The protective effects of dexmedetomidine via AMPK/SIRT1 pathway activation in a rat model of alzheimer’s disease: evidence from preliminary findings

Metabolic dysfunction and impaired energy signaling play critical roles in Alzheimer’s disease (AD). The AMP-activated protein kinase (AMPK) / sirtuin-1 (SIRT1) pathway is a key regulator of neuronal energy homeostasis and survival. Dexmedetomidine (Dex), a selective α -2 adrenergic receptor agonist, has shown neuroprotective effects in acute neurological injury and energy homeostasis; however, its efficacy in metabolically driven AD models remains unclear.

Forty-two adult male Wistar rats were randomly assigned to seven groups: control, sham, STZ, sham + Dex 25, STZ + Dex 25, STZ + Dex 50, and STZ + Dex 100 (n = 6/group). Sporadic AD was induced by bilateral intracerebroventricular injections of streptozotocin (STZ, 3 mg/kg) on days 1 and 3. Dex was administered intraperitoneally at doses of 25, 50, or 100 µg/kg following STZ injection. Hippocampal neuronal injury was assessed by Nissl staining, and AMPK and SIRT1 protein levels were evaluated using Western blot analysis 30 days after STZ administration.

STZ administration significantly increased neuronal injury in the hippocampal CA1 region and markedly reduced AMPK and SIRT1 expression compared with control and sham groups (p < 0.05–0.001). Dex treatment at all doses significantly attenuated CA1 neuronal damage, with the most pronounced histological protection observed at 25 µg/kg (p < 0.001). In parallel, Dex reversed STZ-induced downregulation of AMPK and SIRT1, with maximal molecular upregulation observed at 100 µg/kg (p < 0.05).

Dex mitigates STZ-induced hippocampal neurodegeneration, at least in part, through modulation of the AMPK/SIRT1 signaling pathway. These findings support the therapeutic potential of Dex in metabolically driven models of sporadic AD.