RESUMO
A encefalomalácia nutricional é um distúrbio metabólico caracterizado por sinais clínicos neurológicos e sua etiologia é atribuída à hipovitaminose E. Atinge frangos jovens acarretando altos prejuízos aos criadores e agroindústrias pela sua alta morbidade e mortalidade. O objetivo do presente estudo foi relatar as alterações macroscópicas e histopatológicas de um caso de encefalomalácia nutricional. Um frango de corte com quatro semanas de vida, foi encaminhado ao Laboratório de Patologia Animal da Universidade Federal de Rondônia. Ao exame físico apresentou escore corporal 1 e sinais neurológicos como, ataxia, andar em círculos, lateralização da cabeça, prostração e hiperestesia, caracterizada por espasmos corporais iniciados após estímulos como sons altos e toque físico. Após eutanásia, realizou-se exame necroscópico e exame histopatológico. Para isto, foram coletados fragmentos de órgãos e fixados em formalina tamponada a 10%. No exame necroscópico constatou-se necrose coliquativa no encéfalo, o qual apresentou-se extremamente friável, com coloração pálida. Na análise histopatológica foram observadas alterações como vacuolização citoplasmática, degeneração de células de Purkinje e malácia focal extensa na substância cinzenta cortical e da substância branca do cerebelo. Pela história clínica e as observações necroscópicas e histopatológicas, o caso foi diagnosticado como encefalomalácia nutricional por hipovitaminose E.(AU)
Nutritional encephalomalacia is a metabolic disorder characterized by clinical neurological signs and its etiology is attributed to hypovitaminosis E. It affects young chickens causing high losses to breeders and agroindustries due to their high morbidity and mortality. The aim of the present study was to report macroscopic and histopathological changes in a case of nutritional encephalomalacia. A young chicken with four weeks of life conducted to the Animal Pathology Laboratory of Federal University of Rondônia. Physical examination showed poor body score and neurological signs, such as ataxia, circling, head lateralization, prostration and hypersensitivity, characterized by body spasms initiated after stimuli such as loud sounds and physical touch. After euthanasia, necroscopic examination was performed, organ fragments were collected and fixed in 10% buffered formalin. Necroscopic examination revealed collictive necrosis in the brain, which was extremely friable, with a pale color. In histopathological analysis, changes such as cytoplasmic vacuolization, Purkinje cell degeneration and extensive focal malacia in the cortical gray matter and white matter of the cerebellum were observed. From the clinical history and necroscopic and histopathological observations, the case was diagnosed as nutritional encephalomalacia by hypovitaminosis E.(AU)
Assuntos
Animais , Encefalomalacia/veterinária , Encefalomalacia/fisiopatologia , Deficiência de Vitaminas/complicações , Deficiência de Vitamina E/complicações , Galinhas , Encefalopatias Metabólicas/fisiopatologia , Cérebro/patologiaRESUMO
A encefalomalácia nutricional é um distúrbio metabólico caracterizado por sinais clínicos neurológicos e sua etiologia é atribuída à hipovitaminose E. Atinge frangos jovens acarretando altos prejuízos aos criadores e agroindústrias pela sua alta morbidade e mortalidade. O objetivo do presente estudo foi relatar as alterações macroscópicas e histopatológicas de um caso de encefalomalácia nutricional. Um frango de corte com quatro semanas de vida, foi encaminhado ao Laboratório de Patologia Animal da Universidade Federal de Rondônia. Ao exame físico apresentou escore corporal 1 e sinais neurológicos como, ataxia, andar em círculos, lateralização da cabeça, prostração e hiperestesia, caracterizada por espasmos corporais iniciados após estímulos como sons altos e toque físico. Após eutanásia, realizou-se exame necroscópico e exame histopatológico. Para isto, foram coletados fragmentos de órgãos e fixados em formalina tamponada a 10%. No exame necroscópico constatou-se necrose coliquativa no encéfalo, o qual apresentou-se extremamente friável, com coloração pálida. Na análise histopatológica foram observadas alterações como vacuolização citoplasmática, degeneração de células de Purkinje e malácia focal extensa na substância cinzenta cortical e da substância branca do cerebelo. Pela história clínica e as observações necroscópicas e histopatológicas, o caso foi diagnosticado como encefalomalácia nutricional por hipovitaminose E.
Nutritional encephalomalacia is a metabolic disorder characterized by clinical neurological signs and its etiology is attributed to hypovitaminosis E. It affects young chickens causing high losses to breeders and agroindustries due to their high morbidity and mortality. The aim of the present study was to report macroscopic and histopathological changes in a case of nutritional encephalomalacia. A young chicken with four weeks of life conducted to the Animal Pathology Laboratory of Federal University of Rondônia. Physical examination showed poor body score and neurological signs, such as ataxia, circling, head lateralization, prostration and hypersensitivity, characterized by body spasms initiated after stimuli such as loud sounds and physical touch. After euthanasia, necroscopic examination was performed, organ fragments were collected and fixed in 10% buffered formalin. Necroscopic examination revealed collictive necrosis in the brain, which was extremely friable, with a pale color. In histopathological analysis, changes such as cytoplasmic vacuolization, Purkinje cell degeneration and extensive focal malacia in the cortical gray matter and white matter of the cerebellum were observed. From the clinical history and necroscopic and histopathological observations, the case was diagnosed as nutritional encephalomalacia by hypovitaminosis E.
