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

• DOI: 10.1016/j.neulet.2020.135031
• Publication Date: 2020-05-19T10:57:22Z
• Authors: Jiani Li; Qinbin Zhang; Sheng Li; Lingchuan Niu; Jingxi Ma; Lan Wen; Lina Zhang; Changqing Li
• Keywords: Male; Neurons; Doublecortin Protein; Neuronal Plasticity; Vagus Nerve Stimulation; alpha7 Nicotinic Acetylcholine Receptor; Vagus Nerve; Axons; Brain Ischemia; Rats, Sprague-Dawley; Stroke; 03 medical and health sciences; 0302 clinical medicine; Animals; Ischemic Stroke

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.