RESUMO
The rapid spread of the coronavirus disease 2019 (COVID-19) pandemic has shaken hospitals worldwide. Some authors suggest that neurologic involvement could further complicate the disease. This descriptive study is a cross-sectional review of 103 patients diagnosed with COVID-19 who underwent neuroimaging (of a total of 2249 patients with COVID-19 in our center). Analyzed variables were neurologic symptoms and acute imaging findings. The most frequent symptoms that motivated neuroimaging examinations were mild nonfocal neurologic symptoms, code stroke (refers to patients presenting with signs and symptoms of stroke whose hyperacute assessment and care is prioritized), focal neurologic symptoms, postsedation encephalopathy, and seizures. No cases of encephalitis or direct central nervous system involvement were detected. Thirteen patients presented with acute ischemic events, and 7, with hemorrhagic events; however, most reported multiple vascular risk factors. Despite the large cohort of patients with COVID-19, we found a large number of symptomatic patients with negative neuroimaging findings, and no conclusions can be drawn concerning concrete associations between neuroimaging and COVID-19.
Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Neuroimagem , Pneumonia Viral/complicações , Acidente Vascular Cerebral/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19 , Estudos Transversais , Encefalite , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Fatores de Risco , SARS-CoV-2RESUMO
INTRODUCTION: Alzheimer disease (AD) is a major neurodegenerative disorder which eventually results in total intellectual disability. The high global prevalence and the socioeconomic burden associated with the disease pose major challenges for public health in the 21st century. In this review we focus on both existing treatments and the therapies being developed, which principally target the ß-amyloid protein. DISCUSSION: The amyloidogenic hypothesis proposes that ß-amyloid plays a key role in AD. Several pharmacological approaches aim to reduce the formation of ß-amyloid peptides by inhibiting the ß-secretase and γ-secretase enzymes. In addition, both passive and active immunotherapies have been developed for the purpose of inhibiting ß-amyloid peptide aggregation. CONCLUSIONS: Progress in identifying the molecular basis of AD may provide better models for understanding the causes of this neurodegenerative disease. The lack of efficacy of solanezumab (a humanised monoclonal antibody that promotes ß-amyloid clearance in the brain), demonstrated by 2 recent Phase III clinical trials in patients with mild AD, suggests that the amyloidogenic hypothesis needs to be revised.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide , Secretases da Proteína Precursora do Amiloide/metabolismo , Anticorpos Monoclonais Humanizados , HumanosRESUMO
With upcoming age, the capability to fight against harmful stimuli decreases and the organism becomes more susceptible to infections and diseases. Here, the objective was to demonstrate the effect of dietary resveratrol in aged mice in potentiating brain defenses against LipoPolySaccharide (LPS). Acute LPS injection induced a strong proinflammatory effect in 24-months-old C57/BL6 mice hippocampi, increasing InterLeukin (Il)-6, Tumor Necrosis Factor-alpha (Tnf-α), Il-1ß, and C-X-C motif chemokine (Cxcl10) gene expression levels. Resveratrol induced higher expression in those cytokines regarding to LPS. Oxidative Stress (OS) markers showed not significant changes after LPS or resveratrol, although for resveratrol treated groups a slight increment in most of the parameters studies was observed, reaching signification for NF-kB protein levels and iNOS expression. However, Endoplasmic Reticulum (ER) stress markers demonstrated significant changes in resveratrol-treated mice after LPS treatment, specifically in eIF2α, BIP, and ATF4. Moreover, as described, resveratrol is able to inhibit the mechanistic Target of Rapamycin (mTOR) pathway and this effect could be linked to (eIF2α) phosphorylation and the increase in the expression of the previously mentioned proinflammatory genes as a response to LPS treatment in aged animals. In conclusion, resveratrol treatment induced a different cellular response in aged animals when they encountered acute inflammatory stimuli.
