CP-96,345, a Substance P Antagonist, Inhibits Rat Intestinal Responses to Clostridium difficile Toxin A but not Cholera Toxin

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 91; no. 3; pp. 947 - 951
• Main Authors: Pothoulakis, Charalabos, Castagliuolo, Ignazio, Lamont, J. Thomas, Jaffer, Amir, O'Keane, J. Conor, Snider, R. Michael, Leeman, Susan E.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 01-02-1994; National Acad Sciences
• Subjects: Animals; Bacterial Toxins - antagonists & inhibitors; Bacterial Toxins - toxicity; Biological and medical sciences; Biphenyl Compounds - pharmacology; Bones, joints and connective tissue. Antiinflammatory agents; Cholera; Cholera Toxin - toxicity; Clostridium difficile; Control loops; Diarrhea - etiology; Diarrhea - prevention & control; Enterocolitis - etiology; Enterocolitis - prevention & control; Enterotoxins - antagonists & inhibitors; Enterotoxins - toxicity; Fluid permeability; Gastroenterology; Ileum - drug effects; Ileum - pathology; Ileum - physiopathology; Male; Mast cells; Mast Cells - drug effects; Mast Cells - metabolism; Medical sciences; Mucosa; Neutrophils; Pharmacology. Drug treatments; Pretreatment; Rats; Rats, Wistar; Secretion; Substance P - antagonists & inhibitors; Toxins; Vibrio cholerae; Intraperitoneal administration; Rat; Substance P; Vibrio cholerae; Rodentia; Clostridium difficile; Clostridiales; Inflammation; Neuropeptide; Toxin; Vertebrata; Chemotherapy; Mammalia; Treatment; Animal; Clostridiaceae; Digestive diseases; Bacteria; Intestinal disease; Vibrionaceae; Enteritis; Antagonist
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.91.3.947

Toxin A from Clostridium difficile mediates acute inflammatory enterocolitis in experimental animals, while cholera toxin causes noninflammatory secretory diarrhea. The purpose of this study was to investigate whether an antagonist to the peptide substance P, a constituent of primary sensory neurons known to participate in inflammatory responses, would inhibit toxin A-mediated enteritis in the rat ileum. Pretreatment of rats with CP-96,345 (2.5 mg per kg of body weight), a substance P antagonist, dramatically inhibited fluid secretion (P < 0.01) and mannitol permeability (P < 0.01) in ileal loops exposed to toxin A. The protective effects, which were dose dependent, caused a significant reduction of inflammation in the lamina propria, reduction of the necrosis of intestinal epithelial cells, and complete inhibition of toxin A-mediated release of rat mast cell protease II, a specific product of rat mucosal mast cells. An inactive enantiomer of the substance P antagonist, CP-96,344, had no effect. In contrast, pretreatment with CP-96,345 had no inhibitory effect on the intestinal effects caused by administration of cholera toxin into the ileal loops. From these data, we conclude that the peptide substance P is involved in the secretory and inflammatory effects of toxin A but not of cholera toxin.