Probucol modulates oxidative stress and excitotoxicity in Huntington's disease models in vitro.

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disease characterized by symptoms attributable to the death of striatal and cortical neurons. The molecular mechanisms mediating neuronal death in HD seem to be related to oxidative stress, excitotoxicity and misbalance in energetic metabolism. In this study we evaluated the potential relationship between energetic impairment, excitotoxicity and oxidative stress in rat striatal slices exposed to quinolinic acid (QA; as an excitotoxic model), 3-nitropropionic acid (3-NP; as an inhibitor of mitochondrial succinate dehydrogenase), as well as a combined model produced by the co-administration of these two toxins at subtoxic concentrations. We took advantage of the direct antioxidant/scavenger properties of Probucol in order to investigate the role of reactive oxygen species (ROS) in mediating the toxicity of both compounds alone or in association. Experiments with MK-801 (a NMDA type glutamate receptor antagonist) and succinate (an energy precursor agent) were also performed in an attempt to better comprehend the mechanisms of damage and neuroprotection. QA (1 mM), 3-NP (1 mM) and QA plus 3-NP (0.1 mM of both) significantly induced mitochondrial dysfunction and produced an increase in ROS generation, as well as a significant increase in lipid peroxidation in striatal slices. Probucol (10 and 30 µM) prevented ROS formation and lipid peroxidation in all used models, but did not protect against the mitochondrial dysfunction induced by 3-NP (only by QA or QA plus 3-NP). Sodium succinate (1 mM) protected the striatal slices only against 3-NP-induced mitochondrial dysfunction. On the other hand, MK-801 protected against mitochondrial dysfunction in all used models. Our data suggest that the two studied toxic models (QA and 3-NP) or the combined model (QA plus 3-NP) can generate complex patterns of damage, which involve metabolic compromise, ROS formation, and oxidative stress. Moreover, a partial inhibition of SDH by subtoxic 3-NP and moderate excitotoxicty by subtoxic QA are potentiated when both agents are associated. The toxic action of QA plus 3-NP seems to be involved with Ca2+ metabolism and ROS formation, and can be prevented or attenuated by antioxidant/scavenger compounds and NMDAr antagonists.

Chronic treatment with fluphenazine alters parameters of oxidative stress in liver and kidney of rats.

The aim of this study was to assess the toxic effects of chronic exposure to fluphenazine in liver and kidney of rats, as well as the possible protective effect of diphenyl diselenide on the fluphenazine-induced damage. Long-term treatment with fluphenazine caused an increase in lipid peroxidation levels in liver and kidney homogenates. Diphenyl diselenide treatment did not affect delta-aminolevulinate dehydratase (delta-ALA-D) activity, but fluphenazine alone or in combination with diphenyl diselenide showed an inhibitory effect on delta-ALA-D activity in liver. Diphenyl diselenide plus fluphenazine treatment increased the reactivation index of hepatic delta-ALA-D by approximately 80%. Superoxide dismutase activity decreased in liver of rats treated with fluphenazine alone. The combined treatment with fluphenazine and diphenyl diselenide was able to ameliorate superoxide dismutase activity in liver of rats. Catalase activity was augmented in liver from rats treated with fluphenazine, and this increase was prevented when diphenyl diselenide was co-administered. Taken together, these results indicate that the association of diphenyl diselenide with fluphenazine could protect the liver from lipid peroxidation and ameliorate superoxide dismutase and catalase activities. Moreover, our data point to the relationship between the oxidative stress and fluphenazine treatment in liver and kidney of rats.

Butane-2,3-dionethiosemicarbazone: an oxime with antioxidant properties.

Oximes are compounds generally used to reverse the acetylcholinesterase (AChE) inhibition caused by organophosphates (OPs). The aim of this study was to examine the capacity of the butane-2,3-dionethiosemicarbazone oxime to scavenge different forms of reactive species (RS) in vitro, as well as counteract their formation. The potential antioxidant and toxic activity of the oxime was assayed both in vitro and ex vivo. The obtained results indicate a significant hydrogen peroxide (H2O2), nitric oxide (NO) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity at 0.275, 0.5 and 5microM of oxime, respectively (p< or =0.05). The oxime exhibited a powerful inhibitory effect on dihydroxybenzoate formation (25microM) (p< or =0.05) and also decreased deoxyribose degradation induced by Fe2+ and via Fenton reaction (0.44 and 0.66mM, respectively) (p< or =0.05). The oxime showed a significant inhibitory effect on sigma-phenantroline reaction with Fe2+ (0.4mM) suggesting a possible interaction between the oxime and iron. A significant decrease in the basal and pro-oxidant-induced lipid peroxidation in brain, liver, and kidney of mice was observed both in vitro and ex vivo (p< or =0.05). In addition, in our ex vivo experiments the oxime did not depict any significant changes in thiol levels of liver, kidney and brain as well as did not modify the delta-aminolevulinate dehydratase (delta-ALA-D) activity in these tissues. Taken together our results indicate an in vitro and ex vivo antioxidant activity of the oxime possibly due to its scavenging activity toward different RS and a significant iron interaction.

Antioxidant properties of oxime 3-(phenylhydrazono) butan-2-one.

Oximes are a class of compounds normally used to reverse the acetylcholinesterase (AChE) inhibition caused by organophosphates (OPs). Conversely, researches focusing on the possible antioxidant properties of these compounds are lacking in the literature. The aim of this study was to investigate the potential antioxidant and toxic properties of 3-(phenylhydrazono) butan-2-one oxime in mice. In vitro, hydrogen peroxide-induced lipid peroxidation was decreased by low concentrations of the oxime (0.1-1.0 microM); (P < 0.05). Similarly, lipoperoxidation induced by malonate and iron (Fe2+) was significantly decreased by the oxime (0.4-1.0 microM) (P < 0.05). Oxime pre-treatment did not modify the basal peroxidation level nor prevented the induced lipid peroxidation determined ex-vivo. The present results suggest that 3-(phenylhydrazono) butan-2-one oxime could be a good antioxidant compound. The absence of toxicity signs after in vivo administration of 3-(phenylhydrazono) butan-2-one oxime to mice may indicate that it could be a safe drug for further studies.