Vagus nerve stimulation using clinically approved parameters suppresses TNF production in endotoxemic mice

Abstract

The central nervous system, via efferent vagus nerve signaling, modulates peripheral inflammatory responses. Electrical stimulation of the vagus nerve significantly attenuates pro-inflammatory cytokine release following endotoxin challenge or ischemia/reperfusion injury. We investigated whether electrical vagus nerve stimulation, using current FDA approved parameters for the treatment of medically refractory epilepsy, is sufficient to activate the cholinergic anti-inflammatory pathway in a murine endotoxemia model. In the first part of the experiment, BALB/c mice were infused with endotoxin (7.5 mg/kg, IP) and randomized to receive either electrical stimulation of the vagus nerve for 30 s (0.2 mA, 30 Hz, 0.5 ms) or sham surgery. Animals were euthanized 2 h after LPS infusion, and blood was collected for analysis of TNF by ELISA. In the second part of the experiment, mice underwent electrical vagus nerve stimulation or sham surgery, followed by infusion with endotoxin (7.5 mg/kg, IP) either 2 or 4 h later. Animals were euthanized 2 h after LPS infusion, and blood was collected for analysis of TNF by ELISA. Electrical vagus nerve stimulation using clinically approved epilepsy parameters significantly suppressed serum TNF levels compared with LPS alone (electrical = 70% reduction versus no stimulation, P < 0.05, n = 5/group). In the 2-h delay experiment, electrical vagus nerve stimulation significantly suppressed serum TNF levels compared with LPS alone (electrical = 71% reduction versus no stimulation, P < 0.05, n = 5/group). In the 4-h delay experiment, electrical vagus nerve stimulation did not suppress TNF levels compared with LPS alone (electrical = 0% reduction versus no stimulation, n = 5/group). These data indicate that electrical vagus nerve stimulation using clinically approved parameters is sufficient for activation of the cholinergic anti-inflammatory pathway and suppression of TNF production in endotoxemic mice. Furthermore, the data indicate that this activation has an effective half-life of 2–4 h.