Vagus nerve stimulation improves locomotion and neuronal populations in a model of Parkinson's disease

Abstract

Background Parkinson’s disease (PD) is a progressive, neurodegenerative disorder with no disease-modifying therapies, and symptomatic treatments are often limited by debilitating side effects. In PD, locus coeruleus noradrenergic (LC-NE) neurons degenerate prior to substantia nigra dopaminergic (SN-DA) neurons. Vagus nerve stimulation (VNS) activates LC neurons, and decreases pro-inflammatory markers, allowing improvement of LC targets, making it a potential PD therapeutic. Objective To assess therapeutic potential of VNS in a PD model. Methods To mimic the progression of PD degeneration, rats received a systemic injection of noradrenergic neurotoxin DSP-4, followed one week later by bilateral intrastriatal injection of dopaminergic neurotoxin 6-hydroxydopamine. At this time, a subset of rats also had vagus cuffs implanted. After eleven days, rats received a precise VNS regimen twice a day for ten days, and locomotion was measured during each afternoon session. Immediately following final stimulation, rats were euthanized, and left dorsal striatum, bilateral SN and LC were sectioned for immunohistochemical detection of monoaminergic neurons (tyrosine hydroxylase, TH), α-synuclein, astrocytes (GFAP) and microglia (Iba-1). Results VNS significantly increased locomotion of lesioned rats. VNS also resulted in increased expression of TH in striatum, SN, and LC; decreased SN α-synuclein expression; and decreased expression of glial markers in the SN and LC of lesioned rats. Additionally, saline-treated rats after VNS, had higher LC TH and lower SN Iba-1. Conclusions Our findings of increased locomotion, beneficial effects on LC-NE and SN-DA neurons, decreased α-synuclein density in SN TH-positive neurons, and neuroinflammation suggest VNS has potential as a novel PD therapeutic.

Respiratory disturbances in a mouse model of Parkinson's disease

“…Previous studies have shown that in the rodent model of PD induced by 6-OHDA, there were no anatomical changes of catecholaminergic neurons in the LC (Farrand et al, 2017;Ostock, Lindenbach, Goldenberg, Kampton, & Bishop, 2014;Shin et al, 2014;Tuppy et al, 2015), which was confirmed by the present study. Previous findings also demonstrated in a rat model of PD that central chemoreception is initially reduced, but then recovers during the course of PD (Oliveira et al, 2017).…”

Modulation of neuroinflammation and memory dysfunction using percutaneous vagus nerve stimulation in mice

“…In our study pVNS improved microglial morphology after LPS injection, with more cells retaining ramified branches as found under homeostatic states. As anticipated, pVNS reduced microglial activation, including Iba-1 and CD68, at 24 h in a manner similar to other VNS approaches [13, 37, 38]. These effects on glia activation may result from the systemic anti-inflammatory effects of VNS leading to a reduction in the overall neuroinflammatory burden, including Toll-like receptors signaling, rather than through a direct action as mediated through α7 nAChRs on microglia cells.…”

Freezing of gait in Parkinson’s disease: pathophysiology, risk factors and treatments

“…Recently, it has been reported that VNS administered for 10 days improved locomotion in a rodent model of PD [151]. Thus, an observational, open-label, pilot study explored the effect of single-dose, noninvasive VNS on gait pattern and FOG in 12 patients with FOG.…”

“…The mechanism was still unknown. One possibility is that locus coeruleus noradrenergic neurons degenerate prior to substantia nigra dopaminergic neurons in PD, and VNS may activate locus coeruleus neurons [151]. A multicenter, doubleblind, placebo/sham-controlled randomized trial of noninvasive VNS in patients with PD are needed.…”