title: MitoQ modulates oxidative stress and decreases inflammation following hemorrhage.
abstract: BACKGROUND
  Oxidative stress associated with hemorrhagic shock and reperfusion (HSR) results in the production of superoxide radicals and other reactive oxygen species, leading to cell damage and multiple-organ dysfunction. We sought to determine if MitoQ, a mitochondria-targeted antioxidant, reduces morbidity in a rat model of HSR by limiting oxidative stress.
  
  
  METHODS
  HSR was achieved in male rats by arterial blood withdrawal to a mean arterial pressure of 25 ± 2 mm Hg for 1 hour before resuscitation. MitoQ (5 mg/kg), TPP (triphenylphosphonium, 5 mg/kg) or saline (0.9% vol./vol.) was administered intravenously 30 minutes before resuscitation, followed by an intraperitoneal administration (MitoQ, 20 mg/kg) immediately after resuscitation (n = 5 per group). Morbidity was assessed based on cumulative markers of animal distress (0-10 scale). Rats were sacrificed 2 hours after procedure completion, and liver tissue was collected and processed for histology or assayed for lipid peroxidation (thiobarbituric acid reactive substance [TBARS]) or endogenous antioxidant (catalase, glutathione peroxidase [GPx], and superoxide dismutase) activity.
  
  
  RESULTS
  HSR significantly increased morbidity as well as TBARS and catalase activities versus sham. Conversely, no difference in GPx or superoxide dismutase activity was measured between sham, HSR, and TPP, MitoQ administration reduced morbidity versus HSR (5.8 ± 0.3 vs. 7.6 ± 0.3; p < 0.05), while TPP administration significantly reduced hepatic necrosis versus both HSR and HSR-MitoQ (1.2 ± 0.1 vs. 2.0 ± 0.2 vs. 1.9 ± 0.2; p < 0.05, n = 5). Analysis of oxidative stress demonstrated increased TBARS and GPx in HSR-MitoQ versus sham (12.0 ± 1.1 μM vs. 6.2 ± 0.5 μM and 37.9 ± 3.0 μmol/min/mL vs. 22.9 ± 2.7 μmol/min/mL, TBARS and GPx, respectively, n = 5; p < 0.05). Conversely, catalase activity in HSR-MitoQ was reduced versus HSR (1.96 ± 1.17 mol/min/mL vs. 2.58 ± 1.81 mol/min/mL; n = 5; p < 0.05). Finally, MitoQ treatment decreased tumor necrosis factor α (0.66 ± 0.07 pg/mL vs. 0.92 ± 0.08 pg/mL) and interleukin 6 (7.3 ± 0.8 pg/mL vs. 11 ± 0.9 pg/mL) versus HSR as did TPP alone (0.58 ± 0.05 pg/mL vs. 0.92 ± 0.08 pg/mL; 6.7 ± 0.6 pg/mL vs. 11 ± 0.9 pg/mL; n = 5; p < 0.05).
  
  
  CONCLUSIONS
  Our data demonstrate that MitoQ treatment following hemorrhage significantly limits morbidity and decreases hepatic tumor necrosis factor α and interleukin 6. In addition, MitoQ differentially modulates oxidative stress and hepatic antioxidant activity.
authors.affiliation: From the FH "Sammy" Ross Trauma Center (R.D.P., J.H.S., K.L.K., T.T.H., I.H.M., S.L.E.), Department of Surgery, Carolinas Medical Center, Charlotte, North Carolina; and MRC Mitochondrial Biology Unit (M.P.M.), Wellcome Trust, Cambridge, United Kingdom.
authors.forename: Rebecca D
authors.initials: RD
authors.lastname: Powell
authors.forename: Jacob H
authors.initials: JH
authors.lastname: Swet
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Kennedy
authors.forename: Toan T
authors.initials: TT
authors.lastname: Huynh
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.forename: Iain H
authors.initials: IH
authors.lastname: Mckillop
authors.forename: Susan L
authors.initials: SL
authors.lastname: Evans
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006470:Hemorrhage / Q000150:complications*; D007150:Immunohistochemistry; D007249:Inflammation / Q000517:prevention & control; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation / Q000379:methods; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D009943:Organophosphorus Compounds; D017392:Thiobarbituric Acid Reactive Substances; D014451:Ubiquinone; C429014:mitoquinone; D002374:Catalase