Efeitos de compostos orgânicos de selênio frente à toxicidade induzida por glutamato e metilmercúrio

• Autor(a) principal: Dalla Corte, Cristiane Lenz
• Data de Publicação: 2012
• Tipo de documento: Tese
• Idioma: por
• Título da fonte: Manancial - Repositório Digital da UFSM
• dARK ID: ark:/26339/001300000c88t
• Texto Completo: http://repositorio.ufsm.br/handle/1/4455
• topic: Compostos orgânicos de selênio; Metilmercúrio; Disfunção mitocondrial; Glutamato; Estresse oxidativo; Organoselenium compounds; Methylmercury; Mitochondrial dysfunction; Glutamate; Oxidative stress; CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA

Organoselenium compounds have been proposed as potential pharmacological agents in the treatment of diseases associated with the oxidative stress. Particularly, ebselen and diphenyl diselenide has been demonstrated as potential antioxidant agents in a variety of experimental models. Thus, the aims of the present study were: to evaluate the effect of ebselen and diphenyl diselenide, as well as, their combination with guanosine on the oxidative stress induced by glutamate in different regions of rat brains (article 1), to test the effects of diphenyl diselenide on mitochondrial dysfunction induced by methylmercury (MeHg) in rat s liver slices (manuscript 1), and investigate the effects of MeHg (5 mg/ kg/ day, i.g.) and/ or diphenyl diselenide (1 mg/ kg /day, i.p.) on mitochondrial dysfunction, thioredoxin reductase (TrxR) activity, mercury levels and locomotor activity after 21 days of treatment in rats (manuscript 2). In article 1, the organoselenium compounds (ebselen and diphenyl diselenide) and guanosine were able to reduce the glutamate-induced reactive oxygen species (ROS) production in cortex, striatum and hippocampus of rat when used isolated or in combination. Guanosine also prevented glutamate uptake in the regions of rat brains tested. The combination of guanosine with organoselenium compounds was more effective against glutamate-induced ROS production than the individual compounds alone. The results in manuscript 1, show that diphenyl diselenide, at low concentrations (0.5 μM), protected against the MeHg-induced mitochondrial dysfunction in liver slices, which may be associated with the interaction between diphenyl diselenide s selenol intermediate and MeHg, with the formation of inert complex(es), as well as, with the antioxidant properties of the selenophenol intermediate. In manuscript 2, it was observed that diphenyl deiselenide protected against thiol depletion by MeHg in cerebral and hepatic mitochondria, but it didn t prevent the mitochondrial dysfunction induced by MeHg in brain and liver, nor protected from TrxR activity inhibition by MeHg in brain, liver and kidney. Moreover, the co-treatment with MeHg and diphenyl diselenide caused an increase in mercury deposition in brain and liver, increased the motor deficits and the loss of body weight. Taken together, the results present here reinforce the central role of the mitochondrial dysfunction on the toxicity induced by MeHg both in vivo and in vitro, and the role of TrxR as a molecular target for MeHg in rats. Moreover, the results indicate that organoselenium compounds, such as ebselen and diphenyl diselenide, are promising agents against the oxidative damage induced by both glutamate and MeHg in vitro, however, caution must be taken on the extrapolation of these results to in vivo situations, since the co-treatment with diphenyl diselenide and MeHg increased the neurotoxicity in rats. .