RESUMO
Copper performs an important role in the brain, but in high levels it can be neurotoxic. Further, some authors have described that copper dyshomeostasis could be related with neurodegenerative diseases. Thus, this review was performed to observe whether high copper levels are related to Alzheimer's and Parkinson's diseases (AD and PD), using the literature published recently. Articles that measured copper levels in AD or PD patients was included, as well as they that measured copper levels in models used to mimic these diseases. Also, results about high copper levels effects and its relationship with AD and PD observed in laboratory animals are considered. In summary, 38 and 24 articles with AD and PD patients were included, respectively. Despite of the heterogeneity between the studies in humans, meta-analysis has demonstrated that there is an increase in free and total copper levels in the blood of AD patients compared to controls, and a decrease in copper levels in PD patients. A decrease in the metal content in postmortem brain tissue was observed in AD and PD. In manuscripts using animal models that mimic AD and PD, it was included seven and three articles, respectively. Two of them have reported an increase in copper concentrations in AD model, and one in PD model. Finally, studies with laboratory animals have concluded that high copper levels are related to oxidative stress, neuroinflammation, mitochondrial dysfunction, changes in neurotransmitter levels, cell death, and reduced both cognitive and locomotor activity, which are also described in AD or PD.
Assuntos
Doença de Alzheimer , Doença de Parkinson , Humanos , Animais , Doença de Alzheimer/metabolismo , Cobre/metabolismo , Doença de Parkinson/metabolismo , MetaisRESUMO
Manganese (Mn) is an essential metal for many functions in the body. However, in excess, it can be neurotoxic and cause a Parkinson-like syndrome, known as manganism. Here, we aimed to identify a protective effect of probucol, a lipid-lowering agent with anti-inflammatory and antioxidant properties, against Mn-induced toxicity in human neuroblastoma (SH-SY5Y) and glioblastoma (C6) cell lines. The cells were incubated with increasing concentrations of Mn followed by probucol addition 1, 3, 6, and/or 24 h to assess the metal toxic doses and measure the protective effect of probucol against Mn-induced oxidative damage. Longer exposition to Mn showed decreased SH-SY5Y cellular viability in concentrations higher than 100 µM, and probucol was able to prevent this effect. The C6 cells were more sensitive to the Mn deleterious actions, decreasing the cell viability after 6 h of 500 µM Mn exposure. In addition, probucol prevents the complex I and II of the mitochondrial respiratory chain (MRC) inhibition caused by Mn and decreased the intracellular ROS production. Taken together, our results showed that Mn toxicity affects differently both cell lines and probucol has a protective effect against the oxidative imbalance in the central nervous system.
Assuntos
Manganês , Probucol , Encéfalo/metabolismo , Linhagem Celular Tumoral , Humanos , Manganês/metabolismo , Manganês/toxicidade , Estresse Oxidativo , Probucol/metabolismo , Probucol/farmacologiaRESUMO
Several investigators demonstrated that glyphosate formulations produce neurotoxicity associated with oxidative stress, alterations in glutamatergic system, inhibition of acetylcholinesterase activity and mitochondrial dysfunction. However, the underlying molecular mechanisms following exposure to this herbicide on astrocytes are unclear. Thus, the aim of the present study was to determine the activity of enzymes related to energy metabolism, in addition to oxidative stress parameters, mitochondrial mass, nuclear area, and autophagy in astrocytes treated with a glyphosate-based herbicide. Our results showed that 24 h exposure to a glyphosate-based herbicide decreased (1) cell viability, (2) activities of mitochondrial respiratory chain enzymes and creatine kinase (CK), (3) mitochondrial mass, and (4) nuclear area in rat astroglioma cell line (C6 cells). However, non-protein thiol (NPSH) levels were increased but catalase activity was not changed in cells exposed to the herbicide at non-cytotoxic concentrations. Low glyphosate concentrations elevated content of cells positive to autophagy-related proteins. Nuclear factor erythroid 2-related factor (Nrf2), NAD(P)H dehydrogenase [quinone] 1 (NQO1) and PTEN-induced kinase 1 (PINK1) labeling were not markedly altered in cells exposed to glyphosate at the same concentrations that an increase in NPSH levels and positive cells to autophagy were found. It is conceivable that mitochondria and CK may be glyphosate-based herbicides targets. Further, autophagy induction and NPSH increase may be mechanisms initiated to avoid oxidative stress and cell death. However, more studies are needed to clarify the role of autophagy in astrocytes exposed to the herbicide and which components of the formulation might be triggering the effects observed here.