Assuntos
Anti-Inflamatórios/farmacologia , Hipocampo/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Inflamação/prevenção & controle , Resveratrol/farmacologia , Fatores Etários , Envelhecimento , Animais , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fator de Iniciação 2B em Eucariotos/metabolismo , Regulação da Expressão Gênica , Hipocampo/metabolismo , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/metabolismo , Lipopolissacarídeos , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismoRESUMO
Metabolic stress induced by high-fat (HF) diet leads to cognitive dysfunction and aging, but the physiological mechanisms are not fully understood. Senescence-accelerated prone mouse (SAMP8) models were conducted under metabolic stress conditions by feeding HF for 15 weeks, and the preventive effect of resveratrol was studied. This dietary strategy demonstrates cognitive impairment in SAMP8-HF and significant preventive effect by resveratrol-treated animals. Hippocampal changes in the proteins involved in mitochondrial dynamics optic atrophy-1 protein (OPA1) and mitofusin 2 (MFN2) comprised a differential feature found in SAMP8-HF that was prevented by resveratrol. Electronic microscopy showed a larger mitochondria in SAMP8-HF + resveratrol (SAMP8-HF + RV) than in SAMP8-HF, indicating increases in fusion processes in resveratrol-treated mice. According to the mitochondrial morphology, significant increases in the I-NDUFB8, II-SDNB, III-UQCRC2, and V-ATPase complexes, in addition to that of voltage-dependent anion channel 1 (VDAC1)/porin, were found in resveratrol-treated animals with regard to SAMP8-HF, reaching control-animal levels. Moreover, tumor necrosis factor alpha (TNF-α) and interleukin (IL-6) were increased after HF, and resveratrol prevents its increase. Moreover, we found that the HF diet affected the Wnt pathway, as demonstrated by ß-catenin inactivation and modification in the expression of several components of this pathway. Resveratrol induced strong activation of ß-catenin. The metabolic stress rendered in the cognitive and cellular pathways altered in SAMP8 focus on different targets in order to act on preventing cognitive impairment in neurodegeneration, and resveratrol can offer therapeutic possibilities for preventive strategies in aging or neurodegenerative conditions.
Assuntos
Encéfalo/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Estilbenos/farmacologia , Estresse Fisiológico/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Encéfalo/fisiologia , Senescência Celular/fisiologia , Dieta Hiperlipídica/efeitos adversos , Masculino , Camundongos , Mitocôndrias/fisiologia , Fármacos Neuroprotetores/farmacologia , Distribuição Aleatória , Resveratrol , Via de Sinalização Wnt/fisiologiaRESUMO
Dexibuprofen-loaded PEGylated PLGA nanospheres have been developed to improve the biopharmaceutical profile of the anti-inflammatory drug for ocular administration. Dexibuprofen is the active enantiomer of ibuprofen and therefore lower doses may be applied to achieve the same therapeutic level. According to this, two batches of nanospheres of different drug concentrations, 0.5 and 1.0mg/ml respectively, have been developed (the latter corresponding to the therapeutic ibuprofen concentration for inflammatory eye diseases). Both batches were composed of negatively charged nanospheres (--14.1 and --15.9mV), with a mean particle size below 200nm, and a high encapsulation efficiency (99%). X-ray, FTIR, and DSC analyses confirmed that the drug was dispersed inside the matrix of the nanospheres. While the in vitro release profile was sustained up to 12h, the ex vivo corneal and scleral permeation profile demonstrated higher drug retention and permeation in the corneal tissue rather than in the sclera. These results were also confirmed by the quantification of dexibuprofen in ocular tissues after the in vivo administration of drug-loaded nanospheres. Cell viability studies confirmed that PEGylated-PLGA nanospheres were less cytotoxic than free dexibuprofen in the majority of the tested concentrations. Ocular in vitro (HET-CAM test) and in vivo (Draize test) tolerance assays demonstrated the non-irritant character of both nanosphere batches. In vivo anti-inflammatory effects were evaluated in albino rabbits before and after inflammation induction. Both batches confirmed to be effective to treat and prevent ocular inflammation.
