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. 2022 Dec;10(24):1314.
doi: 10.21037/atm-22-5366.

Right vagus nerve stimulation improves motor behavior by exerting neuroprotective effects in Parkinson's disease rats

Chaofan Wang  1 , Tong Su  2 , Lifei Xiao  1 , Yangyang Wang  1 , Xianhao Huo  1 , Wenchao Li  1 , Jiangwei Ding  1 , Tao Sun  1
Affiliations

Right vagus nerve stimulation improves motor behavior by exerting neuroprotective effects in Parkinson's disease rats

Chaofan Wang et al. Ann Transl Med. 2022 Dec.

Abstract

Background: Parkinson's disease (PD) is a common movement disorder disease. Left vagus nerve stimulation (LVNS) is a potential treatment option for PD. Compared with the left vagus nerve, the right vagus nerve is more closely connected with the midbrain dopaminergic neurons, which are the lesion locations of PD. However, whether right vagus nerve stimulation (RVNS) has a therapeutic effect on PD has not yet been studied. Therefore, in this study, we studied the therapeutic effect and underlying mechanism of RVNS using a PD rat model.

Methods: To establish the PD rat model, 8-week-old male Sprague-Dawley rats were intraperitoneally injected with rotenone for 21 days. The cuff electrodes were implanted into the right cervical vagal carotid sheaths of the rats. The right vagus nerve was continuously stimulated for 14 days using a radio stimulation system. Behavioral tests were performed before and after stimulation. Finally, tyrosine hydroxylase (TH), vesicular monoamine transporter 2 (VMAT2), and α-synuclein in the midbrain, including the substantia nigra (SN) and ventral tegmental area (VTA), were detected by immunofluorescence.

Results: A markedly lower distance traveled and rearing number was observed in the rotenone, rotenone + sham, and rotenone + RVNS groups compared to the vehicle group. After the stimulation days, the distance traveled and rearing number were both higher in the rotenone + RVNS group compared to the rotenone and rotenone + sham groups (P<0.01, P<0.0001). A remarkable increase in distance traveled and rearing number was observed in the rotenone + RVNS group after stimulation. TH expression in the vehicle group was significantly up-regulated than the other groups. RVNS markedly up-regulated TH expression level. A significantly higher expression of α-synuclein was observed in the rotenone, rotenone + sham, and rotenone + RVNS groups compared to the vehicle group. The expression of α-synuclein was lower in the rotenone + RVNS group compared to the rotenone and rotenone + sham groups. A markedly higher VMAT2 expression was observed in the vehicle group compared to other groups. RVNS significantly up-regulated VMAT2 expression.

Conclusions: The improved motor behavior and neuroprotective effects on the midbrain dopaminergic neurons in the PD rat model suggest that RVNS could be used as a potential treatment for PD.

Keywords: Parkinson’s disease (PD); rat model; right vagus nerve stimulation (RVNS); vagus nerve stimulation.

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Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-5366/coif). TS reports funding support from the National Natural Science Foundation of China (No. 82260282). The other authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Experimental design. (A) Rotenone was injected intraperitoneally for 21 days to establish the PD rat model. The cuff electrodes were then implanted in the rotenone + sham and rotenone + RVNS groups. Behavioral tests were performed on all of the rats after 2 days of postoperative rest. RVNS was performed for 14 days on rats in the rotenone + RVNS group. Following stimulation, all of the rats underwent behavioral tests. Finally, the rats were euthanized to perform immunofluorescence. (B) The cuff electrode consisted of a radio pulse receiver, electrode wire, and electrode tip. The radio pulse receiver was implanted subcutaneously in the abdomens of the rats. The electrode wire was threaded through the subcutaneous tunnel to the neck, and the cuff electrode tip was wrapped around the right vagus carotid sheath. (C) The radio stimulation system consisted of a radio pulse generator and a radio pulse emission surface. RVNS, right vagus nerve stimulation; IF, immunofluorescent; PD, Parkinson’s disease.
Figure 2
Figure 2
RVNS improves motor behavior in PD rats. (A) The distance traveled by the rats before and after the stimulation days. (B) The rearing number before and after the stimulation days. (C) Comparison of the distance traveled by the rats before and after the stimulation days in each group. (D) Comparison of the rearing number before and after the stimulation days in each group. One-way and two-way ANOVA were applied for statistical analysis. **P<0.01; ****P<0.0001. ns, no statistical significance; sham, sham surgery; RVNS, right vagus nerve stimulation; PD, Parkinson’s disease; ANOVA, analysis of variance.
Figure 3
Figure 3
RVNS increases TH expression and decreases α-synuclein expression in PD rats. (A) Red TH and blue DAPI immunofluorescence images in the SN and VTA. (B) Immunofluorescence images of the red TH and green α-synuclein in the SN and VTA. (C,D) The image analysis results of TH (C) and α-synuclein (D) immunofluorescence. One-way ANOVA was used for statistical analysis. **P<0.01; ***P<0.001; ****P<0.0001. TH, tyrosine hydroxylase; DAPI, 4',6-diamidino-2-phenylindole; sham, sham surgery; RVNS, right vagus nerve stimulation; ns, no statistical significance; PD, Parkinson’s disease; SN, substantia nigra; VTA, ventral tegmental area; ANOVA, analysis of variance.
Figure 4
Figure 4
RVNS increases VMAT2 expression in PD rats. (A,B) Red TH-labeled dopaminergic neurons in the SN and VTA. (C) Immunofluorescence images of green VMAT2 in the SN and VTA. (D) The image analysis results of VMAT2 immunofluorescence. One-way ANOVA was used for statistical analysis. **P<0.01; ***P<0.001; ****P<0.0001. sham, sham surgery; RVNS, right vagus nerve stimulation; TH, tyrosine hydroxylase; SN, substantia nigra; VTA, ventral tegmental area; VMAT2, vesicular monoamine transporter 2; ns, no statistical significance; PD, Parkinson’s disease; ANOVA, analysis of variance.
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