Vagus Nerve Stimulation Reduces Neuroinflammation Through Microglia Polarization Regulation to Improve Functional Recovery After Spinal Cord Injury

Abstract

BackgroundSpinal cord injury (SCI) is a devastating disease that lacks effective treatment. Interestingly, recent studies indicated that vagus nerve stimulation (VNS), neuromodulation that is widely used in a variety of central nervous system (CNS) diseases, improved motor function recovery after SCI. But the exact underlying mechanism of how VNS ameliorates SCI is unclear. This study aimed to confirm the efficacy and further explore the potential therapeutic mechanism of VNS in SCI.MethodA T10 spinal cord compression model was established in adult female Sprague-Dawley rats. Then the stimulation electrode was placed in the left cervical vagus nerve (forming Sham-VNS, VNS, and VNS-MLA groups). Basso-Beattie-Bresnahan (BBB) behavioral scores and Motor evoked potentials (MEPs) analysis were used to detect motor function. A combination of histological and molecular methods was used to clarify the relevant mechanism.ResultsCompared with the Sham-VNS group, the VNS group exhibited better functional recovery, reduced scar formation (both glial and fibrotic scars), tissue damage, and dark neurons, but these beneficial effects of VNS were diminished after alpha 7 nicotinic acetylcholine receptor (α7nAchR) blockade. Specifically, VNS inhibited the pro-inflammatory factors TNF-α, IL-1β, and IL-6 and increased the expression of the anti-inflammatory factors IL-10. Furthermore, we found that VNS promotes the shift of M1-polarized Iba-1+/CD86+ microglia to M2-polarized Iba-1+/CD206+ microglia via upregulating α7nAchR to alleviate neuroinflammation after SCI.ConclusionOur results demonstrated that VNS promotes microglial M2 polarization through upregulating α7nAChR to reduce neuroinflammation, thus improving motor function recovery after SCI. These findings indicate VNS might be a promising neuromodulation strategy for SCI.

Consequences of spinal cord injury on the sympathetic nervous system

“…Importantly, vagus nerve stimulation does not appear to exacerbate autonomic dysreflexia events, alluding to its safety as a possible therapeutic to improve autonomic function after SCI (Sachdeva et al, 2020). Interestingly, vagus nerve stimulation in a rodent SCI model reduces neuroinflammation, i.e., expression of pro-inflammatory cytokines while also increasing the expression of anti-inflammatory cytokines, after SCI (Chen et al, 2022), suggesting that vagus nerve stimulation has broad effects and any recovery may be through multiple mechanisms.…”

Narrative review of current neuromodulation modalities for spinal cord injury

“…Although clinical studies assessing the efficacy of VNS in SCI patients is limited, pre-clinical studies highlight possible mechanisms and provide promising results. VNS was shown to alleviate neuroinflammation after SCI through promoting the shift of pro-inflammatory M1-polarized microglia to anti-inflammatory M2 phenotype via upregulation of alpha 7 nicotinic acetylcholine receptors ( 113 ). Specifically, VNS inhibited pro-inflammatory factors such as Tumor Necrosis Factor (TNF)-α, Interleukin (IL)-1β, IL-6 and increased expression of anti-inflammatory factor IL-10.…”

Pharmacological and non-pharmacological therapeutic interventions for the treatment of spinal cord injury-induced pain

“…Interestingly, individuals with SCI have reduced vagal tone, suggesting vagal nerve stimulation could be beneficial in this population. Indeed, Chen et al, used electrical vagal nerve stimulation in spinally injured rats and found that it improved functional recovery, reduced tissue damage, and reduced the release of pro-inflammatory cytokines (TNFα, IL1 β, and IL6) and increased levels of anti-inflammatory cytokine IL10 ( 175 ), however pain was not assessed.…”