Oxaliplatin‐induced enteric neuronal loss and intestinal dysfunction is prevented by co‐treatment with BGP‐15
Author(s) -
McQuade Rachel M,
Stojanovska Vanesa,
Stavely Rhian,
Timpani Cara,
Petersen Aaron C,
Abalo Raquel,
Bornstein Joel C,
Rybalka Emma,
Nurgali Kulmira
Publication year - 2018
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14114
Subject(s) - oxaliplatin , myenteric plexus , interstitial cell of cajal , medicine , oxidative stress , enteric nervous system , ex vivo , pharmacology , endocrinology , in vivo , gastroenterology , biology , immunohistochemistry , colorectal cancer , cancer , microbiology and biotechnology
Background and Purpose Gastrointestinal side effects of chemotherapy are an under‐recognized clinical problem, leading to dose reduction, delays and cessation of treatment, presenting a constant challenge for efficient and tolerated anti‐cancer treatment. We have found that oxaliplatin treatment results in intestinal dysfunction, oxidative stress and loss of enteric neurons. BGP‐15 is a novel cytoprotective compound with potential HSP72 co‐inducing and PARP inhibiting properties. In this study, we investigated the potential of BGP‐15 to alleviate oxaliplatin‐induced enteric neuropathy and intestinal dysfunction. Experimental Approach Balb/c mice received oxaliplatin (3 mg·kg −1 ·day −1 ) with and without BGP‐15 (15 mg·kg −1 ·day −1 : i.p.) tri‐weekly for 14 days. Gastrointestinal transit was analysed via in vivo X‐ray imaging, before and after treatment. Colons were collected to assess ex vivo motility, neuronal mitochondrial superoxide and cytochrome c levels and for immunohistochemical analysis of myenteric neurons. Key Results Oxaliplatin‐induced neuronal loss increased the proportion of neuronal NO synthase‐immunoreactive neurons and increased levels of mitochondrial superoxide and cytochrome c in the myenteric plexus. These changes were correlated with an increase in PARP‐2 immunoreactivity in the colonic mucosa and were attenuated by BGP‐15 co‐treatment. Significant delays in gastrointestinal transit, intestinal emptying and pellet formation, impaired colonic motor activity, reduced faecal water content and lack of weight gain associated with oxaliplatin treatment were restored to sham levels in mice co‐treated with BGP‐15. Conclusion and Implications Our results showed that BGP‐15 ameliorated oxidative stress, increased enteric neuronal survival and alleviated oxaliplatin‐induced intestinal dysfunction, suggesting that BGP‐15 may relieve the gastrointestinal side effects of chemotherapy.