Role of auricular vagus nerve stimulation in alleviating neuronal apoptosis and cognitive dysfunction in male rats with vascular dementia.

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 A2A receptor (A2AR) 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 A2AR 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 A2AR agonist and/or a protein kinase A (PKA) inhibitor to verify the involvement of the A2AR-Nrf2/HO-1 pathway. Expression levels of inflammatory cytokines (IL-1β and IL-6), key signaling proteins (A2AR, 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 A2AR 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.