Assuntos
Animais , Deficiência de Vitamina E/complicações , Deficiência de Vitaminas/complicações , Encefalomalacia/fisiopatologia , Encefalomalacia/veterinária , Galinhas , Cérebro/patologia , Encefalopatias Metabólicas/fisiopatologiaRESUMO
JUSTIFICATIVA E OBJETIVOS: As encefalopatias compõem um grupo heterogêneo de etiologias, onde a pronta e correta atuação médica direcionada à causa da doença, pode modificar o prognóstico do paciente. O objetivo deste estudo foi rever os aspectos fisiopatológicos das diferentes encefalopatias bem como seus principais fatores desencadeantes e manuseio clínico.CONTEÚDO: Foram selecionadas as mais frequentes encefalopatias observadas na prática clínica e discutir sua fisiopatologia, bem como sua abordagem terapêutica, destacando: encefalopatia hipertensiva, hipóxico-isquêmica, metabólica, Wernicke-Korsakoff, traumática e tóxica.CONCLUSÃO: Trata-se de uma complexa condição clínica que exige rápida identificação e preciso manuseio clínico com o intuito de reduzir sua elevada taxa de morbimortalidade. O atraso no reconhecimento dessa condição clínica poderá ser extremamente prejudicial ao paciente que estará sofrendo lesão cerebral muitas vezes irreversível.
BACKGROUND AND OBJECTIVES: Encephalopathies comprise a heterogeneous group of clinical conditions, in which the prompt and adequate medical intervention can modify patient prognosis. This paper aims to discuss the pathophysiological aspects of different encephalopathies, their etiology, and clinical management.CONTENTS: We selected the main encephalopathies observed in clinical practice, such as hypertensive, hypoxic-ischemic, metabolic, Wernicke-Korsakoff, traumatic, and toxic encephalopathies, and to discuss their therapeutic approaches.CONCLUSION: This is a complex clinical condition that requires rapid identification and accurate clinical management with the aim of reducing its high morbidity and mortality rates. Delay in recognizing this condition can be extremely harmful to the patient who is suffering from often irreversible brain injury.
Assuntos
Encefalopatias/diagnóstico , Encefalopatias/etiologia , Encefalopatias/fisiopatologia , Encefalopatia Hepática/diagnóstico , Encefalopatia Hepática/etiologia , Encefalopatia Hepática/fisiopatologia , Encefalopatia Hipertensiva/diagnóstico , Encefalopatia Hipertensiva/etiologia , Encefalopatia Hipertensiva/fisiopatologia , Encefalopatia de Wernicke/diagnóstico , Encefalopatia de Wernicke/etiologia , Encefalopatia de Wernicke/fisiopatologia , Encefalopatias Metabólicas/diagnóstico , Encefalopatias Metabólicas/etiologia , Encefalopatias Metabólicas/fisiopatologia , Hipóxia-Isquemia Encefálica/diagnóstico , Hipóxia-Isquemia Encefálica/etiologia , Hipóxia-Isquemia Encefálica/fisiopatologia , Lesão Encefálica Crônica/diagnóstico , Lesão Encefálica Crônica/etiologia , Lesão Encefálica Crônica/fisiopatologiaRESUMO
The influence of physical exercise on the effects elicited by homocysteine on glutamate uptake and some parameters of oxidative stress, namely thiobarbituric acid-reactive substances, 2',7'-dichlorofluorescein (H(2)DCF) oxidation, as well as enzymatic antioxidant activities, superoxide dismutase, catalase and glutathione peroxidase in rat cerebral cortex were investigated. Wistar rats received subcutaneous administration of homocysteine or saline (control) from the 6th to 29th day of life. The physical exercise was performed from the 30th to 60th day of life; 12 h after the last exercise session animals were sacrificed and the cerebral cortex was dissected out. It is shown that homocysteine reduces glutamate uptake increases thiobarbituric acid-reactive substances and disrupts enzymatic antioxidant defenses in cerebral cortex. Physical activity reversed the homocysteine effects on glutamate uptake and on antioxidant enzymes activities; although the increase in thiobarbituric acid-reactive substances was only partially reversed by exercise. These findings allow us to suggest that physical exercise may have a protective role against homocysteine-induced oxidative imbalance and brain damage to the glutamatergic system.
