RESUMO
Vitamin A supplementation among women is a common habit worldwide in an attempt to slow aging progression due to the antioxidant potential attributed to retinoids. Nonetheless, vitamin A elicits a myriad of side effects that result from either therapeutic or inadvertent intake at varying doses for different periods. The mechanism behind such effects remains to be elucidated. In this regard, we performed the present work aiming to investigate the effects of vitamin A supplementation at 100, 200, or 500IU/kgday(-1) for 2 months on female rat brain, analyzing tissue lipid peroxidation levels, antioxidant enzyme activities (both Cu/Zn-superoxide dismutase - SOD - and Mn-SOD); glutathione S-transferase (GST) and monoamine oxidase (MAO) enzyme activity; mitochondrial respiratory chain activity and redox parameters in mitochondrial membranes, as well as quantifying α- and ß-synucleins, ß-amyloid peptide(1-40), immunoglobulin heavy-chain binding protein/78kDa glucose-regulated protein (BiP/GRP78), receptor for advanced glycation end products (RAGE), D2 receptor, and tumor necrosis factor-α (TNF-α) contents in rat frontal cortex, hippocampus, striatum, and cerebellum. We observed increased lipid peroxidation marker levels, altered Cu/Zn-SOD and Mn-SOD enzyme activities, mitochondrial nitrosative stress, and impaired respiratory chain activity in such brain regions. On the other hand, we did not find any change in MAO and GST enzyme activities, and on α- and ß-synucleins, ß-amyloid peptide(1-40), GRP78/BiP, RAGE, D2 receptor, and TNF-α contents. Importantly, we did not observed any evidence regarding an antioxidant effect of such vitamin at low doses in this experimental model. The use of vitamin A as an antioxidant therapy among women needs to be reexamined.
Assuntos
Química Encefálica/efeitos dos fármacos , Doenças Mitocondriais/induzido quimicamente , Membranas Mitocondriais/metabolismo , Tirosina/análogos & derivados , Vitamina A/toxicidade , Vitaminas/toxicidade , Peptídeos beta-Amiloides/metabolismo , Animais , Antioxidantes/metabolismo , Transporte de Elétrons/fisiologia , Ensaio de Imunoadsorção Enzimática , Ciclo Estral/fisiologia , Feminino , Produtos Finais de Glicação Avançada/metabolismo , Monoaminoxidase/metabolismo , Estresse Oxidativo/fisiologia , Ratos , Ratos Wistar , Receptores de Dopamina D2/metabolismo , Succinato Desidrogenase/metabolismo , Superóxido Dismutase/metabolismo , Sinucleínas/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Tirosina/metabolismo , Ubiquinona/metabolismoRESUMO
Even though RA is involved in differentiation and apoptosis of normal and cancer cells, being sometimes used as adjuvant in chemotherapy, its mechanisms of action involve multiple overlapping pathways that still remain unclear. Recent studies point out that RA exerts rapid and non-genomic effects, which are independent of RAR/RXR-mediated gene transcription. In this work, we reported that RA treatment for 24 h decreases cell viability, induces apoptosis dependent on caspase-3 activation, and activates the transcription factor AP-1 in cultured Sertoli cells. Moreover, RA induced a rapid and non-classical stimulation of ERK1/2. ERK1/2 activation was mediated by MEK1/2, and the protein synthesis inhibitor cycloheximide did not alter the pattern of RA-induced ERK1/2 phosphorylation. Pharmacological inhibition of MEK1/2-ERK1/2 pathway with UO126 blocked caspase-3 activation, decreased AP-1 binding to DNA and inhibited apoptosis. Overall, our data suggest that a rapid and non-genomic effect of RA upon MEK1/2-ERK1/2 pathway leads to caspase-3 activation and caspase-3-dependent apoptosis in cultured Sertoli cells. The non-canonical RA signaling presented in this work evokes new perspectives of RA action, which may play an important role in mediating early biological effects of RA modulating cell death in normal and tumor cells.