Assuntos
Autofagia/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Glicina/análogos & derivados , Herbicidas/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular , Glicina/toxicidade , Humanos , Espécies Reativas de Oxigênio , GlifosatoRESUMO
INTRODUCTION: Manganese (Mn) is an essential element required for several biological systems. However, it is toxic in excessive accumulation. The toxic effects following Mn overexposure is well known in the CNS but other studies evaluating other target tissues remain scarce. OBJECTIVE: This study aimed to investigate sex-related differences in oxidative stress, metabolic parameters and Mn deposition in peripheral organs of Wistar rats exposed to subacute model of intoxication. METHODS: Male and female adult Wistar rats received 6 or 15â¯mg/kg of MnCl2, intraperitoneally, 5 days a week, for 4 consecutive weeks to mimic subacute intoxication. Control group received sterile saline 0,9% following the same protocol. After this period, the metal accumulation, oxidative stress, mitochondrial activity and histological parameters in cardiac muscle, kidney, lungs and liver were analysed. RESULTS: Increased Mn concentrations were found in all organs, especially kidneys. The cardiac muscle analysis revealed increased lipid peroxidation and decreasing of GSH levels in both doses of Mn in male and female rats. The increase of lipid peroxidation in liver was more evident in the male group, and there was a significant decrease of antioxidant capacity in males' kidney. Nevertheless, there was an increase of mitochondrial complex I activity in kidney of females and increase of mitochondrial complex II activity in male group. Histological analysis revealed morphological changes in hepatic and pulmonary tissue. CONCLUSION: Taken together, our results showed that subacute Mn exposure lead to significant metabolic, biochemical alterations especially in kidney and liver. Nevertheless, despite Mn deposition was virtually the same in the peripheral organs of male and female rats, it promotes different toxic effects between sexes.
Assuntos
Coração/efeitos dos fármacos , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Manganês/farmacocinética , Manganês/toxicidade , Caracteres Sexuais , Animais , Relação Dose-Resposta a Droga , Feminino , Rim/metabolismo , Fígado/metabolismo , Pulmão/metabolismo , Masculino , Manganês/administração & dosagem , Manganês/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Chronic metabolic alterations may represent a risk factor for the development of cognitive impairment, dementia, or neurodegenerative diseases. Hyperglycemia and obesity are known to imprint epigenetic markers that compromise the proper expression of cell survival genes. Here, we showed that chronic hyperglycemia (60 days) induced by a single intraperitoneal injection of streptozotocin compromised cognition by reducing hippocampal ERK signaling and by inducing neurotoxicity in rats. The mechanisms appear to be linked to reduced active DNA demethylation and diminished expression of the neuroprotective transcription factor REST. The impact of the relationship between adiposity and DNA hypermethylation on REST expression was also demonstrated in peripheral blood mononuclear cells in obese children with reduced levels of blood ascorbate. The reversible nature of epigenetic modifications and the cognitive impairment reported in obese children, adolescents, and adults suggest that the correction of the anthropometry and the peripheral metabolic alterations would protect brain homeostasis and reduce the risk of developing neurodegenerative diseases.
