The cholinergic anti-inflammatory pathway in chronic kidney disease—review and vagus nerve stimulation clinical pilot study

Figures

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  FIGURE 1. The CAP. Pro-inflammatory cytokines (IL-1, TNF) as well as PAMPs and DAMPs stimulate the sensory afferent vagus nerve endings. A signal is referred to the nucleus tractus solitarius via the nodose ganglion. The dorsal motor nucleus of the vagus is the orgin of the efferent motor vagus, which is activated by intermediate neurons. From here, the signal is spread to the celiac plexus, where the splenic nerve begins. Splenic nerve terminals are found in the vicinity of T cells and B cells in the red pulp and marginal zone in the spleen. Specialized T cells with the enzyme ChAT are activated by NE that binds to ARs of the ChAT T cell. Activated ChAT cells results in production and release of acetylcholine (ACh). ACh binds to the α7nAChR on macrophages and other immune cells and release of TNF is inhibited. Stimulation of muscarinic acetylcholine receptors (mAChR) or acetylcholinesterase (AChE) inhibitor in the central nervous system also activates the CAP. Acupuncture at the Hegu point causes activation of brain mAChR, resulting in activation the CAP [139]. Figure reprinted with permission from Nature Science.

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  FIGURE 2. The inflammatory reflex. The celiac plexus receives efferent signals from both the efferent vagus nerve and the sympathetic trunk. Efferent signals from the vagus nerve activate the splenic nerve to release NE that interacts with ARs on ChAT T cells. ChAT T cells release acetylcholine that binds to α7nAChR on macrophages and inhibits further release of pro-inflammatory cytokines. Figure reprinted with permission from Wiley & Sons.

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  FIGURE 3. Study protocol. Timetable for blood samples, electrocardiogram (ECG) and intervention treatment. Blood sampling and ECG at baseline, after 2 and 4 weeks during the intervention period and at 8 and 12 weeks of follow-up.

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  FIGURE 4. The minimally invasive treatment device. A plastic tube with inflatable tip of thin latex. (A) The tube is inserted in the left nostril and (B) secured in position by a specially designed headband [129]. Images reprinted with permission from Headache.

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  FIGURE 5. HRV in a healthy volunteer (A) before and (B) after 10 min of treatment. Augmentation of time domain variables SDNN (47.7–61.0 ms), RMSSD (34–41.5 ms) and frequency domain variables LF (559–1749 ms2) and HF (255–382 ms2).

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  FIGURE 6. N = 12. Unstimulated levels of hsCRP, TNF, IL-1b and IL-10 at baseline, at 2 and 4 weeks during the intervention and at 8 and 12 weeks of follow-up.

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  FIGURE 7. N = 12. Levels of TNF, IL-1 and IL-10 in the whole blood model at baseline, at 2 and 4 weeks during the intervention and at 8 and 12 weeks of follow-up. Whole blood stimulated with LPS 10 and 100 ng/mL.

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  FIGURE 8. N = 12. Levels of TNF in the whole blood model stimulated with LPS 100 ng/mL (red line) and the reduction with cholinergic analogue GTS-21 90 μmol/mL (green line). Results shown for 2 and 4 weeks during the intervention and 8 and 12 weeks of follow-up.

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  FIGURE 9. N = 8. Levels of TNF for eight patients that went through the study without obstacles. Whole blood model stimulated with LPS 100 ng/mL (red line) and the reduction with GTS-21 90 μmol/mL (green line). Results shown for 2 and 4 weeks during the intervention and 8 and 12 weeks of follow-up.