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Protective effect of metronidazole on uncoupling mitochondrial oxidative phosphorylation induced by NSAID: a new mechanism
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  1. A Z A Leitea,
  2. A M Sipahia,
  3. A O M C Damiãoa,
  4. A M M Coelhoa,
  5. A T Garcezb,
  6. M C C Machadoa,
  7. C A Buchpiguelb,
  8. F P Lopassoa,
  9. M L Lordelloa,
  10. C L O Agostinhoa,
  11. A A Laudannaa
  1. aDepartment of Gastroenterology, University of São Paulo (USP) Medica1 School, São Paulo, Brazil, Laboratory of Medical Investigation (LIM 07), General Clinics Hospital of the USP Medical School, bDepartment of Radiology USP Medical School, São Paulo, Brazil, General Clinics Hospital of the USP Medical School
  1. Dr A Z A Leite, 10900 Euclid Avenue, BRB 409B, Cleveland, Ohio, USA 44106-4952. azl{at}po.cwru.edu

Abstract

BACKGROUND The pathogenesis of non-steroidal anti-inflammatory drug (NSAID) enteropathy is complex. It involves uncoupling of mitochondrial oxidative phosphorylation which alters the intercellular junction and increases intestinal permeability with consequent intestinal damage. Metronidazole diminishes the inflammation induced by indomethacin but the mechanisms remain speculative. A direct effect on luminal bacteria has traditionally been thought to account for the protective effect of metronidazole. However, a protective effect of metronidazole on mitochondrial oxidative phosphorylation has never been tested.

AIMS To assess the protective effect of metronidazole on mitochondrial uncoupling induced by indomethacin and also on the increased intestinal permeability and macroscopic damage.

MATERIAL AND METHODS The protective effect of metronidazole was evaluated in rats given indomethacin; a macroscopic score was devised to quantify intestinal lesions, and intestinal permeability was measured by means of 51Cr-ethylenediaminetetraacetic acid. The protective effect of metronidazole against mitochondrial uncoupling induced by indomethacin was assessed using isolated coupled rat liver mitochondria obtained from rats pretreated with metronidazole or saline.

RESULTS Metronidazole significantly reduced the macroscopic intestinal damage and increase in intestinal permeability induced by indomethacin; furthermore, at the mitochondrial level, it significantly reduced the increase in oxygen consumption in state 4 induced by indomethacin and caused less reduction of the respiratory control rate.

CONCLUSION Our study confirmed the beneficial effects of metronidazole on intestinal damage and intestinal permeability, and demonstrated, for the first time, a direct protective effect of metronidazole on uncoupling of mitochondrial oxidative phosphorylation caused by NSAIDs.

  • uncoupling agents
  • intestinal permeability
  • enteropathy
  • non-steroidal anti-inflammatory drugs
  • metronidazole
  • indomethacin
  • rats
  • Abbreviations used in this paper

    NSAIDs
    non-steroidal anti-inflammatory drugs
    DMSO
    dimethyl sulphoxide
    51Cr-EDTA
    51Cr-ethylenediaminetetraacetic acid
    EGTA
    ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid
    HEPES
    N-(2-hydroxyethyl)piperazine-N′- (2-ethanesulphonic acid)
    RCR
    respiratory control rate
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  • Abbreviations used in this paper

    NSAIDs
    non-steroidal anti-inflammatory drugs
    DMSO
    dimethyl sulphoxide
    51Cr-EDTA
    51Cr-ethylenediaminetetraacetic acid
    EGTA
    ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid
    HEPES
    N-(2-hydroxyethyl)piperazine-N′- (2-ethanesulphonic acid)
    RCR
    respiratory control rate
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