http://www.jem.org/cgi/content/full/195/6/f25
Remarkably, compared with sham-operated controls, electrical stimulation of the efferent vagus nerve very markedly inhibited TNF levels in serum and in the liver and almost totally blocked hypotension caused by a lethal intravenous dose of LPS. Interestingly, vagotomy without stimulation resulted in a significant increase in TNF levels and shortened the time to development of shock as compared with sham-operated controls. This, of course, might be expected if tonic suppression of the aforementioned responses by ACh was removed as a result of vagotomy. These findings were the first to demonstrate a previously unrecognized, parasympathetic antiinflammatory pathway by which the CNS modulates systemic inflammatory responses. The Tracey group termed this the "cholinergic antiinflammatory pathway" (Fig. 1).
In this study (17), Bernik et al. have expanded and markedly extended their work on the cholinergic antiinflammatory pathway with an experimental therapeutic. This compound, CNI-1493, is a tetravalent guanylhydrazone molecule that inhibits systemic inflammation. CNI-1493 is currently undergoing testing in Phase II clinical trials for Crohn's disease and in preclinical testing has been shown to be protective in a number of models, including endotoxic shock, acute respiratory distress syndrome, sepsis, pancreatitis, experimental allergic encephalitis, stroke, rheumatoid arthritis, and dextran sulfate colitis (for a review, see reference 22). Prior to the present report, the antiinflammatory effect of CNI-1493 was assumed to be through its known ability to inhibit the phosphorylation of p38 mitogen-activated protein kinase (MAPK), which plays a key role in regulation of proinflammatory cytokine synthesis (22). However, while evaluating the activity of CNI-1493 in cerebral ischemia the authors made an unexpected observation. As expected, the compound when injected intracerebroventricularly inhibited cerebral TNF synthesis. Surprisingly, by an intracerebroventricular route it also inhibited the systemic TNF response to LPS, which was used as a control. CNI-1493 also directly stimulated vagal nerve activity. These observations led this group to a remarkable possibility. Could the systemic antiinflammatory action of CNI-1493 actually be mediated by a central activation of the cholinergic antiinflammatory pathway? This is precisely the conclusion that is reached, and it is based on quite persuasive results. First, CNI-1493 administered intracerebroventricularly was 100,000-fold more effective in suppressing LPS-induced TNF release and shock as compared with intravenous administration. Thus, doses that are ineffective systemically are active when given centrally. Second, surgical or chemical (using the ACh antagonist atropine) vagotomy ablated the effects of CNI-1493 on LPS-induced TNF synthesis and shock whether the compound was given intracerebroventricular or intravenous. Lastly, electrical stimulation of the intact vagus nerve conferred protection against endotoxic shock and TNF release (Fig. 1).
These findings have some truly provocative implications. Perhaps the most profound is the possibility of developing new classes of systemic antiinflammatory agents that act centrally. Prior studies implicating the CNS in mediating certain antiinflammatory actions of {alpha}-melanocyte–stimulating hormone (23) and salicylates (24) via a sympathetic neural route suggest that there are pathways in addition to the one herein described that might be exploited. CNI-1493 may well serve as a prototype for the developments of such new drugs. The identification of the CNS receptor(s) for CNI-1493, as well as the central neural fiber tract(s) that mediate its action, will be important first steps in this process. A particularly interesting future question will be whether CNI-1493 inhibition of inflammatory cytokine production will also cause a blockade of cytokine-mediated afferent vagal stimulation. If so, the compound might ameliorate fever and sickness behavior as well as shock (Fig. 1). It will also be important to determine whether vagus nerve stimulation, which is a clinically approved therapy for epilepsy and depression (with minimal morbidity) (25), can alter proinflammatory cytokines in humans. If so, this might represent another modality for activation of the cholinergic antiinflammatory pathway for the treatment of inflammatory diseases. Bringing these ideas to fruition may now provide a means for harnessing the possibly powerful influences of the CNS over the immune system.
-potential treatment also in CFS?