Copper and iron overloads induce an adaptive response of cytosolic antioxidant enzymes mediated by Nrf-2

ACOSTA, JM; DAMIANO, A.; TORTI, H; SAPORITO MAGRIÑÁ, C.; FUDA, J; REPETTO, M; MUSACCO SEBIO, R; CASTRO PARODI, M; BOVERIS, A

Buenos Aires

Congreso; III International Congress of Translational Medicine; 2016

Maestría Internacional en Ciencias Biomédicas, Facultad de Farmacia y Bioquímica y Facultad de Medicina, UBA

Introduction: The bioelements iron (Fe) and copper (Cu) exhibit the phenomenon of hormesis: they are need at low concentrations for health in mammals but at higher than normal concentrations they become toxic. Both metals are known by its ability to catalyze the formation of OH? radical through the Fenton/Haber-Weiss reaction. Fe and Cu overloads produce oxidative damage in rat brain, among other tissues. Hypothesis: Fe- and Cu- induced oxidative damage to rat brain is responsible for an adaptive response of the antioxidant enzymes that is regulated at a transcriptional level: the activation of Nrf2-ARE signaling pathway, one of the physiologic mechanisms in cellular defense against oxidative stress that controls the expression of genes whose proteins products, is involved in detoxification and elimination of reactive oxidants and by enhancing cellular antioxidant content. The aim of the present study was to determine the characteristics of the adaptive response in rat brain after Fe and Cu ions overloads. Methodology: The time course of the genomic response that involves the expression of cytosolic superoxide dismutase (SOD1), catalase and Nrf2 in rat brain was evaluated in the period of 0-24 h after Fe and Cu ions loads: Sprague-Dawley male rats (220 ± 8 g) were given intraperitoneally single doses of 13.5 mg FeSO4/100 g or of 2.8 mg CuSO4/100 g and the brain response to these overdoses was followed. The activities and expressions of brain cytosolic superoxide dismutase (SOD1), and catalase were determined as well as the levels of the regulatory transcription factor Nrf2 in the cytosol and nucleus. The ratio of reduced glutathione/oxidized glutathione (GSH/GSSG) was determined as a reflection of the ?SH/-SS- ratio of regulatory control proteins of neuronal metabolism and function. Results: SOD1, catalase, glutathione transferase and Nrf2 increased their activities/expressions in an adaptive response to oxidative stress: after 24 h of Fe and Cu administration, expression was increased: SOD1, 2.5 and 1.8 times respectively; catalase, 2 and 2.5 times (p