Efeitos do difenil disseleneto sobre a disfunção mitocondrial na insuficiência hepática aguda induzida por paracetamol em camundongos

Abstract

Acute liver failure (ALF) induced by acetaminophen (APAP) is a complex process associated with glutathione (GSH) depletion, energetics metabolism changes and mitochondrial dysfunction, resulting in the impairment of maintenance of tissue normal function. On this matter, organoselenium compounds, such as diphenyl diselenide (PhSe)2, have been highlighted in the last years due to the antioxidant properties and the hepatoprotective effects, however, the (PhSe)2 hepatoprotection mechanism remains unclear. So, this work was aimed to deepen into understanding of the effects of (PhSe)2 on the mitochondrial dysfunction as well as the signaling pathway during the ALF induced by APAP. Firstly, it was performed a comparative study between the organoselenium compound and the classical antidote (N-acetylcysteine, NAC) in the liver homogenate. (PhSe)2 presented similar results to the NAC reducing the oxidative damage markers, maintaining the GSH levels and enhancing the survival after the APAP overdose. The treatment with (PhSe)2 reduced plasmatic levels of transaminases (aspartate and alanine aminotransferase) and the morphological/histological changes. In addition, (PhSe)2 was able to reduce significantly the oxidative damage such as lipid peroxidation, reactive oxygen and nitrogen species generation, mitochondrial protein carbonylation and mitochondrial viability after ALF induced by APAP. In this context, the levels of non enzymatic antioxidants, such as GSH, and enzymatic antioxidants, such as catalase, Mn superoxide dismutase, glutathione peroxidase and glutathione reductase remained to the control levels. In general, the results noticed in this work the probably (PhSe)2 mechanism is closely related with the maintenance of antioxidant defense system and inhibition of mitochondrial transition permeability (MPT) indicated by reduction of mitochondrial swelling, activity preservation of respiratory complexes I, II and ATPase, and maintenance of H+ gradient with the mitochondrial membrane potential (Δψm) generation. It was observed that (PhSe)2 was able to limit the impairment of mitochondrial bioenergetics function with the normalization of oxidative phosphorilation (OXPHOS) and activation of heat shock protein pathway through the enhance of HSP70 levels, which in turn, modulates the MPT protecting the mitochondrial viability. (PhSe)2 treatment was able to maintain the appropriated levels of cytokines associated with the liver recovery, such as tumoral necrosis factor alfa (TNF-α), interleukin 6 (IL-6) and nuclear factor kappa B (NF-κB). Moreover, the integrity of cellular bioenergetic function could be associated with the increase of peroxisome proliferator-activated receptor-γ coactivator (PGC-1α), helping to restore the nuclear respiratory factor 1 (NRF1) levels associated with the mitochondrial biogenesis. Finally, (PhSe)2 could be a useful therapeutic alternative that would contribute to the liver recovery, controlling the quality of mitochondrial function and maintaining homeostasis and cellular health.