Yan Zhang, Pingping Ge, Jing Mao, Ting Wang, Hai Yuan
Background and Purpose Vascular dementia (VD) is characterized by cognitive impairment resulting from cerebrovascular damage. Prior studies have shown that vagus nerve stimulation improves learning and memory in patients with Alzheimer's disease. This study, therefore, investigated whether auricular vagus nerve stimulation (aVNS) ameliorates cognitive dysfunction in a rat model of VD through activation of the adenosine A 2 A receptor (A 2 AR) and nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathways. Methods Fifty male rats were randomly assigned to five groups by a computer-generated sequence: control (A), sham-operated (B), VD model (C), aVNS-treated (D), and aVNS combined with the A 2 AR antagonist SCH 58261 (E). Rats in the aVNS group received stimulation (0.6 mA, 40 Hz, 0.5 ms square pulses) for 4 weeks. Spatial learning and memory were evaluated using the Morris water maze test. Rat brain microvascular endothelial cells were cultured and treated with an A 2 AR agonist and/or a protein kinase A (PKA) inhibitor to verify the involvement of the A 2 AR–Nrf2/HO-1 pathway. Expression levels of inflammatory cytokines (IL-1β and IL-6), key signaling proteins (A 2 AR, p-PKA, p-Nrf2, and HO-1), and phosphorylated tau (p-tau) were measured using western blot or enzyme-linked immunosorbent assays. Results Compared with Groups C and E, Group D exhibited improved spatial learning and memory. aVNS markedly increased the p-PKA and p-Nrf2/HO-1 levels while reducing p-tau and proinflammatory cytokine levels. In vitro experiments showed that A 2 AR agonist treatment upregulated p-PKA and p-Nrf2/HO-1 expression; however, this effect was abolished by PKA inhibition. Conclusion aVNS ameliorates cognitive impairments in VD rats and attenuates neuronal apoptosis, p-tau accumulation, and neuroinflammation, and these effects are associated with activation of the A₂AR/PKA/Nrf2/HO-1 signaling pathway. These findings suggest that aVNS may represent a promising therapeutic strategy for cognitive impairment associated with VD.