Resveratrol alleviates oxidative damage in enteric neurons and associated gastrointestinal dysfunction caused by chemotherapeutic agent oxaliplatin

Abstract

Oxaliplatin is a first-line chemotherapeutic agent used for the treatment of colorectal cancer. Its use is associated with severe gastrointestinal (GI) side-effects, associated with oxidative damage and neurotoxicity to the enteric neurons. Resveratrol is a potent anti-oxidant that has been shown to protect against oxidative damage and neurotoxicity in other neurons and could therefore prevent oxaliplatin-induced damage to enteric neurons. We determined whether co-administration of resveratrol with oxaliplatin alleviates enteric neuron toxicity and GI dysfunction in mice. Colons were collected for immunohistochemical analysis of myenteric neurons and assessment of motor activity in organ-bath experiments. Morphological damage to the colonic mucosa and muscles was analysed. Oxaliplatin treatment induced translocation of nitrated proteins into the nuclei of myenteric neurons and significant damage to the mucosal lining, vacuolisation and a decrease in muscle thickness. This damage is linked to motor dysfunction due to inhibition of the amplitude of colonic contractions, leading to chronic constipation. Co-treatment with resveratrol prevented oxaliplatin-induced neurotoxicity, alleviated damage to GI mucosa, crypts and muscle layer, resulting in improved contractility and a decrease in constipation. Resveratrol could be integrated as part of a therapeutic regimen to help alleviate oxaliplatin-induced GI dysfunction.

Keywords: Colorectal cancer; Enteric neurons; Neurotoxicity; Oxaliplatin; Oxidative damage; Oxidative stress; Resveratrol.