Brain age-dependent effects of acute endotoxemia on oxidative damage and mitochondrial function

CIMOLAI, MARÍA CECILIA; VANASCO, VIRGINIA; EVELSON, PABLO; BUGGER, HEIKO; ALVAREZ, SILVIA

Friburgo

Congreso; 17th European Bioenergetic Conference; 2012

EBEC

Brain age-dependent effects of acute endotoxemia on oxidative damage and mitochondrial function.   MC. Cimolai1, V. Vanasco1, P. Evelson1, H. Bugger2, S. Alvarez1   1 Laboratory of Free Radical Biology, Physical Chemistry Division, School of Pharmacy and Biochemistry, University of Buenos Aires. 2 Department of Internal Medicine, Division of Cardiology, University of Freiburg, Freiburg, Germany.   Endotoxemia is a systemic inflammatory state secondary to the activation of the innate immune system. Its pathogenic mechanism is still incompletely understood. Impaired mitochondrial function and increased oxidative damage have been proposed as responsible for the septic final state: multi-organ failure. The incidence of endotoxemia and sepsis is increased in elderly adults, and age is an independent predictor of mortality. The mitochondrial  theory of aging hypothesizes that mitochondria are the pacemakers of tissue aging due to the continuous production of oxygen and nitrogen free radicals and related reactive species. Endotoxemia and aging are situations characterized by an increased damage to cellular structures due to increased or cumulative production of reactive oxygen species. Thus, the aim of the present work was to study the occurrence of oxidative stress and mitochondrial contribution to the response in an acute model of endotoxemia, analyzing the effect in animals grouped by age (young adults: 3 mo.; old adults: 12 mo.). O2 utilization was assessed by measuring O2 consumption in whole tissue and mitochondria. Whole tissue O2 consumption was found invariable in young animals (control: 3.88 ± 0.42. 103 nmol O2 / min. g tissue), being non-mitochondrial O2 consumption increased in a 45% (p<0.01) in endotoxemic young mice. The percentage of O2 used by the mitochondria (KCN sensitive) was decreased by 17% (p<0.01) in LPS-treated animals. Furthermore, Complex I activity was found 10% decreased in LPS-treated young animals (p<0.05) and the same effect was observed due to the aging process itself. Organ Chemiluminesce (CL) was measured as a marker of steady-state concentration of oxidants and occurrence of oxidative stress. Age was found to be a source of variation, old control animals present a two-fold increase in the CL value (31.0 ± 2 cps/cm2; p<0.0001). LPS treatment produced a 65% increase in CL only in young animals (control value: 15.0 ± 2 cps/cm2; p<0.001). Stable oxidized products, measured as TBARS in brain tissue homogenates, were found also increased in a 66% in young animals due to the treatment with LPS (control: 0.210 ± 0.03 nmol MDA/mg protein).These results suggest that endotoxemia induces changes in the cellular utilization of oxygen, generating increased production of oxidative species and decreasing mitochondrial function. Young mice group demonstrated to be more sensitive to the endotoxemic challenge than the old mice group.