upregulating autophagy through the AMPK/mTOR pathway, suggesting a role of DEX in treating POCD in diabetic patients.
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The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.
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Funding
This research was supported by the National Natural Science Foundation of China (Grant No. 82171186); the Joint Funds for the Innovation of Science and Technology, Fujian Province (2019Y9028); the Natural Science Foundation of Fujian Province (Grant No. 2021J01366 and 2020J011078); Provincial special subsidy funds for health care of Fujian Provincial Department of Finance (No. 2020467); Fujian Undergraduate Education and Teaching Reform Research Major Project (FBJG20200022) and Education and Teaching Reform Research Project of Fujian Medical University (J20001). Startup Fund for scientific research, Fujian Medical University (2021QH1307); The Training Project for Talents of Fujian Provincial Health Commission (2019-ZQN-1).
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Conceptualization: TZ, XZ; Methodology: PC, XC, HZ, YC; Formal analysis and investigation: PC, HZ, JC, ML, HQ, FG, YC; Writing—original draft preparation: PC, HZ; Writing—review and editing: XC, CG, TZ; Supervision: TZ, XZ.
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Chen, P., Chen, X., Zhang, H. et al. Dexmedetomidine Regulates Autophagy via the AMPK/mTOR Pathway to Improve SH-SY5Y-APP Cell Damage Induced by High Glucose. Neuromol Med 25, 415–425 (2023). https://doi.org/10.1007/s12017-023-08745-2
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DOI: https://doi.org/10.1007/s12017-023-08745-2