Assuntos
Transtornos Cognitivos/etiologia , Diabetes Mellitus Experimental/complicações , Hipocampo/metabolismo , Hiperglicemia/complicações , Proteínas Repressoras/metabolismo , Animais , Aprendizagem da Esquiva/fisiologia , Transtornos Cognitivos/genética , Transtornos Cognitivos/metabolismo , Metilação de DNA , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Humanos , Hiperglicemia/genética , Hiperglicemia/metabolismo , Aprendizagem em Labirinto/fisiologia , Ratos , Proteínas Repressoras/genéticaRESUMO
Parkinson's disease (PD), the second-most prevalent neurodegenerative disease, is primarily characterized by neurodegeneration in the substantia nigra pars compacta, resulting in motor impairment. Loss-of-function mutations in parkin are the major cause of the early onset familial form of the disease. Although rodents deficient in parkin (parkin(-/-) ) have some dopaminergic system dysfunction associated with central oxidative stress and energy metabolism deficiencies, these animals only display nigrostriatal pathway degeneration under inflammatory conditions. This study investigated the impact of the inflammatory stimulus induced by lypopolisaccharide (LPS) on tetrahydrobiopterin (BH4) synthesizing enzymes (de novo and salvage pathways), since this cofactor is essential for dopamine synthesis. The mitochondrial content and architecture was investigated in the striatum of LPS-exposed parkin(-/-) mice. As expected, the LPS (0.33 mg/kg; i.p.) challenge compromised spontaneous locomotion and social interaction with juvenile parkin(-/-) and WT mice. Moreover, the genotype impacted the kinetics of the investigation of the juvenile. The inflammatory scenario did not induce apparent changes in mitochondrial ultrastructure; however, it increased the quantity of mitochondria, which were of smaller size, and provoked the perinuclear distribution of the organelle. Furthermore, the BH4 de novo biosynthetic pathway failed to be up-regulated in the LPS challenge, a well-known stimulus for its activation. The LPS treatment increased sepiapterin reductase (SPR) expression, suggesting compensation by the salvage pathway. This might indicate that dopamine synthesis is compromised in parkin(-/-) mice under inflammatory conditions. Finally, this scenario impaired the striatal expression of the transcription factor BDNF, possibly favoring cell death.
Assuntos
Biopterinas/análogos & derivados , Corpo Estriado/metabolismo , Ubiquitina-Proteína Ligases/genética , Oxirredutases do Álcool/metabolismo , Animais , Comportamento Animal , Biopterinas/biossíntese , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Lipopolissacarídeos/farmacologia , Locomoção , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Plasticidade Neuronal/fisiologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Doença de Parkinson/veterinária , Ubiquitina-Proteína Ligases/deficiência , Regulação para Cima/efeitos dos fármacosRESUMO
Interest in biochemistry of organoselenium compound has increased in the last decades, mainly due to their chemical and biological activities. Here, we investigated the protective effect of diphenyl diselenide (PhSe)2 (5 µmol/kg), in a mouse model of methylmercury (MeHg)-induced brain toxicity. Swiss male mice were divided into four experimental groups: control, (PhSe)2 (5 µmol/kg, subcutaneous administration), MeHg (40 mg/L, in tap water), and MeHg + (PhSe)2. After the treatment (21 days), the animals were killed and the cerebral cortex was analyzed. Electron microscopy indicated an enlarged and fused mitochondria leading to a reduced number of organelles, in the MeHg-exposed mice. Furthermore, cortical creatine kinase activity, a sensitive mitochondrial oxidative stress sensor, was almost abolished by MeHg. Subcutaneous (PhSe)2 co-treatment rescued from MeHg-induced mitochondrial alterations. (PhSe)2 also behaved as an enhancer of mitochondrial biogenesis, by increasing cortical mitochondria content in mouse-receiving (PhSe)2 alone. Mechanistically, (PhSe)2 (1 µM; 24 h) would trigger the cytoprotective Nrf-2 pathway for activating target genes, since astroglial cells exposed to the chalcogen showed increased content of hemeoxygenase type 1, a sensitive marker of the activation of this via. Thus, it is proposed that the (PhSe)2-neuroprotective effect might be linked to its mitoprotective activity.