Assuntos
Encefalopatias Metabólicas/terapia , Terapia por Exercício/métodos , Ácido Glutâmico/metabolismo , Hiper-Homocisteinemia/terapia , Estresse Oxidativo/fisiologia , Condicionamento Físico Animal/fisiologia , Animais , Animais Recém-Nascidos , Encefalopatias Metabólicas/fisiopatologia , Modelos Animais de Doenças , Hiper-Homocisteinemia/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
This study was designed to investigate the protective effects of the combination of guanosine and 2 organoselenium compounds (ebselen and diphenyl diselenide) against glutamate-induced oxidative stress in different regions of rat brains. Glutamate caused an increase in reactive oxygen species (ROS) generation and a decrease in [(3)H]-glutamate uptake in striatal, cortical, and hippocampal slices. Guanosine, ebselen, and diphenyl diselenide prevented glutamate-induced ROS production in striatal, cortical and hippocampal slices. The combination of guanosine with organoselenium compounds was more effective against glutamate-induced ROS production than the individual compounds alone. Guanosine prevented [(3)H]-glutamate uptake inhibition in striatal, cortical, and hippocampal slices. Thus, protection against the harmful effects of glutamate is possibly due to the combination of the antioxidant properties of organoselenium compounds and the stimulatory effect of guanosine on glutamate uptake. In conclusion, the combination of antioxidants and glutamatergic system modulators could be considered a potential therapy against the prooxidant effects of glutamate.
Assuntos
Azóis/farmacologia , Derivados de Benzeno/farmacologia , Encefalopatias Metabólicas/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Ácido Glutâmico/toxicidade , Guanosina/farmacologia , Compostos Organosselênicos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Encéfalo/fisiologia , Encefalopatias Metabólicas/fisiopatologia , Modelos Animais de Doenças , Sinergismo Farmacológico , Quimioterapia Combinada/métodos , Ácido Glutâmico/metabolismo , Ácido Glutâmico/fisiologia , Isoindóis , Masculino , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/antagonistas & inibidores , Neurotoxinas/toxicidade , Técnicas de Cultura de Órgãos , Estresse Oxidativo/fisiologia , Ratos , Ratos WistarRESUMO
Organic acidurias or organic acidemias constitute a group of inherited disorders caused by deficient activity of specific enzymes of amino acids, carbohydrates or lipids catabolism, leading to large accumulation and excretion of one or more carboxylic (organic) acids. Affected patients usually present neurologic symptoms and abnormalities, sometimes accompanied by cardiac and skeletal muscle alterations, whose pathogenesis is poorly known. However, in recent years growing evidence has emerged indicating that mitochondrial dysfunction is directly or indirectly involved in the pathology of various organic acidemias. Mitochondrial impairment in some of these diseases are generally due to mutations in nuclear genes of the tricarboxylic acid cycle or oxidative phosphorylation, while in others it seems to result from toxic influences of the endogenous organic acids to the mitochondrion. In this minireview, we will briefly summarize the present knowledge obtained from human and animal studies showing that disruption of mitochondrial homeostasis may represent a relevant pathomechanism of tissue damage in selective organic acidemias. The discussion will focus on mitochondrial alterations found in patients affected by organic acidemias and by the deleterious effects of the accumulating organic acids on mitochondrial pathways that are crucial for ATP formation and transfer. The elucidation of the mechanisms of toxicity of these acidic compounds offers new perspectives for potential novel adjuvant therapeutic strategies in selected disorders of this group.
Assuntos
Trifosfato de Adenosina/metabolismo , Ácidos Carboxílicos/metabolismo , Homeostase/fisiologia , Erros Inatos do Metabolismo/fisiopatologia , Mitocôndrias/fisiologia , Doenças Mitocondriais/fisiopatologia , Acetil-CoA C-Aciltransferase/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Animais , Síndrome de Barth/fisiopatologia , Encefalopatias Metabólicas/fisiopatologia , Encefalopatias Metabólicas Congênitas/fisiopatologia , Glutaril-CoA Desidrogenase/deficiência , Humanos , Mitocôndrias/metabolismo , Acidemia Propiônica/fisiopatologia , Púrpura/fisiopatologiaRESUMO
Dystrophin is a protein found at the plasmatic membrane in muscle and postsynaptic membrane of some neurons, where it plays an important role on synaptic transmission and plasticity. Its absence is associated with Duchenne's muscular dystrophy (DMD), in which cognitive impairment is found. Oxidative stress appears to be involved in the physiopathology of DMD and its cognitive dysfunction. In this regard, the present study investigated oxidative parameters (lipid and protein peroxidation) and antioxidant enzymes activities (superoxide dismutase and catalase) in prefrontal cortex, cerebellum, hippocampus, striatum and cortex tissues from male dystrophic mdx and normal C57BL10 mice. We observed (1) reduced lipid peroxidation in striatum and protein peroxidation in cerebellum and prefrontal cortex; (2) increased superoxide dismutase activity in cerebellum, prefrontal cortex, hippocampus and striatum; and (3) reduced catalase activity in striatum. It seems by our results, that the superoxide dismutase antioxidant mechanism is playing a protective role against lipid and protein peroxidation in mdx mouse brain.
