Dexmedetomidine Regulates Autophagy via the AMPK/mTOR Pathway to Improve SH-SY5Y-APP Cell Damage Induced by High Glucose

Abstract

Neurodegenerative diseases and postoperative cognitive dysfunction (POCD) 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 the autophagy inhibitor 3methyladenine (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 ow cytometric assays, respectively. Autophagy was analyzed by monodansylcadaverine (MDC) staining of autophagic vacuoles. Autophagy-and apoptosis-related protein expression and the phosphorylation levels of AMPK/mTOR pathway molecules were quanti ed by western blotting. DEX pretreatment signi cantly 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 involved DEX-mediated autophagy. Compound C signi cantly suppressed autophagy and reversed the protective effect of DEX against high glucose in SH-SY5Y/APP695 cells. Our ndings 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.

Axonal protection by combination of ripasudil and brimonidine with upregulation of p-AMPK in TNF-induced optic nerve degeneration

“…On the other hand, the α2-adrenoreceptor agonist dexmedetomidine protected cardiovascular endothelial cells via AMPK-autophagy [ 32 ]. In addition, it was shown that dexmedetomidine exerted neuroprotection via AMPK-autophagy in SH-SY5Y-APP cells [ 33 ]. These findings are in line with the present findings that the combination of ripasudil and brimonidine activates AMPK in the optic nerve.…”