dizocilpine-maleate and diphenyldiselenide

Excessive formation of reactive oxygen species (ROS) and disruption of glutamate uptake have been hypothesized as key mechanisms contributing to quinolinic acid (QA)-induced toxicity. Thus, here we investigate if the use of diphenyl diselenide (PhSe)(2), guanosine (GUO) and MK-801, alone or in combination, could protect rat brain slices from QA-induced toxicity. QA (1 mM) increased ROS formation, thiobarbituric acid reactive substances (TBARS) and decreased cell viability after 2 h of exposure. (PhSe)(2) (1 μM) protected against this ROS formation in the cortex and the striatum and also prevented decreases in cell viability induced by QA. (PhSe)(2) (5 μM) prevented ROS formation in the hippocampus. GUO (10 and 100 μM) blocked the increase in ROS formation caused by QA and MK-801 (20 and 100 μM) abolished the pro-oxidant effect of QA. When the noneffective concentrations were used in combination produced a decrease in ROS formation, mainly (PhSe)(2) + GUO and (PhSe)(2) + GUO + MK-801. These results demonstrate that this combination could be effective to avoid toxic effects caused by high concentrations of QA. Furthermore, the data obtained in the ROS formation and cellular viability assays suggest different pathways in amelioration of QA toxicity present in the neurodegenerative process.

Topics: Animals; Antioxidants; Benzene Derivatives; Brain Chemistry; Cell Survival; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glutamic Acid; Guanosine; Indicators and Reagents; Lipid Peroxidation; Male; Nerve Tissue Proteins; Organoselenium Compounds; Oxidants; Oxidative Stress; Quinolinic Acid; Rats; Reactive Oxygen Species; Thiobarbituric Acid Reactive Substances

Excessive formation of reactive oxygen species (ROS) and disruption of glutamate uptake have been pointed as two key mechanisms in methylmercury-toxicity. Thus, here we investigate the involvement of glutamatergic system in methylmercury (MeHg) neurotoxicity and whether diphenyl diselenide, ebselen and guanosine could protect cortical rat brain slices from MeHg-induced ROS generation. MeHg (100 and 200 microM) increased 2',7'-dichlorodihydrofluorescin (DCFH) oxidation after 2h of exposure. At 50 microM, MeHg increased DCFH oxidation only after 5h of exposure. Guanosine (1 and 5 microM) did not caused any effect per se; however, it blocked the increase in DCFH caused by 200 or 50 microM MeHg. Ebselen (5 and 10 microM) decreased significantly the DCFH oxidation after 2 and 5h of exposure to MeHg. Diphenyl diselenide (5 microM) did not change the basal DCFH oxidation, but abolished the pro-oxidant effect of MeHg. MK-801 also abolished the pro-oxidant effect of MeHg. These results demonstrate for the first time the potential antioxidant properties of organoseleniun compounds and guanosine against MeHg-induced ROS generation after short-term exposure in a simple in vitro model. In conclusion, endogenous purine (guanosine) and two synthetic organoselenium compounds can modulate the pro-oxidant effect of MeHg in cortical brain slices.

Topics: Animals; Azoles; Benzene Derivatives; Brain; Cell Survival; Dizocilpine Maleate; Drug Combinations; Glutamic Acid; Guanosine; Isoindoles; L-Lactate Dehydrogenase; Male; Methylmercury Compounds; Organ Culture Techniques; Organoselenium Compounds; Oxidative Stress; Rats; Rats, Wistar

The aim of this study was to investigate the possible involvement of the glutamatergic system in the toxicity of organochalcogens, since this is an important neurotransmitter system for signal transduction and neural function. The results indicated that 100 microM diphenyl diselenide (PhSe)(2) and diphenyl ditelluride (PhTe)(2) inhibit by 50 and 70% (P<0.05), respectively, [(3)H]glutamate binding in vitro. Acute administration of 25 micromol/kg (PhSe)(2) or 3 micromol/kg (PhTe)(2) caused a significant reduction in [(3)H]glutamate (30%, P<0.05) or [(3)H]MK-801 binding (30%, P<0.05) to rat synaptic membranes. These results suggest that (PhSe)(2) and (PhTe)(2) affect, in a rather complex way, the glutamatergic system after acute in vivo exposure in rats. In vitro, total [(3)H]GMP-PNP binding was inhibited about 40% at 100 microM (PhSe)(2) and (PhTe)(2). Acute exposure in vivo to (PhSe)(2) decreased the stable [(3)H]GMP-PNP binding to 25% and (PhTe)(2) to 68% of the control value (P<0.05, for both compounds). Simultaneously, the unstable binding of [(3)H]GMP-PNP was decreased about 30 and 50% (P<0.05, for both compounds) after exposure to (PhSe)(2) and (PhTe)(2), respectively. GMP-PNP stimulated adenylate cyclase (AC) activity significantly in control animals. (PhSe)(2)- and (PhTe)(2)-treated animals increased the basal activity of this enzyme, but GMP-PNP stimulation was totally abolished. These results suggest that the toxic effects of organochalcogens could result from action at different levels of neural signal transduction pathways, possibly involving other neurotransmitters besides the glutamatergic system.

Topics: Animals; Benzene Derivatives; Binding, Competitive; Brain; Dithiothreitol; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Glutamic Acid; Guanylyl Imidodiphosphate; Male; Neurotoxins; Organometallic Compounds; Organoselenium Compounds; Presynaptic Terminals; Rats; Rats, Wistar; Subcellular Fractions; Synaptic Membranes; Synaptic Transmission; Tellurium; Tritium