Assuntos
Encefalopatias Metabólicas/metabolismo , Encéfalo/metabolismo , Distrofina/metabolismo , Estresse Oxidativo/genética , Superóxido Dismutase/metabolismo , Animais , Encéfalo/anatomia & histologia , Encéfalo/fisiopatologia , Encefalopatias Metabólicas/genética , Encefalopatias Metabólicas/fisiopatologia , Catalase/genética , Catalase/metabolismo , Cerebelo/metabolismo , Cerebelo/fisiopatologia , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/fisiopatologia , Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , Modelos Animais de Doenças , Distrofina/genética , Regulação Enzimológica da Expressão Gênica/genética , Predisposição Genética para Doença/genética , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Metabolismo dos Lipídeos/genética , Peroxidação de Lipídeos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Distrofia Muscular de Duchenne/complicações , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/fisiopatologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Superóxido Dismutase/genéticaRESUMO
Cystinosis is a systemic genetic disease caused by a lysosomal transport deficiency accumulating cystine in the lysosomes of almost all tissues. Although tissue damage might depend on cystine accumulation, the mechanisms of tissue damage are still obscures. Adenylate kinase, along with creatine kinase, is responsible for the enzymatic phosphotransfer network, crucial for energy homeostasis. Taking into account that cystine is known to inhibit creatine kinase activity, the two enzymes have thiol groups, and the strong interaction between the two activities, our main objective was to investigate the effect of cystine on adenylate kinase activity in the brain cortex of Wistar rats. For the in vivo studies, the animals were injected twice a day with 1.6 micromol/g body weight of cystine dimethylester and/or 0.46 micromol/g body weight of cysteamine from the 25th to the 29th postpartum day and sacrificed after 12 h. Cystine inhibited the enzyme activity in vitro in a concentration dependent way, whereas cysteamine prevented the inhibition. Adenylate kinase activity was found diminished in the brain cortex of rats loaded with cystine dimethylester and co-administration of cysteamine prevented the diminution of the enzyme activity. Considering that adenylate kinase together with creatine kinase is crucial for energy homeostasis, the release of cystine from lysosomes with consequent enzymes inhibition could impair energy homeostasis, contributing to tissue damage in patients with cystinosis.
Assuntos
Adenilil Ciclases/efeitos dos fármacos , Encefalopatias Metabólicas/tratamento farmacológico , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Cisteamina/farmacologia , Cistina/metabolismo , Cistinose/tratamento farmacológico , Adenilil Ciclases/metabolismo , Animais , Química Encefálica/efeitos dos fármacos , Química Encefálica/fisiologia , Encefalopatias Metabólicas/metabolismo , Encefalopatias Metabólicas/fisiopatologia , Creatina Quinase/química , Creatina Quinase/metabolismo , Cisteamina/química , Cisteamina/metabolismo , Cistina/análogos & derivados , Cistina/toxicidade , Cistinose/metabolismo , Cistinose/fisiopatologia , Relação Dose-Resposta a Droga , Interações Medicamentosas/fisiologia , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Ratos , Ratos WistarRESUMO
OBJECTIVES: We aimed to describe the clinical and imaging characteristics; associated risk factors and neurological outcome of posterior reversible encephalopathy syndrome (PRES) in patients with systemic lupus erythematosus (SLE). METHODS: From October 2001 to January 2007, we identified patients with SLE and the criteria for PRES in our institution, which is a tertiary-care referral center for patients with SLE; the patients were evaluated at baseline and followed to determine the clinical outcome. RESULTS: We identified 22 episodes of PRES in 21 patients; 20 (95.2%) were women, mean age of onset was 24.9+/-8.6 years, all patients had high systemic activity (SLEDAI scores from 12 to 39). Acute hypertension was observed in 18 episodes (81.8%), and renal failure in 16 (72.7%); only 3 patients were on cyclophosphamide at the time of the onset of PRES. Persistent neurological deficit was observed in 2 cases; one patient died during the acute episode. CONCLUSIONS: PRES is a central nervous system syndrome that is observed in SLE patients. It was associated mainly to high systemic activity, acute hypertension, and renal failure. Although reversibility is common, residual neurological damage may be observed.
Assuntos
Encefalopatias Metabólicas/etiologia , Encefalopatias Metabólicas/patologia , Hipertensão/etiologia , Lúpus Eritematoso Sistêmico/complicações , Insuficiência Renal/etiologia , Adulto , Encefalopatias Metabólicas/epidemiologia , Encefalopatias Metabólicas/fisiopatologia , Ciclofosfamida/uso terapêutico , Feminino , Humanos , Hipertensão/epidemiologia , Lúpus Eritematoso Sistêmico/patologia , Imageamento por Ressonância Magnética , Masculino , Insuficiência Renal/epidemiologia , Adulto JovemRESUMO
Depressive disorders, including major depression, are serious and disabling. However, the exact pathophysiology of depression is not clearly understood. Life stressors contribute in some fashion to depression and are an extension of what occurs normally. In this context, chronic stress has been used as an animal model of depression. Based on the hypothesis that metabolism impairment might be involved in the pathophysiology of depression, in the present work we evaluated the activities of mitochondrial respiratory chain complexes and creatine kinase in brain of rats subjected to chronic stress. After 40 days of mild stress, a reduction in sweet food ingestion was observed, as well as increased adrenal gland weight, when compared to control group. We also verified that control group gained weight after 40 days, but stressed group did not. Moreover, our findings showed that complex I, III and IV were inhibited in stress group only in cerebral cortex and cerebellum. On the other hand, complex II and creatine kinase were not affected in stressed group. Although it is difficult to extrapolate our findings to the human condition, the inhibition of mitochondrial respiratory chain by chronic stress may be one mechanism in the pathophysiology of depressive disorders.
