title: A superoxide dismutase mimetic with catalase activity (EUK-8) reduces the organ injury in endotoxic shock.
abstract: Reactive oxygen species contribute to the multiple organ failure in endotoxic shock. Here, we investigate the effects of a salen-manganese complex, which exhibits both superoxide dismutase and catalase activity (EUK-8), on the circulatory failure, renal and liver injury and dysfunction caused by endotoxin in the anaesthetised rat. Endotoxaemia (6 mg/kg i.v., Escherichia coli lipopolysaccharide) for 6 h caused hypotension, renal dysfunction and liver injury. Treatment of rats with EUK-8 (0.3 or 1 mg/kg bolus injection followed by an infusion of 0.3 or 1 mg/kg/h) attenuated the renal and liver injury and dysfunction in a dose-related fashion. In addition, the higher dose of EUK-8 attenuated the delayed hypotension caused by endotoxin in the rat. Thus, an enhanced formation of reactive oxygen species importantly contributes to the circulatory failure, as well as the organ injury and dysfunction associated with endotoxic shock. We propose that small molecules, which have the catalytic activity of both superoxide dismutase and catalase, may represent a novel therapeutic approach for the therapy of endotoxic shock.
authors.affiliation: The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, Charterhouse Square, EC1M 6BQ, London, UK.
authors.forename: Michelle C
authors.initials: MC
authors.lastname: McDonald
authors.forename: Roberta
authors.initials: R
authors.lastname: d'Emmanuele di Villa Bianca
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Wayman
authors.forename: Aldo
authors.initials: A
authors.lastname: Pinto
authors.forename: Martyn A
authors.initials: MA
authors.lastname: Sharpe
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.forename: Prabal K
authors.initials: PK
authors.lastname: Chatterjee
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiemermann
mesh_terms: D000818:Animals; D001775:Blood Circulation / Q000187:drug effects; D002374:Catalase / Q000737:chemistry*; D004731:Endotoxins; D005029:Ethylenediamines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D007022:Hypotension / Q000517:prevention & control; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D018716:Molecular Mimicry; D009102:Multiple Organ Failure / Q000209:etiology / Q000517:prevention & control*; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000209:etiology / Q000517:prevention & control; D013482:Superoxide Dismutase / Q000737:chemistry*; D013997:Time Factors
chemical_list: D004731:Endotoxins; D005029:Ethylenediamines; D008070:Lipopolysaccharides; D009942:Organometallic Compounds; C090577:N,N'-bis(salicylideneamino)ethane-manganese(II); D002374:Catalase; D013482:Superoxide Dismutase