The novel orally active guanylhydrazone CPSI-2364 prevents postoperative ileus in mice independently of anti-inflammatory vagus nerve signaling.
OBJECTIVE
Postoperative ileus (POI) is an iatrogenic complication of abdominal surgery, mediated by a severe inflammation of the muscularis externa (ME). Previously, we demonstrated that intravenous application of the tetravalent guanylhydrazone semapimod (CNI-1493) prevents POI, but the underlying mode of action could not definitively be confirmed. Herein, we investigated the effect of a novel orally active salt of semapimod (CPSI-2364) on POI in rodents and distinguished between its inhibitory peripheral and stimulatory central nervous effects on anti-inflammatory vagus nerve signaling.


METHODS
Distribution of radiolabeled orally administered CPSI-2364 was analyzed by whole body autoradiography and liquid scintillation counting. POI was induced by intestinal manipulation with or without preoperative vagotomy. CPSI-2364 was administered preoperatively via gavage in a dose- and time-dependent manner. ME specimens were assessed for p38-MAP kinase activity by immunoblotting, neutrophil extravasation, and nitric oxide production. Furthermore, in vivo gastrointestinal (GIT) and colonic transit were measured.


RESULTS
Autoradiography demonstrated a near-exclusive detection of CPSI-2364 within the gastrointestinal wall and contents. Preoperative CPSI-2364 application significantly reduced postoperative neutrophil counts, nitric oxide release, GIT deceleration, and delay of colonic transit time, while intraoperatively administered CPSI-2364 failed to improve POI. CPSI-2364 also prevents postoperative neutrophil increase and GIT deceleration in vagotomized mice.


CONCLUSIONS
Orally administered CPSI-2364 shows a near-exclusive dispersal in the gastrointestinal tract and effectively reduces POI independently of central vagus nerve stimulation. Its efficacy after single oral dosage affirms CPSI-2364 treatment as a promising strategy for prophylaxis of POI.
Department of Surgery, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
S
S
Wehner
T O
TO
Vilz
N
N
Sommer
T
T
Sielecki
G S
GS
Hong
M
M
Lysson
B
B
Stoffels
D
D
Pantelis
J C
JC
Kalff
D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D001345:Autoradiography; D004195:Disease Models, Animal; D005772:Gastrointestinal Transit / Q000187:drug effects; D006835:Hydrazones / Q000008:administration & dosage / Q000494:pharmacology*; D045823:Ileus / Q000517:prevention & control*; D007421:Intestine, Small / Q000601:surgery*; D049449:Luminescence; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D010766:Phosphorylation; D011183:Postoperative Complications / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012588:Scintillation Counting; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000813:Anilides; D006146:Guanidines
D006835:Hydrazones; D009569:Nitric Oxide; D009195:Peroxidase; D048051:p38 Mitogen-Activated Protein Kinases; C097256:semapimod; D000813:Anilides; D006146:Guanidines