Assuntos
Encefalopatias Metabólicas/metabolismo , Encéfalo/metabolismo , Transtorno Depressivo/metabolismo , Transporte de Elétrons/fisiologia , Mitocôndrias/metabolismo , Estresse Psicológico/metabolismo , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/fisiopatologia , Animais , Regulação do Apetite/fisiologia , Biomarcadores/análise , Biomarcadores/metabolismo , Peso Corporal/fisiologia , Encéfalo/anatomia & histologia , Encéfalo/fisiopatologia , Encefalopatias Metabólicas/complicações , Encefalopatias Metabólicas/fisiopatologia , Doença Crônica , Creatina Quinase/análise , Creatina Quinase/metabolismo , Transtorno Depressivo/etiologia , Transtorno Depressivo/fisiopatologia , Modelos Animais de Doenças , Regulação para Baixo/fisiologia , Transporte de Elétrons/efeitos dos fármacos , Metabolismo Energético/fisiologia , Masculino , Mitocôndrias/efeitos dos fármacos , Tamanho do Órgão/fisiologia , Fosforilação Oxidativa , Ratos , Ratos Wistar , Estresse Psicológico/complicações , Estresse Psicológico/fisiopatologiaRESUMO
The present work investigated the in vitro effects of lysine on important parameters of oxidative stress in cerebral cortex of young rats. Our results show that lysine significantly induced lipid peroxidation, as determined by increase of thiobarbituric acid-reactive substances and chemiluminescence levels, as well as protein oxidative damage since carbonyl formation and sulfhydryl oxidation were enhanced by this amino acid. Furthermore, the addition of free radical scavengers significantly prevented lysine-induced lipid oxidative damage, suggesting that free radicals were involved in this effect. Lysine also significantly diminished glutathione levels in cortical supernatants, decreasing, therefore, the major brain antioxidant defense. Finally, lysine markedly oxidized a glutathione commercial solution in a medium devoid of brain supernatants, indicating that it behaved as a direct acting oxidant. The present data indicate that lysine induces oxidative stress in cerebral cortex of young rats. Therefore, it is presumed that this pathomechanism may be involved at least in part in the neurological damage found in patients affected by disorders with hyperlysinemia.
Assuntos
Encefalopatias Metabólicas/metabolismo , Córtex Cerebral/metabolismo , Glutationa/metabolismo , Peroxidação de Lipídeos/fisiologia , Lisina/metabolismo , Estresse Oxidativo/fisiologia , Animais , Animais Recém-Nascidos , Antioxidantes/metabolismo , Encefalopatias Metabólicas/fisiopatologia , Córtex Cerebral/fisiopatologia , Regulação para Baixo/fisiologia , Sequestradores de Radicais Livres/metabolismo , Sequestradores de Radicais Livres/farmacologia , Compostos Carbonílicos de Ferro/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Lisina/toxicidade , Degeneração Neural/induzido quimicamente , Degeneração Neural/metabolismo , Degeneração Neural/fisiopatologia , Proteínas do Tecido Nervoso/metabolismo , Neurotoxinas/metabolismo , Neurotoxinas/toxicidade , Oxidantes/metabolismo , Oxidantes/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Compostos de Sulfidrila/metabolismoRESUMO
Glutamate is the main excitatory neurotransmitter in the mammalian nervous system and is essential for its normal functions. However, overstimulation of glutamatergic system due to hyperactivation of NMDA receptors and/or impairment of glutamate reuptake system has been implicated in many acute and chronic neurological diseases. Regulation of extracellular glutamate concentrations relies on the function of glutamate transporters which can be reversed in situations related to excitotoxicity. Guanosine-5'-monophosphate (GMP), a guanine nucleotide which displays important extracellular roles, such as trophic effects to neurons and astrocytes, behaves as antagonist of glutamate receptors and is neuroprotective in hippocampal slices against excitotoxicity or ischemic conditions. Hippocampal slices exposed to 1 or 10 mM glutamate, or 100 microM NMDA with 10 microM glycine for 1 h and evaluated after 6 or 18 h, showed reduced cell viability and DNA fragmentation, respectively. Glutamate- or NMDA-induced cell death was prevented by 50 microM MK-801, but only NMDA-induced cell damage was prevented by GMP (1 mM). Glutamate-induced cell viability impairment and glutamate-induced l-[(3)H]glutamate release were both prevented by adding DL-TBOA (10 microM). Otherwise, NMDA-induced cell viability loss was not prevented by 10 microM of DL-TBOA and NMDA did not induce l-[(3)H]glutamate release. Our results demonstrate that GMP is neuroprotective when acting selectively at NMDA receptors. Glutamate-induced hippocampal slice damage and glutamate release were blocked by glutamate transporter inhibitor, indicating that glutamate-induced toxicity also involves the reversal of glutamate uptake, which cannot be prevented by GMP.
