Abstract
Vagus nerve stimulation (VNS) has been used since 1997 for treatment of drug-resistant epilepsy. More recently, an off-label use of VNS has been explored in animal models and clinical trials for treatment of a number of conditions involving the innate immune system. The underlying premise has been the notion of the cholinergic antiinflammatory pathway (CAP), mediated by the vagus nerves. While the macroanatomic substrate - the vagus nerve - is understood, the physiology of the pleiotropic VNS effects and the "language" of the vagus nerve, mediated brain-body communication, remain an enigma. Tackling this kind of enigma is precisely the challenge for and promise of bioelectronic medicine. We review the state of the art of this emerging field as it pertains to developing strategies for use of the endogenous CAP to treat inflammation and infection in various animal models and human clinical trials. This is a systematic PubMed review for the MeSH terms "vagus nerve stimulation AND inflammation." We report the diverse profile of currently used VNS antiinflammatory strategies in animal studies and human clinical trials. This review provides a foundation and calls for devising systematic and comparable VNS strategies in animal and human studies for treatment of inflammation. We discuss species-specific differences in the molecular genetics of cholinergic signaling as a framework to understand the divergence in VNS effects between species. Brain-mapping initiatives are needed to decode vagus-carried brain-body communication before hypothesis-driven treatment approaches can be devised.
Highlights
Rationale Vagus nerve stimulation (VNS) has been used for treatment of drug-resistant epilepsy since 1997, when the US Food and Drug Administration approved it [1,2,3]
80% of the studies were conducted in rodents, 19 in rats and nine in mice; 69% of the studies were done in male adult subjects, and left or right cervical vagus nerve was stimulated
We found a large variance in VNS settings, with approximately one-third of the studies not reporting the intensity of the stimulus
Summary
Rationale Vagus nerve stimulation (VNS) has been used for treatment of drug-resistant epilepsy since 1997, when the US Food and Drug Administration approved it [1,2,3]. The underlying systemic antiinflammatory mechanism is mediated by the vagus nerves relaying onto the spleen’s α7 nicotinic acetylcholine receptor (α7nAChR) expressing macrophages as part of the cholinergic antiinflammatory pathway (CAP) [6]. While the macroanatomic wiring through the vagus nerve seems clear, the physiology of the pleiotropic VNS effects and the “language” of the vagus nerve–mediated brain-body communication remain an enigma. Tackling this kind of enigma is precisely the challenge for and promise of bioelectronic medicine [7]
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