Assuntos
Apoptose/efeitos dos fármacos , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Células de Sertoli/efeitos dos fármacos , Tretinoína/toxicidade , Vitaminas/toxicidade , Animais , Butadienos/farmacologia , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cicloeximida/farmacologia , DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ativação Enzimática , MAP Quinase Quinase 1/metabolismo , Masculino , Nitrilas/farmacologia , Inibidores da Síntese de Proteínas/farmacologia , Ratos , Células de Sertoli/enzimologia , Células de Sertoli/patologia , Fator de Transcrição AP-1/biossíntese , Fator de Transcrição AP-1/fisiologia , Transcrição Gênica/efeitos dos fármacosRESUMO
Vitamin A (retinol) exerts a major role in several biological functions. However, it was observed that retinol induces oxidative stress on different cellular types. Catalase (EC 1.11.1.6; CAT) is a hydrogen peroxide metabolizing enzyme, and its activity and expression is widely used as an index to measure oxidative stress and perturbations in the cellular redox state. The aim of this study was to investigate the effects of retinol and its major biologically active metabolite, all-trans retinoic acid (RA), on CAT regulation. For this purpose, cultured Sertoli cells (a physiological target of vitamin A) were treated with retinol or RA. Retinol (7 microM, 14 microM) and RA (100 nM, 1 microM) enhanced intracellular reactive species production and increased CAT activity after 24 h of treatment. Retinol increased CAT immunocontent but did not alter CAT mRNA expression, while the increase in CAT activity by RA was not related to alterations in immunocontent or mRNA expression. In vitro incubation of purified CAT with retinol or RA did not alter enzyme activity.
Assuntos
Antineoplásicos/toxicidade , Catalase/metabolismo , Células de Sertoli/efeitos dos fármacos , Tretinoína/toxicidade , Vitamina A/toxicidade , Vitaminas/toxicidade , Animais , Catalase/genética , Células Cultivadas , Relação Dose-Resposta a Droga , Radicais Livres/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Células de Sertoli/enzimologiaRESUMO
Vitamin A participates in the maintenance of normal hippocampal function during embryonic and postnatal stages of the vertebrate life. Some works demonstrated that vitamin A metabolites impair learning and induce a depression-like behavior in mice, among other effects. Since vitamin A has prooxidant effects on other experimental models, we decided to investigate whether vitamin A can induce oxidative stress in the adult rat hippocampus. We analyzed the sub acute effects of therapeutic (1000 and 2500 I.U./kg) or excessive (4500 and 9000 I.U./kg) vitamin A doses on the hippocampal redox state, as well as on levels of anxiety, and locomotory and exploratory activity. Vitamin A supplementation induced lipid peroxidation, protein carbonylation, and oxidation of the protein thiol content in the rat hippocampus in all periods analyzed. Increased superoxide dismutase (SOD) activity and decreased catalase (CAT) activity were also observed, which gives rise to an imbalance in the principal cellular enzymatic antioxidant system. Then, our results show, for the first time, that vitamin A induced oxidative stress in the adult rat hippocampus, is anxiogenic, and decreases locomotion in and exploration of an open field.
Assuntos
Ansiedade/induzido quimicamente , Comportamento Animal/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Vitamina A/toxicidade , Vitaminas/toxicidade , Envelhecimento/metabolismo , Animais , Catalase/metabolismo , Relação Dose-Resposta a Droga , Glutationa Peroxidase , Hipocampo/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Oxirredução , Carbonilação Proteica/efeitos dos fármacos , Ratos , Ratos Wistar , Compostos de Sulfidrila/metabolismo , Superóxido Dismutase/metabolismoRESUMO
Vitamin A is an essential micronutrient to the normal brain function. However, there is an increasing concern regarding the use of vitamin A at high doses even therapeutically. Here, we show that acute and chronic vitamin A supplementation induces oxidative stress to submitochondrial particles (SMP) isolated from rat cerebral cortex and cerebellum. Both chronic and acute vitamin A supplementation at therapeutic (1000 IU/kg or 2500 IU/kg) or excessive (4500 IU/kg or 9000 IU/kg) doses induced lipid peroxidation, protein carbonylation, and oxidation of protein thiol groups in cerebral cortex and cerebellum SMP. Furthermore, vitamin A supplementation induced an increase in the superoxide (O(2)(-)) anion production, indicating an uncoupling in the electron transfer chain (ETC). Locomotory and exploratory activity, which are associated to cerebral cortex and cerebellum, also were affected by both acute and chronic vitamin A supplementation. Vitamin A induced a decrease in both locomotory and exploratory behavior. Together, these results show that vitamin A could be toxic at the sub cellular level, inducing mitochondrial dysfunction and altering cerebral cortex and/or cerebellum-dependent behavior.