Assuntos
Ibuprofeno/análogos & derivados , Ácido Láctico/química , Nanosferas/química , Ácido Poliglicólico/química , Administração Oftálmica , Animais , Disponibilidade Biológica , Morte Celular/efeitos dos fármacos , Córnea/efeitos dos fármacos , Liberação Controlada de Fármacos , Ibuprofeno/administração & dosagem , Ibuprofeno/farmacologia , Inflamação/patologia , Masculino , Permeabilidade , Polietilenoglicóis/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Coelhos , Esclera/efeitos dos fármacosRESUMO
(±)3,4-Methylenedioxymethamphetamine (MDMA) is a relatively selective dopaminergic neurotoxin in mice. This study was designed to evaluate whether MDMA exposure affects their recognition memory and hippocampal expression of plasticity markers. Mice were administered with increasing doses of MDMA once per week for 8 weeks (three times in 1 day, every 3 h) and killed 2 weeks (2w) or 3 months (3m) later. The treatment did not modify hippocampal tryptophan hydroxylase 2, a serotonergic indicator, but induced an initial reduction in dopaminergic markers in substantia nigra, which remained stable for at least 3 months. In parallel, MDMA produced a decrease in dopamine (DA) levels in the striatum at 2w, which were restored 3 months later, suggesting dopaminergic terminal regeneration (sprouting phenomenon). Moreover, recognition memory was assessed using the object recognition test. Young (2w) and mature (3m) adult mice exhibited impaired memory after 24-h but not after just 1-h retention interval. Two weeks after the treatment, animals showed constant levels of CREB but an increase in its phosphorylated form and in c-Fos expression. Brain-derived neurotrophic factor (BDNF) and especially Arc overexpression was sustained and long-lasting. We cannot rule out the absence of MDMA injury in the hippocampus being due to the generation of BDNF. The levels of NMDAR2B, PSD-95, and synaptophysin were unaffected. In conclusion, the young mice exposed to MDMA showed increased expression of early key markers of plasticity, which sometimes remained for 3 months, and suggests hippocampal maladaptive plasticity that could explain memory deficits evidenced here.
Assuntos
Envelhecimento/patologia , Hipocampo/fisiopatologia , Transtornos da Memória/fisiopatologia , Plasticidade Neuronal , Animais , Biomarcadores/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/metabolismo , Masculino , Memória , Camundongos Endogâmicos C57BL , N-Metil-3,4-Metilenodioxianfetamina , Neurônios/metabolismo , Neurônios/patologia , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
A growing body of evidence suggests that ß-amyloid peptides (Aß) are unlikely to be the only factor involved in Alzheimer's disease (AD) aetiology. In fact, a strong correlation has been established between AD patients and patients with type 2 diabetes and/or cholesterol metabolism alterations. In addition, a link between adipose tissue metabolism, leptin signalling in particular, and AD has also been demonstrated. In the present study we analyzed the expression of molecules related to metabolism, with the main focus on leptin and prolactin signalling pathways in an APPswe/PS1dE9 (APP/PS1) transgenic mice model, at 3 and 6 months of age, compared to wild-type controls. We have chosen to study 3 months-old APP/PS1 animals at an age when neither the cognitive deficits nor significant Aß plaques in the brain are present, and to compare them to the 6 months-old mice, which exhibit elevated levels of Aß in the hippocampus and memory loss. A significant reduction in both mRNA and protein levels of the prolactin receptor (PRL-R) was detected in the hippocampi of 3 months old APP/PS1 mice, with a decrease in the levels of the leptin receptor (OB-R) first becoming evident at 6 months of age. We proceeded to study the expression of the intracellular signalling molecules downstream of these receptors, including stat (1-5), sos1, kras and socs (1-3). Our data suggest a downregulation in some of these molecules such as stat-5b and socs (1-3), in 3 months-old APP/PS1 brains. Likewise, at the same age, we detected a significant reduction in mRNA levels of lrp1 and cyp46a1, both of which are involved in cholesterol homeostasis. Taken together, these results demonstrate a significative impairment in adipokine receptors signalling and cholesterol regulation pathways in the hippocampus of APP/PS1 mice at an early age, prior to the Aß plaque formation.
