Effects of Oxaliplatin Treatment on the Enteric Glial Cells and Neurons in the Mouse Ileum

Abstract

SummaryOxaliplatin, currently used for treatment of colorectal and other cancers, causes severe gastrointestinal side effects, including nausea, vomiting, diarrhea, and constipation that are attributed to mucosal damage. However, delayed onset and long-term persistence of these side effects suggest that damage to the enteric nervous system (ENS) regulating physiological function of the gastrointestinal tract may also occur. The ENS comprises myenteric and submucosal neurons and enteric glial cells (EGCs). This study aimed to investigate the effects of oxaliplatin treatment on enteric neurons and EGCs within the mouse ileum. BALB/c mice received repeated intraperitoneal injections of oxaliplatin (3 mg/kg, 3 injections/week). Tissues were collected 3, 7, 14, and 21 days from the commencement of treatment. Decreases in glial fibrillary acidic protein-immunoreactive (IR) EGCs and protein gene product 9.5/β-Tubulin III-IR neurons as well as increase in s100β-IR EGCs after chronic oxaliplatin administration were observed in both the myenteric and submucosal plexi. Changes in EGCs were further observed in cross-sections of the ileum at day 14 and confirmed by Western blotting. Alterations in EGCs correlated with loss of myenteric and submucosal neurons in the ileum from oxaliplatin-treated mice. These changes to the ENS may contribute to the mechanisms underlying gastrointestinal side effects associated with oxaliplatin treatment. (J Histochem Cytochem 64:530-545, 2016)

Role of oxidative stress in oxaliplatin‐induced enteric neuropathy and colonic dysmotility in mice

“…Increased expression of caspase‐3 observed in our study is indicative of oxaliplatin‐induced apoptosis which resulted in 43% loss of myenteric neurons in the distal colon, 16% of myenteric neurons in the proximal colon and 30% of submucosal neurons in the distal colon. Similarly, oxaliplatin treatment induced 12% loss of myenteric and 21% submucosal neurons in the mouse ileum at day 14 (Robinson et al, ). Although oxaliplatin causes neuronal death in all studied intestinal regions, it seems that neurons in the distal colon are more susceptible to oxaliplatin‐induced damage than neurons in the proximal colon and ileum.…”

“…There may be many reasons for these regional differences, but it should be noted that the proportion of the nNOS‐IR neurons was significantly increased in the distal, but not proximal colon, consistent with a role for NO in oxaliplatin‐induced enteric neuronal loss. Moreover, repeated in vivo oxaliplatin administration induces decreases in glial fibrillary acidic protein‐IR enteric glia, contrasting with increases in s100β‐IR enteric glial cells in both the myenteric and submucosal ganglia at day 14 after commencement of treatment (Robinson et al, ).…”

The pathogenesis of mucositis: updated perspectives and emerging targets

“…However, there is a dearth of papers that have directly examined changes in motility in response to cancer therapy, both in preclinical models and the clinic. Some papers have recently assessed changes in enteric neuron populations following chemotherapy [73,74] and provide mechanistic insight to the underlying functional changes. Furthermore, neural support cells, enteric glia, have been shown in vitro to mitigate altered permeability following exposure to inflammatory cytokines [75].…”

Chemotherapy-Induced Constipation and Diarrhea: Pathophysiology, Current and Emerging Treatments

“…Similar results have been demonstrated following oxaliplatin administration in mice, and cisplatin administration in rats, where enteric neuronal loss was associated with a reduction in colonic motor activity and reduced GI transit time, respectively (Vera et al, 2011; Wafai et al, 2013). Loss of enteric neurons following administration of cisplatin and oxaliplatin has been correlated with an increase in a population of the myenteric neurons expressing neuronal nitric oxide synthase (Vera et al, 2011; Wafai et al, 2013) and changes in glial cell populations (Robinson et al, 2016). These studies emphasize the importance of enteric neuronal integrity in GI function whilst suggesting neuroprotection as a potential therapeutic pathway for the treatment of chemotherapy-induced GI disorders.…”