Alterations in the small intestinal wall and motor function after repeated cisplatin in rat

• Published in: Neurogastroenterology and motility Vol. 29; no. 7
• Main Authors: Uranga, J. A., García‐Martínez, J. M., García‐Jiménez, C., Vera, G., Martín‐Fontelles, M. I., Abalo, R.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.07.2017
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - toxicity; c-Kit protein; Cancer; Chemotherapy; chemotherapy‐induced adverse effects; Cisplatin; Cisplatin - administration & dosage; Cisplatin - toxicity; Complications; Gastric motility; gastrointestinal motility; Gastrointestinal Motility - drug effects; Gastrointestinal Motility - physiology; gene expression; histopathology; Immunohistochemistry; Interstitial cells; Interstitial cells of Cajal; Intestinal Mucosa - drug effects; Intestinal Mucosa - pathology; Intestinal Mucosa - physiopathology; Intestine, Small - drug effects; Intestine, Small - pathology; Intestine, Small - physiopathology; Male; Motility; Motor neurons; Motor task performance; Mucosa; Nodules; Phosphopyruvate hydratase; Rats; Rats, Wistar; Rodents; Side effects; Small intestine; chemotherapy-induced adverse effects; gastrointestinal motility; histopathology; cisplatin; gene expression
• ISSN: 1350-1925; 1365-2982
• DOI: 10.1111/nmo.13047

Background Gastrointestinal adverse effects occurring during cancer chemotherapy are well known and feared; those persisting once treatment has finished are relatively unknown. We characterized the alterations occurring in the rat small intestine, after repeated treatment with cisplatin. Methods Male Wistar rats received saline or cisplatin (2 mg kg−1 week−1, for 5 weeks, ip). Gastric motor function was studied non‐invasively throughout treatment (W1‐W5) and 1 week after treatment finalization (W6). During W6, upper gastrointestinal motility was also invasively studied and small intestinal samples were collected for histopathological and molecular studies. Structural alterations in the small intestinal wall, mucosa, submucosa, muscle layers, and lymphocytic nodules were histologically studied. Periodic acid‐Schiff staining and immunohistochemistry for Ki‐67, chromogranin A, and neuronal‐specific enolase were used to detect secretory, proliferating, endocrine and neural cells, respectively. The expression of different markers in the tunica muscularis was analyzed by RT/qPCR. Key Results Repeated cisplatin induced motility alterations during and after treatment. After treatment (W6), the small intestinal wall showed histopathological alterations in most parameters measured, including a reduction in the thickness of circular and longitudinal muscle layers. Expression of c‐KIT (for interstitial cells of Cajal), nNOS (for inhibitory motor neurons), pChAT, and cChAT (for excitatory motor neurons) increased significantly (although both ChATs to a lesser extent). Conclusions & Inferences Repeated cisplatin induces relatively long‐lasting gut dysmotility in rat associated with important histopathological and molecular alterations in the small intestinal wall. In cancer survivors, the possible chemotherapy‐induced histopathological, molecular, and functional intestinal sequelae should be evaluated. In this study, we have evaluated the effects of the antineoplastic drug cisplatin on the rat small intestinal wall 1 week after a five‐cycle treatment. At that time point, small intestinal transit (but not gastric emptying) was delayed, and several histological and immunohistological features of the gut wall and the expression of ICC and different myenteric neuronal populations were altered, supporting the results on motor function.