RESUMO
Antiretrovirals have improved considerably since the introduction of 3'-azido-3'-deoxythymidine (zidovudine or AZT), a molecule with also anticancer effects. Subsequently, a variety of other nucleosides have been synthesized. However, these medications are often associated with serious adverse events and the onset or exacerbation of degenerative processes, diseases, and syndromes, affecting mainly the mitochondria. In this study, we used Caenorhabditis elegans to investigate the toxicity potential of AZT and three new organoselenium derivatives with modifications in the 5' position of the sugar ring in place of the 5'-OH group, with the insertion of a neutral, an electron-withdrawing and an electron-donating group attached to the aryl selenol moiety: 5'-seleno-(4-chloro-phenyl)-3-(amino)-thymidine (ASAT-4-Cl), 5'-seleno-(phenyl)-3-(amino)-thymidine (ASAT-Ph), and 5'-seleno-(4-methoxyphenyl)-3-(amino)- thymidine (ASAT-4-OMe). Analyzes included worm survival, behavior parameters, high-resolution respirometry, citrate synthase activity, and ATP levels. Although all compounds negatively affected C. elegans, ASAT-4-Cl and ASAT-Ph showed lower toxicity compared to AZT, especially in mitochondrial viability and ATP production. Therefore, more studies must be carried out on the use of these new compounds as pharmacological interventions.
Assuntos
Caenorhabditis elegans , Compostos Organosselênicos , Zidovudina , Animais , Caenorhabditis elegans/efeitos dos fármacos , Zidovudina/toxicidade , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/toxicidade , Mitocôndrias/efeitos dos fármacos , Fármacos Anti-HIV/toxicidadeRESUMO
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.
Assuntos
Antioxidantes/farmacologia , Ácido Glutâmico/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Ácido Quinolínico/toxicidade , Animais , Derivados de Benzeno/farmacologia , Química Encefálica/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/metabolismo , Ácido Glutâmico/toxicidade , Guanosina/farmacologia , Indicadores e Reagentes , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Proteínas do Tecido Nervoso/metabolismo , Compostos Organosselênicos/farmacologia , Oxidantes , Ratos , Espécies Reativas de Oxigênio/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
Although physical activity and creatine supplementation have been a documented beneficial effect on neurological disorders, its implications for epilepsy are still controversial. Thus, we decided to investigate the effects of 6 weeks swimming training, creatine supplementation (300 mg/kg; p.o.) or its combination seizures and neurochemical alterations induced by pentylenetetrazol (PTZ). We found that 6 weeks of physical training or creatine supplementation decreased the duration of PTZ-induced seizures in adult male Wistar rats, as measured by cortical and hippocampal electroencephalography and behavioral analysis. Importantly, the combination between physical training and creatine supplementation had additive anticonvulsant effects, since it increased the onset latency for PTZ-induced seizures and was more effective in decrease seizure duration than physical training and creatine supplementation individually. Analysis of selected parameters of oxidative stress and antioxidant defenses in the hippocampus revealed that physical training, creatine supplementation or its combination abrogated the PTZ-elicited increase in levels of thiobarbituric acid-reactive substances (TBARS) and protein carbonylation, as well as decrease in non-protein-thiols content, catalase (CAT) and SOD activities. In addition, this protocol of physical training and creatine supplementation prevented the PTZ-induced decrease in hippocampal Na+,K+-ATPase activity. Altogether, these results suggest that protection elicited physical training and creatine supplementation of selected targets for reactive species-mediated damage decrease of neuronal excitability and consequent oxidative damage elicited by PTZ. In conclusion, the present study shows that physical training, creatine supplementation or its combination attenuated PTZ-induced seizures and oxidative damage in vivo, and provide evidence that combination between creatine supplementation and physical exercise may be a useful strategy in the treatment of convulsive disorders.
Assuntos
Anticonvulsivantes/farmacologia , Convulsivantes/toxicidade , Creatina/administração & dosagem , Pentilenotetrazol/toxicidade , Condicionamento Físico Animal , Convulsões/tratamento farmacológico , Animais , Masculino , Estresse Oxidativo , Ratos , Ratos Wistar , Convulsões/induzido quimicamente , Convulsões/fisiopatologiaRESUMO
In this study, we evaluated the effects of three simple organochalcogenides (diphenyl diselenide, diphenyl ditelluride and diphenyl telluride) and ebselen on the glutamate-driven 45Ca2+ influx into chick embryonic retinal cells, as well as their effects on the excitotoxic injury in retina cells. None of the compounds tested interfered with basal 45Ca2+ uptake. Diphenyl diselenide and diphenyl ditelluride had no effects on glutamate-driven 45Ca2+ influx. Diphenyl telluride (100-400 microM) decreased and ebselen (100-400 microM) completely blocked the glutamate-driven 45Ca2+ influx (P < 0.01) into chick retinal explants. The assessment of neural injury was made spectrophotometrically by quantification of cellularly reduced MTT (3(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide) 24 h after the beginning of glutamate exposure (8 h). Ebselen had no effects on retinal MTT reduction when co-incubated with glutamate for 8 h. However, when ebselen (100 and 400 microM) was co-incubated for 8 h with glutamate and remained in the incubation media until MTT evaluation (24 h after the beginning of incubation), it protected retinal cells against the decrease in MTT reduction induced by glutamate. These data indicate that besides its capacity of interacting with Ca2+ channels, other mechanisms are involved in the neuroprotection afforded by ebselen in this work, possibly its antioxidant properties.