Nerve stimulation may attenuate immune responses of sepsis.
Sepsis is an intense inflammatory state that affects the whole body, mainly caused by severe infections. It hits multiple organs provoking their failure and often leading to the patient’s death: it is in fact the principal non-cardiac cause of death of patients in intensive care units.
The inflammatory response associated with sepsis is extremely powerful because it is evoked by numerous cytokines released in the body as a consequence of its pathological state. The treatment of sepsis would thus require blocking the effects of many diverse inflammatory mediators which is not attainable with current therapies.
In a paper published in Nature Medicine, Torres-Rosas and colleagues (of Rotgers University in Newark, NJ and of the National Medical Center Siglo XXI in Mexico City), report how nerve stimulation by electroacupuncture (EA) may attenuate the immune responses involved in sepsis and control intense inflammatory states.
The scientists employed EA (in which small electrical currents are passed through acupuncture needles) to stimulate the acupuncture point called ST36 Zusanli in mice previously treated to develop peritonitis and sepsis.
The ST36 Zusanli acupoint is located in the leg just below the knee joint at the level of several peripheral nerves, among which the sciatic nerve.
The scientists observed that the electrostimulation of ST36 Zusanli acupoint significantly reduced sepsis and increased mice survival.
How did EA repress inflammation? The researchers went on to demonstrate that crucial to the effect of EA was the stimulation of the sciatic nerve at ST36 Zusanly acupoint, which once activated conveyed signals to the central nervous system and from here to the vagus nerve.
The vagus is a long nerve that comes from the brain and runs along the body, reaching several organs and participating in the regulation of their functions. For example it controls heart beat, gastrointestinal motility, and also cytokine production in the spleen, thus contributing to the control of inflammation.
Surprisingly, the scientists found that removal of the spleen in septic mice did not prevent the therapeutic effects of EA, suggesting that the vagus nerve was regulating inflammation by a mechanism that did not require spleen stimulation.
In fact only when the researchers removed the adrenal glands, organs that also receive vagal innervation, EA became ineffective.
The role of dopamine
This discovery suggests that catecholamines, chemical mediators secreted by the adrenals, might be critical for the antinflammatory response induced by EA. Accordingly, Torres-Rosas and colleagues found that EA increased the blood levels of catecholamines, in particular of dopamine and norepinephrine.
To test their hypothesis the researchers then treated septic mice with reserpine, a catecholamine inhibitor, and found that it prevented EA beneficial effects, thus confirming catecholamine involvement.
But are dopamine and norepinephrine equally important in mediating EA responses?
To clarify this point, the authors separately inhibited each catecholamine and found that while a norepinephrine blocker administered alone did not interfere with EA, a dopamine blocker was able to abrogate its effects, indicating that dopamine is the key intermediate of EA effects.
In line with this, when adrenal glands were removed from septic mice making them unresponsive to EA, the dopamine agonist fenoldopam reduced inflammation, thus proving to be an effective therapeutic substitute of EA.
In conclusion this work establishes a new circuit by which the nervous system can modulate immune responses involved in inflammation: this circuit implies the activation of the sciatic/vagus nerves by an external trigger (EA), which stimulates the adrenals to release the antinflammatory mediator dopamine.
If the same circuit is operative also in humans, these findings have extremely interesting therapeutic implications:
1. they demonstrate that EA, a technically simple, relatively non-invasive and inexpensive procedure, can be successfully employed in the treatment of inflammatory states;
2. they prove that dopamine agonists are potent antinflammatory agents that might be effective in the treatment of sepsis in patients not responsive to EA because of compromised adrenal function, a complication often associated with this condition.
Torres-Rosas R, Yehia G, Peña G, Mishra P, Del Rocio Thompson-Bonilla M, Moreno-Eutimio MA, Arriaga-Pizano LA, Isibasi A, & Ulloa L (2014). Dopamine mediates vagal modulation of the immune system by electroacupuncture. Nature medicine, 20 (3), 291-5 PMID: 24562381
Angus, D., & van der Poll, T. (2013). Severe Sepsis and Septic Shock New England Journal of Medicine, 369 (9), 840-851 DOI: 10.1056/NEJMra1208623
acupuncture, electroacupuncture, sepsis, inflammation, dopamine