Assuntos
Ácido Glutâmico/metabolismo , Guanosina Monofosfato/farmacologia , Hipocampo/efeitos dos fármacos , N-Metilaspartato/metabolismo , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Proteínas Vesiculares de Transporte de Glutamato/antagonistas & inibidores , Animais , Ácido Aspártico/farmacologia , Encefalopatias Metabólicas/tratamento farmacológico , Encefalopatias Metabólicas/metabolismo , Encefalopatias Metabólicas/fisiopatologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Fragmentação do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/toxicidade , Guanosina Monofosfato/uso terapêutico , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Masculino , N-Metilaspartato/antagonistas & inibidores , N-Metilaspartato/toxicidade , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Neurotoxinas/antagonistas & inibidores , Neurotoxinas/metabolismo , Neurotoxinas/toxicidade , Técnicas de Cultura de Órgãos , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Proteínas Vesiculares de Transporte de Glutamato/metabolismoRESUMO
Despite the significant brain abnormalities, the neurotoxic mechanisms of brain injury in hypertryptophanemia are virtually unknown. In this work, we determined the thiobarbituric acid-reactive substances, 2',7'-dihydrodichlorofluorescein oxidation, reduced glutathione and the activities of catalase, superoxide dismutase and glutathione peroxidase in cerebral cortex from rats loaded with L-tryptophan. High L-tryptophan concentrations, similar to those found in hypertryptophanemic patients were induced by three subcutaneous injections of saline-buffered tryptophan (2 micromol/g body weight) to 30-day-old Wistar rats. The parameters were assessed 1 h after the last injection. It was observed that tryptophan significantly increased thiobarbituric acid-reactive substances, 2',7'-dihydrodichlorofluorescein oxidation and reduced glutathione, whereas it reduced catalase activity. Pre-treatment with taurine (1.6 micromol/g of body weight), or alpha-tocopherol plus ascorbic acid (40 and 100 microg/g body weight, respectively) prevented those effects of tryptophan, reinforcing the hypothesis that tryptophan induces oxidative stress in brain cortex of the rats. Therefore, these findings also occur in human hypertryptophanemia or in other neurodegenerative diseases in which tryptophan accumulates, then oxidative stress may be involved in the mechanisms leading to the brain injury observed in patients affected by these disorders.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Encefalopatias Metabólicas/metabolismo , Córtex Cerebral/metabolismo , Degeneração Neural/metabolismo , Estresse Oxidativo/fisiologia , Triptofano/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/induzido quimicamente , Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Animais , Antioxidantes/farmacologia , Encefalopatias Metabólicas/induzido quimicamente , Encefalopatias Metabólicas/fisiopatologia , Catalase/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiopatologia , Modelos Animais de Doenças , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Masculino , Degeneração Neural/induzido quimicamente , Degeneração Neural/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1 , Taurina/farmacologia , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Triptofano/toxicidade , alfa-Tocoferol/farmacologiaRESUMO
Encephalopathy may accompany acute or chronic renal failure, and the mechanisms responsible for neurological complications in patients with renal failure are poorly known. Considering that creatine kinase (CK) is important for brain energy homeostasis and is inhibited by free radicals, and that oxidative stress is probably involved in the pathogenesis of uremic encephalopathy, we measured CK activity (hippocampus, striatum, cerebellum, cerebral cortex and prefrontal cortex) in brain if rats submitted to renal ischemia and the effect of administration of antioxidants (N-acetylcysteine, NAC and deferoxamine, DFX) on this enzyme. We verified that CK activity was not altered in cerebellum and striatum of rats. CK activity was inhibited in prefrontal cortex and hippocampus of rats 12h after renal ischemia. The treatment with antioxidants prevented such effect. Cerebral cortex was also affected, but in this area CK activity was inhibited 6 and 12h after renal ischemia. Moreover, only NAC or NAC plus DFX were able to prevent the inhibition on the enzyme. Although it is difficult to extrapolate our findings to the human condition, the inhibition of brain CK activity after renal failure may be associated to neuronal loss and may be involved in the pathogenesis of uremic encephalopathy.
