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OPTIMIZATION OF SACRAL NERVE STIMULATION FOR COLONIC INFLAMMATION IN TNBS-INDUCED COLITIS IN RATS
Nina Zhang^*, Xuhang Li, Han Zhang, Shengai Zhang, Jieyun Yin, Pankaj J. Pasricha, Jiande Chen
Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD

Background/Aims: Vagal nerve stimulation has been reported to treat inflammation with promising results. The aim of our study was to explore feasibility of sacral nerve stimulation (SNS) that would have less side effects for colonic inflammation in a rodent model of colitis, optimization of SNS methodologies and autonomic and cytokine mechanisms. Methods: Intestinal inflammation was induced by intrarectal administration of TNBS (2,4,6-Trinitrobenzenesulfonic acid) in rats. Five days later, the rats were treated with SNS of different methodologies or sham-SNS for 10 days. Three major efforts were made in optimizing SNS: 1) to determine the best stimulation duration: SNS-0.5h daily, SNS-1h daily, and SNS-3h daily with parameters set at 5 Hz, 10s on, 90s off; 2) to determine the best stimulation location: bilateral, bipolar and unipolar stimulation; 3) to determine the best stimulation parameters: our 5Hz intermittent stimulation vs. 14Hz-210μs continuous stimulation used in treating fecal incontinence and overactive bladder. Inflammatory responses were assessed by disease activity index (DAI), histological sections and myeloperoxidase (MPO) activity. Levels of inflammatory cytokines, plasma norepinephrine (NE) and pancreatic polypeptide (PP) in both plasma and tissues were assessed. Results: 1) Stimulation duration: both SNS-1h and SNS-3h significantly decreased the DAI scores, microscopic scores, MPO activity, pro-inflammatory cytokines (IL-2/EGF/IL-13/IL-1a/IL-12p70 in serum and IL-1a/IL-6/IL-17A/TNF-α in tissue), increased anti-inflammatory cytokines (IL-4 in serum and IL-10 in tissue), compared with sham-SNS (all P value <0.05); SNS-1h was superior to SNS-3h. SNS-1h remarkably decreased plasma NE (2.80±0.54 vs. 8.67±3.98, P=0.04) and increased plasma PP (4.34±0.35 vs. 2.96±0.13, P=0.003) compared with sham-SNS. 2) Stimulation location: bipolar not bilateral or unipolar stimulation significantly decreased the DAI scores, microscopic scores, MPO activity, pro-inflammatory cytokines (IL-5/IL-12p70 in serum and TNF-α in tissue) and plasma NE, increased anti-inflammatory cytokines (IL-10 in tissue) and plasma PP (all P value <0.05); 3) Stimulation parameters: SNS with 5Hz intermittent stimulation but not the 14Hz continuous SNS decreased the DAI scores, microscopic scores, MPO activity, pro-inflammatory cytokines (IL-5/IL-13 in serum and TNF-α/LIX in tissue), increased anti-inflammatory cytokines (IL-4 in serum and IL-10 in tissue) and plasma PP (all P value <0.05). Conclusion: Bipolar stimulation for 1 hour daily using intermittent 5Hz parameters is most effective in improving colonic inflammation in rats by inhibiting pro-inflammatory cytokines and increasing anti-inflammatory cytokines via the modulation of the autonomic function. (Sponsored by the DARPA BTO ElectRx Program under the auspices of Dr. Doug Weber Contract No. N66001-15-2-4059)

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