Effects of acute iron overload on Nrf2-related glutathione metabolism in rat brain.

PILONI NE; VARGAS R; FERNANDEZ V.; VIDELA L.A; PUNTARULO S.

BIOMETALS

SPRINGER

Año: 2021

0966-0844

Iron (Fe) overload triggers free radicalproduction and lipid peroxidation processes that maylead to cell death (ferroptosis). The hypothesis of thiswork was that acute Fe-dextran treatment triggersNrf2-mediated antioxidant regulation in rat braininvolving glutathione (GSH) metabolism. Over theinitial 8 h after Fe-dextran administration (single doseof 500 mg Fe-dextran/kg), total Fe, malondialdehyde(MDA) content, glutathione peroxidase (GPx), GPxSe dependent (GPx-Se) and glutathione S-transferases(GST) activities were increased in rat whole brain. Thecontent of GSH and the activity of glutathionereductase (GR) showed decreases (p 0.05) after 6and 8 h post injection in cortex. A significant increasein nuclear Nrf2 protein levels over control values wasachieved after 6 h of Fe-dextran administration, whileno significant differences were observed in the cytosolic fraction. Nuclear Nrf2/cytosolic Nrf2 ratiosshowed enhancement (p 0.05) after 6 h of Feoverload, suggesting a greater translocation of thefactor to the nucleus. No significant differences wereobserved in the expression of Keap1 in nuclear orcytosolic extracts. It is concluded that acute Feoverload induces oxidative stress in rat brain withthe concomitant lipid peroxidation increase and GSHdepletion, leading to the elevation of Nrf2-controlledGPx, GPx-Se and GST protein expression as aprotective adaptive response. Further studies arerequired to fully comprehend the complex networkof interrelated processes keeping the balance of GSHfunctions as chelator, antioxidant and redox buffer inthe understanding of the ferroptotic and hormeticmechanisms triggered by Fe overload in brain.