Assuntos
Derivados de Benzeno/administração & dosagem , Encéfalo/metabolismo , Heme Oxigenase-1/biossíntese , Mitocôndrias/metabolismo , Compostos Organosselênicos/administração & dosagem , Animais , Encéfalo/patologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Masculino , Intoxicação do Sistema Nervoso por Mercúrio/metabolismo , Intoxicação do Sistema Nervoso por Mercúrio/patologia , Compostos de Metilmercúrio/toxicidade , Camundongos , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacosRESUMO
Interest in organoselenide chemistry and biochemistry has increased in the past three decades, mainly due to their chemical and biological activities. Here, we investigated the protective effect of the organic selenium compound diphenyl diselenide (PhSe)2 (5 µmol/kg), in a mouse model of methylmercury (MeHg)-induced brain toxicity. Our group has previously demonstrated that the oral and repeated administration (21 days) of MeHg (40 mg/L) induced MeHg brain accumulation at toxic concentrations, and a pattern of severe cortical and cerebellar biochemical and behavioral. In order to assess neurotoxicity, the neurochemical parameters, namely, mitochondrial complexes I, II, II-III and IV, glutathione peroxidase (GPx) and glutathione reductase (GR) activities, the content of thiobarbituric acid-reactive substances (TBA-RS), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and brain-derived neurotrophic factor (BDNF), as well as, metal deposition were investigated in mouse cerebral cortex. Cortical neurotoxicity induced by brain MeHg deposition was characterized by the reduction of complexes I, II, and IV activities, reduction of GPx and increased GR activities, increased TBA-RS and 8-OHdG content, and reduced BDNF levels. The daily treatment with (PhSe)2 was able to counteract the inhibitory effect of MeHg on mitochondrial activities, the increased oxidative stress parameters, TBA-RS and 8-OHdG levels, and the reduction of BDNF content. The observed protective (PhSe)2 effect could be linked to its antioxidant properties and/or its ability to reduce MeHg deposition in brain, which was here histochemically corroborated. Altogether, these data indicate that (PhSe)2 could be consider as a neuroprotectant compound to be tested under neurotoxicity.
Assuntos
Antineoplásicos/farmacologia , Derivados de Benzeno/farmacologia , Córtex Cerebral/efeitos dos fármacos , Modelos Animais de Doenças , Fármacos Neuroprotetores/farmacologia , Compostos Organosselênicos/farmacologia , Animais , Antineoplásicos/química , Derivados de Benzeno/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Masculino , Compostos de Metilmercúrio/química , Compostos de Metilmercúrio/farmacologia , Camundongos , Fármacos Neuroprotetores/química , Compostos Organosselênicos/química , Relação Estrutura-AtividadeRESUMO
In the present study, we investigated whether mild-intensity physical exercise represents a successful strategy to enhance spatial learning and memory and hippocampal plasticity in aging rats, as previously described for long-term exposure to running wheel or treadmill exercise. Aging Wistar rats were submitted to short bouts (4-6 min) of exercise treadmill during five consecutive weeks. This mild-intensity exercise program increased muscle oxygen consumption by soleus and heart in aging rats and reversed age-related long-term spatial learning and memory impairments evaluated in the water maze and step-down inhibitory avoidance tasks. Remarkably, the observed cognitive-enhancing properties of short bouts of exercise were accompanied by the activation of serine/threonine protein kinase (AKT) and cAMP response element binding (CREB) pro-survival signaling that culminates in the marked increase on the brain-derived neurotrophic factor (BDNF) mRNA expression and BDNF protein levels on the hippocampus of aging rats. Altogether, these results indicate that short bouts of exercise represent a viable behavioral strategy to improve cognition and synaptic plasticity in aging rats which should be taken into account in further studies addressing the effects of physical exercise in aging subjects.