Assuntos
Antioxidantes/farmacologia , Encefalopatias Metabólicas/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Creatina Quinase/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Uremia/tratamento farmacológico , Acetilcisteína/farmacologia , Acetilcisteína/uso terapêutico , Animais , Antioxidantes/uso terapêutico , Encéfalo/enzimologia , Encéfalo/fisiopatologia , Encefalopatias Metabólicas/enzimologia , Encefalopatias Metabólicas/fisiopatologia , Creatina Quinase/metabolismo , Desferroxamina/farmacologia , Desferroxamina/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Isquemia/complicações , Nefropatias/complicações , Masculino , Degeneração Neural/tratamento farmacológico , Degeneração Neural/enzimologia , Degeneração Neural/fisiopatologia , Estresse Oxidativo/fisiologia , Ratos , Ratos Wistar , Frações Subcelulares , Fatores de Tempo , Resultado do Tratamento , Uremia/enzimologia , Uremia/fisiopatologiaRESUMO
Although vitamin A has been reported to be essential to brain homeostasis, some central nervous system (CNS)-associated deleterious effects may be induced by vitamin A or by its metabolites. In this work, we investigated the effects of acute and chronic vitamin A supplementation at therapeutic (1,000 or 2,500 IU/kg/day) or excessive (4,500 or 9,000 IU/kg/day) doses on the redox state of the rat striatum. We found a 1.8- to 2.7-fold increase of lipid peroxidation in the striatum after acute or chronic supplementation (TBARS method). Therapeutic doses induced a 1.6- to 2.2-fold increase of protein carbonylation (dinitrophenylhydrazine (DNPH) derivatization). Vitamin A supplementation induced a 1.2- to 1.4-fold decrease of protein thiol content acutely and chronically. Superoxide dismutase (SOD) activity, assessed through the inhibition of epinephrine's autoxidation, was increased in a dose-dependent manner chronically. Acutely, both therapeutic and excessive vitamin A doses induced a 1.8- to 2.2-fold decrease of catalase (CAT) activity, as determined through the rate of decrease of hydrogen peroxide (H(2)O(2)). Glutathione peroxidase (GPx) activity did not change in this experimental model. Some vitamin A doses decreased the non-protein thiol content only chronically. Vitamin A supplementation decreased the striatal non-enzymatic antioxidant defenses (TRAP assay). Furthermore, our results show that vitamin A supplementation impaired the SOD/CAT ratio. Moreover, we observed a 1.6- to 2.0-fold decrease of locomotion and exploration in an open field after vitamin A supplementation. Therefore, our results suggest that vitamin A supplementation induces oxidative stress in the rat striatum and that it may be related to a metabolic impairment in such brain area.
Assuntos
Doenças dos Gânglios da Base/induzido quimicamente , Encefalopatias Metabólicas/induzido quimicamente , Corpo Estriado/efeitos dos fármacos , Discinesia Induzida por Medicamentos/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Vitamina A/toxicidade , Animais , Antioxidantes/metabolismo , Doenças dos Gânglios da Base/metabolismo , Doenças dos Gânglios da Base/fisiopatologia , Encefalopatias Metabólicas/metabolismo , Encefalopatias Metabólicas/fisiopatologia , Catalase/efeitos dos fármacos , Catalase/metabolismo , Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Esquema de Medicação , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Oxirredução , Estresse Oxidativo/fisiologia , Carbonilação Proteica/efeitos dos fármacos , Carbonilação Proteica/fisiologia , Ratos , Ratos Wistar , Compostos de Sulfidrila/metabolismo , Superóxido Dismutase/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologiaRESUMO
Acid (aspartyl), basic (arginyl) and neutral (alanyl) aminopeptidases degrade angiotensins, vasopressin, oxytocin, bradykinin and enkephalins. These peptides regulate memory, energy homeostasis, water-salt balance and blood pressure, functions that are mainly exerted in the hippocampus and hypothalamus, and that can be affected by diabetes mellitus. To evaluate the relationship between the diabetes mellitus and processing and inactivation roles of these representative aminopeptidases, we measured their activities in both brain structures of control and streptozotocin-diabetic rats. Hypothalamic soluble aspartyl and arginyl aminopeptidases presented significant decreased activity levels in diabetic rats, which were mitigated by insulin therapy. In addition to membrane-bound puromycin sensitive and insensitive alanyl aminopeptidases, its soluble puromycin sensitive form did not differ between diabetic and control rats in both brain structures. Glucose and/or insulin did not seem to alter in vitro the hypothalamic activities of soluble aspartyl and arginyl aminopeptidases. The implied hypothalamic control of regulatory peptide activity by aspartyl and arginyl aminopeptidases supports the hypothesis that the hydrolytic ability of these enzyme types could be a common link for the disruptions of water-salt balance, blood pressure and energy homeostasis in diabetes mellitus.