Assuntos
Adipocinas/metabolismo , Doença de Alzheimer/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Colesterol/metabolismo , Colesterol 24-Hidroxilase , Diabetes Mellitus Tipo 2/metabolismo , Ingestão de Alimentos/genética , Hipocampo/fisiopatologia , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Masculino , Transtornos da Memória , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Obesidade/genética , Placa Amiloide/genética , Placa Amiloide/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de LDL/genética , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Receptores da Prolactina/genética , Receptores da Prolactina/metabolismo , Proteína SOS1/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Esteroide Hidroxilases/genética , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Proteínas Supressoras de Tumor/genéticaRESUMO
The amyloid precursor protein/presenilin 1 (APP/PS1) mouse model of Alzheimer's disease (AD) has provided robust neuropathological hallmarks of familial AD-like pattern at early ages, whereas senescence-accelerated mouse prone 8 (SAMP8) has a remarkable early senescence phenotype with pathological similarities to AD. The aim of this study was the investigation and characterization of cognitive and neuropathological AD markers in a novel mouse model that combines the characteristics of the APP/PS1 transgenic mouse model with a senescence-accelerated background of SAMP8 mice. Initially, significant differences were found regarding amyloid plaque formation and cognitive abnormalities. Bearing these facts in mind, we determined a general characterization of the main AD brain molecular markers, such as alterations in amyloid pathway, neuroinflammation, and hyperphosphorylation of tau in these mice along their lifetimes. Results from this analysis revealed that APP/PS1 in SAMP8 background mice showed alterations in the pathways studied in comparison with SAMP8 and APP/PS1, demonstrating that a senescence-accelerated background exacerbated the amyloid pathology and maintained the cognitive dysfunction present in APP/PS1 mice. Changes in tau pathology, including the activity of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3 ß (GSK3ß), differs, but not in a parallel manner, with amyloid disturbances.
Assuntos
Envelhecimento/fisiologia , Doença de Alzheimer/etiologia , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/fisiologia , Presenilina-1/fisiologia , Proteínas tau/fisiologia , Envelhecimento/patologia , Doença de Alzheimer/metabolismo , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , FenótipoRESUMO
The autophagic process is a lysosomal degradation pathway, which is activated during stress conditions, such as starvation or exercise. Regular exercise has beneficial effects on human health, including neuroprotection. However, the cellular mechanisms underlying these effects are incompletely understood. Endurance and a single bout of exercise induce autophagy not only in brain but also in peripheral tissues. However, little is known whether autophagy could be modulated in brain and peripheral tissues by long-term moderate exercise. Here, we examined the effects on macroautophagy process of long-term moderate treadmill training (36 weeks) in adult rats both in brain (hippocampus and cerebral cortex) and peripheral tissues (skeletal muscle, liver and heart). We assessed mTOR activation and the autophagic proteins Beclin 1, p62, LC3B (LC3B-II/LC3B-I ratio) and the lysosomal protein LAMP1, as well as the ubiquitinated proteins. Our results showed in the cortex of exercised rats an inactivation of mTOR, greater autophagy flux (increased LC3-II/LC3-I ratio and reduced p62) besides increased LAMP1. Related with these effects a reduction in the ubiquitinated proteins was observed. No significant changes in the autophagic pathway were found either in hippocampus or in skeletal and cardiac muscle by exercise. Only in the liver of exercised rats mTOR phosphorylation and p62 levels increased, which could be related with beneficial metabolic effects in this organ induced by exercise. Thus, our findings suggest that long-term moderate exercise induces autophagy specifically in the cortex.
Assuntos
Autofagia/fisiologia , Córtex Cerebral/metabolismo , Fígado/metabolismo , Condicionamento Físico Animal/fisiologia , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Proteína Beclina-1 , Proteínas de Choque Térmico/metabolismo , Hipocampo/metabolismo , Proteínas de Membrana Lisossomal/metabolismo , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Ratos Sprague-Dawley , Proteína Sequestossoma-1 , Serina-Treonina Quinases TOR/metabolismoRESUMO
An active lifestyle involving regular exercise reduces the deleterious effects of the aging process. At the cerebral level, both synaptic plasticity and neurogenesis are modulated by exercise, although the molecular mechanisms underlying these effects are not clearly understood. In the mature nervous system, the canonical Wnt (Wnt/ß-catenin) signaling pathway is implicated in neuroprotection and synaptic plasticity. Here, we examined whether the Wnt pathway could be modulated in adult male rat hippocampus by long-term moderate exercise (treadmill running) or enrichment (handling/environmental stimulation). Sedentary animals showed higher protein levels of the Wnt antagonist, Dkk-1, the lowest levels being found in the exercised group. Although there was no evidence of any changes in activation of the LRP6 receptor, the total levels of LRP6 were higher in exercised and enriched animals. Analysis of some of the components implicated in the phosphorylation of ß-catenin, which leads ultimately to its proteasomal degradation, revealed higher levels and activation of Axin1 and GSK-3α/ß respectively in sedentary animals. However neither different phosphorylated forms nor total ß-catenin protein levels differed between the experimental groups. Higher protein levels of Axin2 and the antiapoptotic protein, Bcl-2, were found with exercise and handling, whereas the proapototic, Bax, was unaffected. Thus, our results suggest activation of the Wnt pathway not only with moderate exercise, but also with the handling of the animals.
