Protective effect of metronidazole on uncoupling mitochondrial oxidative phosphorylation induced by NSAID: a new mechanism

Background-The pathogenesis of nonsteroidal anti-inflammatory drug (NSAID) enteropathy is complex. It involves uncoupling of mitochondrial oxidative p hosphorylation which alters the intercellular junction and increases intest inal permeability with consequent intestinal damage. Metronidazole diminish es the inflammation induced by indomethacin but the mechanisms remain specu lative. A direct effect on luminal bacteria has traditionally been thought to account for the protective effect of metronidazole. However, a protectiv e effect of metronidazole on mitochondrial oxidative phosphorylation has ne ver been tested. Aims-To assess the protective effect of metronidazole on mitochondrial unco upling induced by indomethacin and also on the increased intestinal permeab ility and macroscopic damage. Material and Methods-The protective effect of metronidazole was evaluated i n rats given indomethacin; a macroscopic score was devised to quantify inte stinal lesions, and intestinal permeability was measured by means of Cr-51- ethylenediaminetetraacetic acid. The protective effect of metronidazole aga inst mitochondrial uncoupling induced by indomethacin was assessed using is olated coupled rat liver mitochondria obtained from rats pretreated with me tronidazole or saline. Results-Metronidazole significantly reduced the macroscopic intestinal dama ge and increase in intestinal permeability induced by indomethacin; further more, at the mitochondrial level, it significantly reduced the increase in oxygen consumption in state 4 induced by indomethacin and caused less reduc tion of the respiratory control rate. Conclusion-Our study confirmed the beneficial effects of metronidazole on i ntestinal damage and intestinal permeability, and demonstrated, for the fir st time, a direct protective effect of metronidazole on uncoupling of mitoc hondrial oxidative phosphorylation caused by NSAIDs.