Assuntos
Aminopeptidases/metabolismo , Encefalopatias Metabólicas/enzimologia , Encefalopatias Metabólicas/etiologia , Diabetes Mellitus Experimental/complicações , Hipocampo/enzimologia , Hipotálamo/enzimologia , Aminopeptidases/análise , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Encefalopatias Metabólicas/fisiopatologia , Antígenos CD13/análise , Antígenos CD13/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/enzimologia , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Doenças do Sistema Endócrino/enzimologia , Doenças do Sistema Endócrino/etiologia , Doenças do Sistema Endócrino/fisiopatologia , Glutamil Aminopeptidase/análise , Glutamil Aminopeptidase/metabolismo , Hipocampo/fisiopatologia , Homeostase/fisiologia , Hipotálamo/fisiopatologia , Insulina/metabolismo , Insulina/farmacologia , Masculino , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Neuropeptídeos/metabolismo , Inibidores da Síntese de Proteínas/farmacologia , Puromicina/farmacologia , Ratos , Ratos Wistar , Equilíbrio Hidroeletrolítico/fisiologiaRESUMO
Glutaric acidemia type I is an inherited metabolic disorder caused by a severe deficiency of the mitochondrial glutaryl-CoA dehydrogenase activity leading to accumulation of predominantly glutaric and 3-hydroxyglutaric acids in the brain tissue of the affected patients. Considering that a toxic role was recently postulated for quinolinic acid in the neuropathology of glutaric acidemia type I, in the present work we investigated whether the combination of quinolinic acid with glutaric or 3-hydroxyglutaric acids or the mixture of glutaric plus 3-hydroxyglutaric acids could alter brain energy metabolism. The parameters evaluated in cerebral cortex from young rats were glucose utilization, lactate formation and (14)CO(2) production from labeled glucose and acetate, as well as the activities of pyruvate dehydrogenase and creatine kinase. We first observed that glutaric (5 mM), 3-hydroxyglutaric (1 mM) and quinolinic acids (0.1 microM) per se did not alter these parameters. Similarly, no change of these parameters occurred when combining glutaric with quinolinic acids or 3-hydroxyglutaric with quinolinic acids. In contrast, co-incubation of glutaric plus 3-hydroxyglutaric acids increased glucose utilization, decreased (14)CO(2) generation from glucose, inhibited pyruvate dehydrogenase activity as well as total and mitochondrial creatine kinase activities. The glutaric plus 3-hydroxyglutaric acids-induced inhibitory effects on creatine kinase were prevented by the antioxidants glutathione and catalase plus superoxide dismutase, indicating the participation of reactive oxygen species. Our data indicate a synergic action of glutaric and 3-hydroxyglutaric acids disturbing energy metabolism in cerebral cortex of young rats.
Assuntos
Química Encefálica/fisiologia , Encefalopatias Metabólicas/metabolismo , Encéfalo/metabolismo , Metabolismo Energético/fisiologia , Glutaratos/metabolismo , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Química Encefálica/efeitos dos fármacos , Encefalopatias Metabólicas/fisiopatologia , Creatina Quinase/metabolismo , Sinergismo Farmacológico , Metabolismo Energético/efeitos dos fármacos , Glucose/metabolismo , Glutaratos/toxicidade , Ácido Láctico/metabolismo , Deficiência Múltipla de Acil Coenzima A Desidrogenase/metabolismo , Deficiência Múltipla de Acil Coenzima A Desidrogenase/fisiopatologia , Técnicas de Cultura de Órgãos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Complexo Piruvato Desidrogenase/metabolismo , Ácido Quinolínico/metabolismo , Ácido Quinolínico/toxicidade , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismoRESUMO
Tissue accumulation of intermediates of the metabolism occurs in various inherited neurodegenerative disorders, including methylmalonic acidemia (MA). Animal cognition is usually tested by measuring learning/memory of rats in behavioral tasks. A procedure in which rats are chronically injected with the metabolites accumulating in the neurometabolic disorder methylmalonic acidemia from the 5th to the 28th day of life is described. The animals were allowed to recover for approximately 30 days, after which they were submitted to the Morris water maze task. This behavioral task consisted of two steps. The first one is called the acquisition phase, where rats were trained for 5 consecutive days performing four trials per day to find the submerged platform. On each trial, the rat was placed in the water in one of four start locations (N, S, W and E). The animal was then allowed to search for the platform for 60 s. Once the rat located the platform, it was permitted to remain on it for 10 s. The acquisition phase was followed by the probe trial 24 h later, in which the platform is not present. The time spent in the quadrant of the former platform position and the correct annulus crossings were obtained as a measure for spatial memory. The next step was the reversal learning (reversal phase) performed 2 weeks later. Animals were trained for 4 days (four trials per day) to find the hidden platform, which had now been moved to a position diagonally opposite (reversed) from its location in the acquisition phase. On the next day, all animals were submitted to a second probe trial, similar to the first one. We observed that rats chronically injected with methylmalonic acid (MA), although presenting no alterations in the acquisition phase, showed a long lasting reversal learning impairment. Moreover, motor activity, evaluated by the swim speed in the maze, was not altered by MA administration. These results are consistent with perseverative behavior.
Assuntos
Encefalopatias Metabólicas/metabolismo , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Ácido Metilmalônico/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Encefalopatias Metabólicas/induzido quimicamente , Encefalopatias Metabólicas/fisiopatologia , Transtornos Cognitivos/psicologia , Modelos Animais de Doenças , Esquema de Medicação , Masculino , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Transtornos da Memória/psicologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Ratos , Ratos Wistar , TempoRESUMO
This study investigated the effects of glutaric acid, which predominantly accumulates in glutaric acidemia type I, on some in vitro parameters of oxidative stress in brain of young rats. We evaluated chemiluminescence, total radical-antioxidant potential (TRAP) and the activities of the antioxidant enzymes catalase, glutathione peroxidase and superoxide dismutase in brain tissue homogenates in the presence of glutaric acid at concentrations ranging from 0.05 to 2.0 mM. The acid significantly increased chemiluminescence (up to 65%) and reduced total radical-antioxidant potential (up to 28%) and glutathione peroxidase activity (up to 46%), without affecting catalase and superoxide dismutase activities. The results provide evidence that glutaric acid induces oxidative stress in vitro in rat brain. If these findings also occur in humans, it is possible that they may contribute to the neuropathology of patients affected by glutaric acidemia type I.