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

Abstract

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 one 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 of the small intestinal wall, mucosa, submucosa, muscle layers, and lymphocytic nodules were histologically studied. PAS staining and immunohistochemistry for Ki-67, chromogranin A and neuronal specific enolase (NSE) 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, ICC), nNOS (for inhibitory motor neurons), pChAT and cChAT (for excitatory motor neurons) increased significantly (although both ChATs to a lesser extent). Conclusions and inferences: Repeated cisplatin induces relatively long-lasting gut dysmotility in the rat associated to important histopathological and molecular alterations of the small intestinal wall. In cancer survivors, the possible chemotherapy-induced histopathological, molecular and functional intestinal sequelae should be evaluated.