Potentially Lethal Effects of Indomethacin and Exercise Training in Mice

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used by athletes to reduce or prevent exercise-induced inflammation and pain. NSAID use however, has been linked to various side effects including mucosal damage in the gastrointestinal tract (GI). Stressful exercise can also cause GI distress and increased GI permeability that can allow translocation of gut bacteria to blood (endotoxemia). We hypothesized that the combined effects could contribute to exaggerated fatigue and potentially lethal conditions such as endotoxic shock and systemic inflammatory response syndrome. PURPOSE: To examine the effects of the NSAID mdomethacm (IND) and intense exercise training on sickness behavior (fatigue, weight loss, and decreased food and fluid consumption) and mortality in mice. METHODS: Male ICR mice (n=10/group) were randomly assigned to one of four treatment groups as follows: exercise 2.5mg/Kg IND (Ex-2.5), control 2.5mg/Kg IND (Con-2.5), exercise 5.0mg/Kg IND (Ex-5.0) and control 5.0mg/Kg IND (Con-5.0). Body weight and food and fluid consumption were recorded for 7 days prior to exercise training and IND treatment. Mice were given IND via gavage 1h prior to exercise or rest for 14 days. Exercise mice were run on a treadmill at 30m/min and 8% grade for a period of 90mins or until they reached volitional fatigue. Treadmill run times, body weight, food and fluid intake and mortality were recorded daily. RESULTS: Treadmill run times were reduced from baseline starting on day 2 (5.0mg/ Kg IND), or day 3 (2.5mg/Kg IND). Body weight and food and fluid consumption decreased significantly in 5mg/Kg IND versus baseline and 2.5mg/Kg IND and the addition of exercise had no additive effect. 5.0mg/Kg IND significantly increased mortality versus 2.5mg/Kg (Con-5.0: 40% and Con-2.5: 0%) and the addition of exercise to 2.5mg/Kg and 5.0mg/Kg further increased mortality (Ex-2.5: 33% and Ex-5.0: 67%). CONCLUSION: Results indicate that intense exercise training combined with indomethacin use can be a lethal combination in mice. Future research is needed to test the hypothesis that this effect is due increased GI permeability and endotoxemia, and whether human are also at risk.