Assuntos
Envelhecimento/fisiologia , Envelhecimento/psicologia , Aprendizagem/fisiologia , Memória/fisiologia , Condicionamento Físico Animal/fisiologia , Condicionamento Físico Animal/psicologia , Idoso , Envelhecimento/genética , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/fisiologia , Feminino , Hipocampo/fisiologia , Humanos , Músculo Esquelético/fisiologia , Plasticidade Neuronal/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais , Comportamento Espacial/fisiologiaRESUMO
Large scale clinical trials have demonstrated that an intensive antihyperglycemic treatment in diabetes mellitus (DM) in individuals reduces the incidence of micro- and macrovascular complications, e.g. nephropathy, retinopathy, DM-accelerated atherosclerosis, myocardial infarction, or limb amputations. Here, we investigated the effect of short- and long-term insulin administration on mitochondrial function in peripheral tissues of streptozotocin (STZ)-induced hyperglycemic rats. In addition, the in vitro effect of methylglyoxal (MG), advanced glycation end products (AGEs) and human diabetic plasma on mitochondrial activity was investigated in skeletal muscle and liver mitochondria and in rat skin primary fibroblasts. Hyperglycemic STZ rats showed tissue-specific patterns of energy deficiency, evidenced by reduced activities of complexes I, II and/or IV after 30 days of hyperglycemia in heart, skeletal muscle and liver; moreover, cardiac tissue was found to be the most sensitive to the diabetic condition, since energy metabolism was impaired after 10 days of the hyperglycemia. Insulin-induced tight glycemic control was effective in protecting against the hyperglycemia-induced inhibition of mitochondrial enzyme activities. Furthermore, the long-term hormone replacement (30 days) also increased these activities in kidney from STZ-treated animals, where the hyperglycemic state did not modify the electron transport activity. Results from in vitro experiments indicate that mitochondrial impairment could result from oxidative stress-induced accumulation of MG and/or AGEs. Further investigations demonstrated that human plasma AGE accumulation elicits reduced mitochondrial function in skin fibroblast. These data suggest that persistent hyperglycemia results in tissue-specific patterns of energy deficiency and that early and continuous insulin therapy is necessary to maintain proper mitochondrial metabolism.
Assuntos
Diabetes Mellitus/fisiopatologia , Metabolismo Energético , Produtos Finais de Glicação Avançada/metabolismo , Hiperglicemia/fisiopatologia , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Mitocôndrias/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antibióticos Antineoplásicos/toxicidade , Glicemia/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Transporte de Elétrons , Fibroblastos/citologia , Fibroblastos/metabolismo , Coração/fisiologia , Humanos , Hiperglicemia/induzido quimicamente , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Mitocôndrias/patologia , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Estresse Oxidativo , Consumo de Oxigênio , Aldeído Pirúvico/metabolismo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Pele/citologia , Pele/metabolismo , Estreptozocina/toxicidadeRESUMO
Selenium can counteract methylmercury (MeHg) neurotoxicity. However, data about the neuroprotective effects of sodium selenite (Na(2)SeO(3)) on the activity of mitochondrial complexes and creatine kinase (mtCK) are scarce. Therefore, this study investigated the effects of the chronic exposure to Na(2)SeO(3) on brain energy metabolism and oxidative stress parameters in MeHg-poisoned mice. Adult male mice were orally treated with MeHg (40 mg L(-1) in drinking water, ad libitum) during 21 days and simultaneously administrated with daily subcutaneous injections of Na(2)SeO(3) (5 µmol kg(-1)), a potential neuroprotectant. Mitochondrial complexes I to IV and mtCK activities were measured in cerebral cortex mitochondria. The cerebro-cortical tissue was also used to evaluate the antioxidant enzymes glutathione peroxidase (GPx) and glutathione reductase (GR) activities, as well as lipid peroxidation. Metal deposition was followed autometalographically (AMG). Na(2)SeO(3) partially prevented MeHg-induced inhibition of complexes II-III, IV and mtCK activities; however, it was unable to prevent MeHg-induced complex I and II inhibition. MeHg increased lipid peroxidation, GR activity and decreased GPx activity in the cerebral cortex; however, Na(2)SeO(3) did not modify such events. Furthermore, Na(2)SeO(3)per se inhibited complexes I, II-III and IV and mtCK activities and increased GPx and GR activities and lipid peroxidation. These data show that inorganic selenium was ineffective in preventing most of the MeHg-induced brain biochemical alterations. However, the most prominent finding was the selenium-induced reduction of cells labelled for metal deposition. Although, the literature supports the beneficial effects of selenium against mercury toxicity, the toxic effects elicited by Na(2)SeO(3), alone or in combination with mercury, should be considered when this compound is proposed as a potential protective therapy for MeHg poisoning.
