semapimod and Ileus

Postoperative ileus (POI) is an iatrogenic complication of abdominal surgery, mediated by a severe inflammation of the muscularis externa (ME). We demonstrated that orally applicated CPSI-2364 prevents POI in rodents by blockade of p38 MAPK pathway and abrogation of NO production in macrophages. In the present experimental swine study we compared the effect of orally and intravenously administered CPSI-2364 on POI and examined CPSI-2364 effect on anastomotic healing.. CPSI-2364 was administered preoperatively via oral or intravenous route. POI was induced by intestinal manipulation of the small bowel. ME specimens were examined by quantitative PCR for CCL2 chemokine gene expression and myeloperoxidase activity. Functional analyzes included measurement of ileal smooth-muscle ex vivo contractility, in vivo intestinal and colonic transit. Furthermore, anastomotic healing of a rectorectostomy after CPSI-2364 treatment was assessed by perianastomotic hydroxyproline concentration, a histochemically evaluated healing score and anastomotic bursting pressure (ABP).. CPSI-2364 abolished inflammation of the ME and improved postoperative smooth muscle contractility and intestinal transit independently of its application route. Hydroxyproline concentration and ABP measurement revealed no wound healing disturbances after oral or intravenous CPSI-2364 treatment whereas histological scoring demonstrated delayed anastomotic healing after intravenous treatment.. CPSI-2364 effectively prevents POI in swine independently of its application route. Impairment of anastomotic healing could be observed after intravenous but not oral preoperative CPSI-2364 treatment. Subsumed, an oral preoperative administration of CPSI-2364 appears to be a safe and efficient strategy for prophylaxis of POI.

Topics: Administration, Intravenous; Administration, Oral; Anastomosis, Surgical; Animals; Hydrazones; Hydroxyproline; Ileus; Macrophages; Male; Muscle, Smooth; Nitric Oxide; p38 Mitogen-Activated Protein Kinases; Postoperative Complications; Rectum; Swine; Wound Healing

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.. 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.. 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.. 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.

Topics: Administration, Oral; Analysis of Variance; Animals; Autoradiography; Disease Models, Animal; Gastrointestinal Transit; Hydrazones; Ileus; Intestine, Small; Luminescence; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; p38 Mitogen-Activated Protein Kinases; Peroxidase; Phosphorylation; Postoperative Complications; Rats; Rats, Sprague-Dawley; Scintillation Counting; Signal Transduction

Electrical stimulation of the vagus nerve reduces intestinal inflammation following mechanical handling, thereby shortening post-operative ileus in mice. Previous studies in a sepsis model showed that this cholinergic anti-inflammatory pathway can be activated pharmacologically by central administration of semapimod, an inhibitor of p38 mitogen-activated protein kinase. We therefore evaluated the effect of intracerebroventricular (i.c.v.) semapimod on intestinal inflammation and post-operative ileus in mice.. Mice underwent a laparotomy or intestinal manipulation 1 h after i.c.v. pre-treatment with semapimod (1 µg·kg(-1) ) or saline. Drugs were administered through a cannula placed in the left lateral ventricle 1 week prior to experimentation. Twenty-four hours after surgery, gastric emptying was measured using scintigraphy, and the degree of intestinal inflammation was assessed. Finally, activation of brain regions was assessed using quantitative immunohistochemistry for c-fos.. Intestinal manipulation induced inflammation of the manipulated intestine and significantly delayed gastric emptying, 24 h after surgery in saline-treated animals. Semapimod significantly reduced this inflammation and improved gastric emptying. Vagotomy enhanced the inflammatory response induced by intestinal manipulation and abolished the anti-inflammatory effect of semapimod. Semapimod but not saline induced a significant increase in c-fos expression in the paraventricular nucleus, the nucleus of the solitary tract and the dorsal motor nucleus of the vagus nerve.. Our findings show that i.c.v. semapimod reduces manipulation-induced intestinal inflammation and prevented post-operative ileus. This anti-inflammatory effect depends on central activation of the vagus nerve.

Topics: Acetylcholine; Animals; Anti-Inflammatory Agents, Non-Steroidal; Brain; Disease Models, Animal; Enteritis; Female; Gastric Emptying; Hydrazones; Ileus; Injections, Intraventricular; Mice; Mice, Inbred BALB C; Motor Neurons; Postoperative Complications; Proto-Oncogene Proteins c-fos; Vagotomy; Vagus Nerve

Postoperative ileus, an iatrogenic complication of abdominal surgery, is mediated by severe inflammation of the tunica muscularis. Macrophages that reside in the muscularis have important roles in initiating the inflammation. We investigated whether activation of the p38 mitogen-activated protein kinase (MAPK) and stress-activated protein kinase is involved in the genesis of postoperative ileus, and whether p38-MAPK inhibition by the macrophage-specific inhibitor semapimod prevents intestinal dysmotility.. Postoperative ileus was induced by intestinal manipulation of the small bowel in mice. Protein kinase phosphorylation was assessed by immunoblotting of muscularis externa preparations. Proinflammatory gene expression was quantified by real-time polymerase chain reaction. Myeloperoxidase histochemistry for neutrophils was performed in jejunal segments. Nitric oxide production was measured by Griess reaction in smooth-muscle organ culture supernatants. Jejunal contractility was assessed within an organ bath setup. Intestinal motility was analyzed by gastrointestinal and colonic transit measurements.. High levels of p38-MAPK and stress-activated protein kinase phosphorylation were observed immediately after intestinal manipulation. Semapimod treatment led to a significant decrease of p38-MAPK phosphorylation in macrophages; proinflammatory gene expression of macrophage inflammatory protein-1alpha, interleukin-6, monocyte chemoattractant protein-1, and intercellular adhesion molecule-1; and neutrophil infiltration. Furthermore, semapimod completely abrogated nitric oxide production within the tunica muscularis. Subsequently, semapimod prevented the suppression of smooth muscle contractility and small intestinal and colonic motility after intestinal manipulation.. A single preoperative semapimod administration prevents intestinal macrophage activation and subsequent gastrointestinal dysmotility induced by abdominal surgery. Semapimod inhibits p38-MAPK and nitric oxide production in macrophages, making it a promising strategy for prophylaxis of postoperative ileus.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Gastrointestinal Motility; Hydrazones; Ileus; Inflammation; Jejunal Diseases; Jejunum; Macrophage Colony-Stimulating Factor; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinase 8; Muscle, Smooth; Nitric Oxide; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Postoperative Complications

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Hydrazones; Ileus; Mice; p38 Mitogen-Activated Protein Kinases; Postoperative Complications