Abstract 33: Vagus Nerve Stimulation for Acute Stroke Treatment: Role of Cholinergic Anti-Inflammatory Pathway
Introduction: Electrical stimulation of the cervical vagus nerve is neuroprotective after MCAO in rats; decrease in infarct volume ranges from ~40% (using surgically implanted electrodes) to ~30% (using clinically applicable non-invasive devices). The exact mechanism of vagus nerve stimulation (VNS)-induced neuroprotection is not known, but so far cerebral blood flow-related mechanism has been eliminated. VNS attenuates systemic inflammation via activation of alpha7 nicotinic acetylcholine receptors (α7 nAChR) on macrophages. We hypothesized that α7 nAChR -mediated anti-inflammatory effect plays a mechanistic role in VNS-induced neuroprotection after cerebral ischemia.
Methods: Focal ischemia was induced by 2 hour transient MCAO in Wistar rats and verified by >60% drop in baseline cerebral blood flow. Methyllycaconitine (MLA; 10 mg/kg, IP) was used to block α7 nAChRs. Animals were randomly assigned to one of four experimental groups: sham stimulation/vehicle, sham stimulation/MLA, VNS/vehicle, VNS/MLA (n=6 in each). VNS was initiated 30 minutes after MCAO and delivered for 1 hour via implanted electrodes, using previously published stimulation parameters. Animals were euthanized 24 hours later to measure infarct volume by TTC. In separate cohorts, immunohistochemistry was used to assess the changes in brain levels of α7 nAChR-related cytokines, TNF-α and high mobility group box protein 1 (HMGB1), in sham-stimulated and VNS groups.
Results: Mean infarct volume in sham-stimulated and VNS groups were 43.83 ± 1.53% and 25.33 ± 3.39%, respectively (p<0.05). MLA abolished the neuroprotective effect of VNS; after MLA treatment mean infarct volume in sham-stimulated and VNS groups were 45.24 ± 4.78% and 48.58 ± 2.78%, respectively (p=n.s.). MLA alone had no effect on ischemic outcome; there was no difference in infarct volume between MLA- treated and untreated sham-stimulated animals (p=n.s.). Ischemia-induced elevation in TNF-α and decrease in HMGB1 levels were completely reversed by VNS as early as 3 hours after ischemia.
Conclusion: This study shows that anti-inflammatory mechanisms via nicotinic acetylcholine receptor-mediated signaling play a role in protective effect of VNS against ischemic tissue damage.
Author Disclosures: I. Ay: Research Grant; Significant; ElectroCore, LLC. R. Nasser: None. H. Ay: None.
This research has received full or partial funding support from the American Heart Association, National Center.
- © 2015 by American Heart Association, Inc.