title: Acute ketamine impairs mitochondrial function and promotes superoxide dismutase activity in the rat brain.
abstract: BACKGROUND
  Ketamine is often associated with altered mitochondrial function and oxidative stress. Nevertheless, limited data are still available regarding the in vivo action of ketamine in mitochondrial bioenergetics and redox state. Accumulating evidence supports a role for nitric oxide (NO) as a possible modulator of ketamine's side effects. In the present study, we investigated the role of NO modulation on ketamine anesthesia at the level of brain mitochondrial function and redox status.
  
  
  METHODS
  Adult male rats received a single dose of ketamine (50, 100, or 150 mg/kg IP) or a combination of ketamine and N-nitro-L-arginine (3 mg/kg IP). Animals were killed 6 hours after treatment. Brain and blood samples were collected for plasma NO determination and mitochondria isolation. Several variables of brain mitochondrial function were evaluated.
  
  
  RESULTS
  Ketamine interfered with complex I function, revealing increased oxygen consumption in state 4, impaired oxidative phosphorylation efficiency of glutamate-malate substrate, and decreased NADH-ubiquinone oxidoreductase activity. In addition, mitochondrial NO synthase (mtNOS) activity and NO plasma levels were increased for the 50 and 100 mg/kg doses. Ketamine administration increased hydrogen peroxide generation and triggered superoxide dismutase activity. All these effects could totally or partially be prevented by mtNOS inhibition through N-nitro-L-arginine.
  
  
  CONCLUSIONS
  Acute ketamine administration impaired the function of mitochondrial complex I leading to increased mtNOS activity, increased generation of hydrogen peroxide and NO, resulting in superoxide dismutase triggering, and improved antioxidant activity. The present findings clarify the role of NO modulation in ketamine anesthesia, providing new data on a relevant clinical mechanism.
authors.affiliation: From the *Centre for the Research and Technology of Agro-Environmental and Biological Sciences, CITAB, University of Trás-os-Montes and Alto Douro, UTAD, Quinta de Prados, Vila Real, Portugal; †Laboratory Animal Science, IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal; ‡Chemistry Centre, Universidade de Trás-os-Montes e Alto Douro, UTAD, Vila Real, Quinta de Prados, Vila Real, Portugal; and §Addiction Biology Group, IBMC - Instituto de Biologia Molecular e Celular, Porto, Portugal.
authors.forename: Carlos
authors.initials: C
authors.lastname: Venâncio
authors.forename: Luís
authors.initials: L
authors.lastname: Félix
authors.forename: Vanessa
authors.initials: V
authors.lastname: Almeida
authors.forename: João
authors.initials: J
authors.lastname: Coutinho
authors.forename: Luís
authors.initials: L
authors.lastname: Antunes
authors.forename: Francisco
authors.initials: F
authors.lastname: Peixoto
authors.forename: Teresa
authors.initials: T
authors.lastname: Summavielle
mesh_terms: D000758:Anesthesia; D000778:Anesthetics, Dissociative / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000378:metabolism*
chemical_list: D000778:Anesthetics, Dissociative; D000975:Antioxidants; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D007649:Ketamine; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D019331:NG-Nitroarginine Methyl Ester