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


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


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 (51)Cr-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.


CONCLUSIONS
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.
Leite
A Z
AZ
Department of Gastroenterology, University of São Paulo (USP) Medica1 School, São Paulo, Brazil. azl@po.cwru.edu
Sipahi
A M
AM
Damião
A O
AO
Coelho
A M
AM
Garcez
A T
AT
Machado
M C
MC
Buchpiguel
C A
CA
Lopasso
F P
FP
Lordello
M L
ML
Agostinho
C L
CL
Laudanna
A A
AA
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D004347:Drug Interactions; D007213:Indomethacin / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008795:Metronidazole / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects*; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012044:Regression Analysis; D018709:Statistics, Nonparametric; D014475:Uncoupling Agents / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D014475:Uncoupling Agents; D008795:Metronidazole; D007213:Indomethacin