Vagus Nerve Stimulation Ameliorates Disease Activity in a Rodent Model of Rheumatoid Arthritis

Vagus Nerve Stimulation Rheumatoid Arthritis
Vagus Nerve Stimulation – Rheumatoid Arthritis

A study published in PLoS ONE is perhaps the first to demonstrate that electrical neurostimulation of the vagus nerve reduces signs of inflammation and disease severity in the collagen-induced arthritis (CIA), a disease model of rheumatoid arthritis in rodents.

Rheumatoid arthritis (RA) is a chronic inflammatory disease, characterized by swollen and tender joints and progressive destruction of cartilage and bone, leading to significant morbidity and increased mortality. RA is currently treated with targeted biological and oral drugs, which have greatly improved disease outcome, however there remains a need for additional and better treatment options.

As per the recently introduced inflammatory reflex, mediators of inflammation are sensed by the peripheral and central nervous system and are reflexively down regulated via the prototypical efferent arm, termed the “cholinergic anti-inflammatory pathway” (CAP). CAP signaling is initiated in brainstem nuclei of the vagus nerve, and continues through the efferent vagus to synapses in the celiac and other peripheral ganglia.

From the celiac ganglion, functional signals continue through the splenic nerve to synapse-like junctions with a subset of splenic CD4+CD44highCD62low acetylcholine-producing T cells which signal to adjacent splenic macrophages bearing the alpha 7 nicotinic acetylcholine receptor (α7nAChR)

Previous research indicates that cholinergic signaling along the vagus nerve is able to affect the production of cytokines such as interleukin (IL)1β, IL-6 and tumor necrosis factor (TNF)-α. Macrophages express nicotinic acetylcholine receptors (nAChRs) that respond to acetylcholine (Ach), the major cholinergic neurotransmitter.

Given the extremely short half-life of ACh, cholinergic modulation of immune cell activation most likely requires close contact (Van Der Zanden EP et al., Neurogastroenterol Motil, 2009, 21:6; Koopman FA et al., Mol Med, 2011, 17:937).

Nearly all neuroanatomical studies indicate that lymphoid organs such as the spleen, thymus or lymph nodes do not receive direct cholinergic/parasympathetic or vagal nerve innervation. Thus, it is not entirely clear how the vagus exerts immunomodulation.

However, as electrical stimulation of the vagus nerve fails to attenuate serum TNF levels in splenectomized mice (cf. Van Der Zanden EP et al., Koopman FA et al.), it was suggested that the vagus nerve affects immune cells within the spleen indirectly via activation of sympathetic postganglionic neurons localized in the coeliac ganglia (see cover image, and, below, its source and legend).

The vagus nerve, via these ganglia, may modulate the noradrenergic/sympathetic neural input to the spleen. This may include the release of catecholamines such as norepinephrine (noradrenaline), and via stimulation of adrenergic receptors, a subsequent inhibition of pro-inflammatory cytokine production.

In the PLoS ONE study, Y. Levine and colleagues, as part of an international research team from the US, UK and the Netherlands used neurostimulation delivered by implanted electrical vagus nerve stimulation cuff electrode, analogous to those now in clinical use for drug-resistant epilepsy (Beekwilder JP & Beems T, J Clin Neurophysiol, 2010, 27:130).

In rats with autoimmune CIA this neurostimulation was related to 52% reduction in ankle diameter, a 57% reduction in ankle diameter and 46% reduction overall histological arthritis score with significant improvements in inflammation, pannus formation, cartilage destruction and bone resorption. This was associated with reductions in IL-1β, IL-2, IL-6, IFN-γ and TNF systemic levels, not reaching statistical significance.

The present study reveals that successful treatment delivery can be accomplished using a simple surgically implanted cuffed nerve electrode system analogous to those used in many other clinical applications in humans.

This is the first study to demonstrate that electrical neurostimulation using an implanted vagus nerve stimulation cuff electrode can activate the cholinergic anti-inflammatory pathway and significantly reduce activity in a widely accepted and utilized preclinical autoimmune disease model.

Thus, the study may justify testing of vagus nerve stimulation in human immune/inflammatory disorders, and/or suggest novel therapeutic strategies in patients with rheumatoid arthritis.

Source: PLoS One, 2014, 9(8):e104530. doi: 10.1371/journal.pone.0104530. eCollection 2014.
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