Rotenone, a mitochondrial respiratory complex I inhibitor, ameliorates lipopolysaccharide/D-galactosamine-induced fulminant hepatitis in mice.
The syntheses of inflammatory mediators are energy-intensive processes and the mitochondria play pivotal roles in supporting these energy-requiring molecular responses. In the present studies, a mitochondrial respiratory complex I inhibitor rotenone was administrated in mice with lipopolysaccharide/D-galactosamine (LPS/D-Gal)-induced fulminant liver injury and the prophylactic and therapeutic effects on tissue injury were evaluated. We found that pretreatment with rotenone suppressed the elevation of plasma aminotransferases, alleviated the histopathological abnormalities and improved the survival rate of LPS/D-Gal-challenged mice. Pretreatment with rotenone has no obvious effects on hepatic malondialdehyde (MDA) contents but it significantly inhibited the up-regulation of both hepatic mRNA level and plasma protein level of TNF-α and IL-6. In the rotenone-pretreated group, the elevation of hepatic caspase-3, caspase-8 and caspase-9 activities induced by LPS/D-Gal decreased and rotenone reduced the count of TUNEL-positive apoptotic hepatocytes. In addition, posttreatment with rotenone at 1h after LPS/D-Gal challenge also suppressed the elevation of plasma aminotransferases. These data suggest that mitochondrial complex I inhibition might be a potential approach for the control of inflammation.
Department of Physiology, Chongqing Medical University, Chongqing, China.
Qing
Q
Ai
Department of Pathophysiology, Chongqing Medical University, Chongqing, China.
Yuping
Y
Jing
Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing, China.
Rong
R
Jiang
Department of Pathophysiology, Chongqing Medical University, Chongqing, China.
Ling
L
Lin
Hospital of Chongqing University of Arts and Sciences, Chongqing, China.
Jie
J
Dai
Department of Pathophysiology, Chongqing Medical University, Chongqing, China.
Qian
Q
Che
Department of Pathophysiology, Chongqing Medical University, Chongqing, China.
Dan
D
Zhou
Department of Pathophysiology, Chongqing Medical University, Chongqing, China.
Mengying
M
Jia
Department of Pharmacology, Chongqing Medical University, Chongqing, China.
Jingyuan
J
Wan
Department of Pathophysiology, Chongqing Medical University, Chongqing, China. Electronic address: zhangli@cqmu.edu.cn.
Li
L
Zhang
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D015536:Down-Regulation; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors; D004734:Energy Metabolism / Q000187:drug effects; D005688:Galactosamine / Q000008:administration & dosage; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D012402:Rotenone / Q000008:administration & dosage* / Q000494:pharmacology; D000637:Transaminases / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D014475:Uncoupling Agents / Q000008:administration & dosage* / Q000494:pharmacology
D018836:Inflammation Mediators; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D014475:Uncoupling Agents; D012402:Rotenone; D005688:Galactosamine; D000637:Transaminases; D020169:Caspases; D042967:Electron Transport Complex I
Hepatitis; Inflammation; Lipopolysaccharide; Mitochondrial complex; Rotenone