α7nAchR mediates transcutaneous auricular vagus nerve stimulation-induced neuroprotection in a rat model of ischemic stroke by enhancing axonal plasticity.

Axonal plasticity is important for neurofunctional recovery after stroke. This study aimed to explore the role of transcutaneous auricular vagus nerve stimulation (ta-VNS) on axonal plasticity and its underlying association with the α7 nicotinic acetylcholine receptor(α7nAchR) after cerebral ischemia/reperfusion (I/R) injury. Adult male Sprague-Dawley rats were pretreated by intraperitoneal injection with either phosphate-buffered saline (PBS) or an α7nAchR antagonist and then subjected to middle cerebral artery occlusion and ta-VNS treatment. α7nAchR expression and localization in the peri-infarct cortex were examined after ta-VNS treatment. Subsequently, neurologic scores were assessed with a battery of tests. Axonal regeneration, indicated by upregulation of growth-associated protein 43 (GAP-43) and neurofilament protein 200 (NF-200), was assessed. Axonal reorganization was examined on the basis of anterograde movement of the neuronal molecular probe biotin dextran amine. Additionally, brain-derived neurotrophic factor (BDNF)-associated signaling was measured 28d after I/R. Our findings showed that ta-VNS treatment enhanced α7nAchR expression in the ischemic cortex. α7nAchR colocalized with DCX and Nestin after reperfusion. Furthermore, ta-VNS-treated I/R rats displayed enhanced neurobehavioral performance and increased axonal plasticity (axonal regeneration and axonal reorganization), as indicated by elevated levels of BDNF/cyclic AMP (cAMP)/protein kinase A (PKA)/phosphorylated cAMP response element-binding protein pathway (p-CREB) pathway members. Strikingly, the beneficial effects of ta-VNS were diminished after α7nAchR blockade. In conclusion, our study is the first to show that α7nAchR is a potential mediator of ta-VNS-induced neuroprotection in the chronic phase of stroke and that its effects may be related to enhanced axonal plasticity through activation of the BDNF/cAMP/PKA/p-CREB pathway.