Assuntos
Córtex Cerebral/efeitos dos fármacos , Compostos de Metilmercúrio/toxicidade , Síndromes Neurotóxicas/metabolismo , Selenito de Sódio/administração & dosagem , Animais , Córtex Cerebral/metabolismo , Transporte de Elétrons/efeitos dos fármacos , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Selenito de Sódio/farmacologiaRESUMO
Methylmercury (MeHg), a potent neurotoxicant, easily passes through the blood-brain barrier and accumulates in brain causing severe irreversible damage. However, the underlying neurotoxic mechanisms elicited by MeHg are still not completed defined. In this study, we aimed to investigate the in vitro toxic effects elicited by crescent concentrations (0-1500 microM) of MeHg on creatine kinase (CK) activity, thiol content (NPSH) and protein carbonyl content (PCC) in mouse brain preparations. In addition, CK activity, MTT reduction and DCFH-DA oxidation (reactive oxygen species (ROS) formation) were also measured in C6 glioma cell linage. CK activity was severely reduced by MeHg treatment in mouse brain preparations. This inhibitory effect was positively correlated to the MeHg-induced reduction of NPSH levels and increment in PCC. Moreover, the positive correlation between brain CK activity and NPSH levels was observed at either 15 or 60 min of MeHg pre-incubation. In addition, MeHg-treated C6 cells showed also a significant inhibition of CK activity at MeHg concentrations, as low as, 50 microM in parallel to reduced mitochondrial function and increased ROS production. Taking together, these data demonstrate that MeHg severely affects CK activity, an essential enzyme for brain energy buffering to maintain cellular energy homeostasis. This effect appears to be mediated by oxidation of thiol groups that might cause subsequent oxidative stress.
Assuntos
Encéfalo/efeitos dos fármacos , Creatina Quinase/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Compostos de Metilmercúrio/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Análise de Variância , Animais , Astrocitoma/patologia , Encéfalo/enzimologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Masculino , Camundongos , Carbonilação Proteica/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Sais de Tetrazólio , Tiazóis , Fatores de TempoRESUMO
Leucine accumulates in fluids and tissues of patients affected by maple syrup urine disease, an inherited metabolic disorder, predominantly characterized by neurological dysfunction. Although, a variable degree of cognition/psychomotor delay/mental retardation is found in a considerable number of individuals affected by this deficiency, the mechanisms underlying the neuropathology of these alterations are still not defined. Therefore, the aim of this study was to investigate the effect of acute intra-hippocampal leucine administration in the step-down test in rats. In addition, the leucine effects on the electrophysiological parameter, long-term potentiation generation, and on the activities of the respiratory chain were also investigated. Male Wistar rats were bilaterally administrated with leucine (80 nmol/hippocampus; 160 nmol/rat) or artificial cerebrospinal fluid (controls) into the hippocampus immediately post-training in the behavioral task. Twenty-four hours after training in the step-down test, the latency time was evaluated and afterwards animals were sacrificed for assessing the ex vivo biochemical measurements. Leucine-treated animals showed impairment in memory consolidation and a complete inhibition of long-term potentiation generation at supramaximal stimulation. In addition, a significant increment in complex IV activity was observed in hippocampus from leucine-administered rats. These data strongly indicate that leucine compromise memory consolidation, and that impairment of long-term potentiation generation and unbalance of the respiratory chain may be plausible mechanisms underlying the deleterious leucine effect on cognition.