Molecular Targets to Alleviate Enteric Neuropathy and Gastrointestinal Dysfunction.

Abstract

Enteric neuropathy underlies long-term gastrointestinal (GI) dysfunction associated with several pathological conditions. Our previous studies have demonstrated that structural and functional changes in the enteric nervous system (ENS) result in persistent alterations of intestinal functions long after the acute insult. These changes lead to aberrant immune response and chronic dysregulation of the epithelial barrier. Damage to the ENS is prognostic of disease progression and plays an important role in the recurrence of clinical manifestations. This suggests that the ENS is a viable therapeutic target to alleviate chronic intestinal dysfunction. Our recent studies in preclinical animal models have progressed into the development of novel therapeutic strategies for the treatment of enteric neuropathy in various chronic GI disorders. We have tested the anti-inflammatory and neuroprotective efficacy of novel compounds targeting specific molecular pathways. Ex vivo studies in human tissues freshly collected after resection surgeries provide an understanding of the molecular mechanisms involved in enteric neuropathy. In vivo treatments in animal models provide data on the efficacy and the mechanisms of actions of the novel compounds and their combinations with clinically used therapies. These novel findings provide avenues for the development of safe, cost-effective, and highly efficacious treatments of GI disorders.