Assuntos
Regulação da Expressão Gênica/fisiologia , Condicionamento Físico Animal/fisiologia , Proteínas Wnt/metabolismo , Via de Sinalização Wnt/fisiologia , Proteínas Adaptadoras de Transdução de Sinal , Análise de Variância , Animais , Proteínas de Transporte/metabolismo , Teste de Esforço , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Tempo , Proteínas Wnt/genética , beta Catenina/metabolismoRESUMO
Melatonin has been shown to down-regulate inflammatory responses and provide neuroprotection. However, the mechanisms underlying the anti-inflammatory properties of melatonin are poorly understood. In the present work, we studied the modulatory effect of melatonin against pro-inflammatory cytokines in glial cell cultures. Treatment with pro-inflammatory cytokines mainly tumor necrosis factor-alpha, interleukin 1-beta, and interferon-gamma induces an increase in inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production. Pre-treatment with melatonin produced an inhibitory effect on iNOS expression and NO production. The biochemical studies revealed that cytokine treatment favors the activation of several pathways, such as mitogen-activated protein kinases (MAPKs), STAT1, and STAT3; however, the anti-inflammatory effect of melatonin was accompanied only by a decrease in p38 MAPK activity. Likewise, SB203580 a p38 kinase inhibitor inhibits NO production. These data indicate that the anti-inflammatory action of melatonin in glial cells after stimulation with pro-inflammatory cytokines may be in part, attributable to p38 inhibition which down-regulates iNOS expression and NO production.
Assuntos
Anti-Inflamatórios/farmacologia , Citocinas/fisiologia , Sistema de Sinalização das MAP Quinases , Melatonina/farmacologia , Neuroglia/metabolismo , Óxido Nítrico/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/farmacologia , Guanilato Ciclase , Mediadores da Inflamação/farmacologia , Mediadores da Inflamação/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Neuroglia/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Current knowledge concerning the molecular mechanisms of the cellular response to excitotoxic insults in neurodegenerative diseases is insufficient. Although glutamate (Glu) has been widely studied as the main excitatory neurotransmitter and principal excitotoxic agent, the neuroprotective response enacted by neurons is not yet completely understood. Some of the molecular participants have been revealed, but the signaling pathways involved in this protective response are just beginning to be identified. Here, we demonstrate in vivo that, in response to the cell damage and death induced by Glu excitotoxicity, neurons orchestrate a survival response through the extracellular signal-regulated kinase (ERK) signaling pathway by increasing ERK expression in the rat hippocampal (CA1) region, allowing increased neuronal survival. In addition, this protective response is specifically reversed by U0126, an ERK inhibitor, which promotes cell death only when it is administered together with Glu. Our findings demonstrate that the ERK signaling pathway has a neuroprotective role in the response to Glu-induced excitotoxicity in hippocampal neurons. Therefore, the ERK signaling pathway may be activated as a cellular response to excitotoxic injury to prevent damage and neural loss, representing a novel therapeutic target in the treatment of neurodegenerative diseases.
Assuntos
Região CA1 Hipocampal/metabolismo , Ácido Glutâmico/toxicidade , Sistema de Sinalização das MAP Quinases , Neurônios/metabolismo , Potenciais de Ação , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/efeitos dos fármacos , Sobrevivência Celular , Células Cultivadas , Neurônios/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Aging is associated with an increased risk of depression in humans. To elucidate the underlying mechanisms of depression and its dependence on aging, here we study signs of depression in male SAMP8 mice. For this purpose, we used the forced swimming test (FST). The total floating time in the FST was greater in SAMP8 than in SAMR1 mice at 9 months of age; however, this difference was not observed in 12-month-old mice, when both strains are considered elderly. Of the two strains, only the SAMP8 animals responded to imipramine treatment. We also applied the dexamethasone suppression test (DST) and studied changes in the dopamine and serotonin (5-HT) uptake systems, the 5-HT2a/2c receptor density in the cortex, and levels of TPH2. The DST showed a significant difference between SAMR1 and SAMP8 mice at old age. SAMP8 exhibits an increase in 5-HT transporter density, with slight changes in 5-HT2a/2c receptor density. In conclusion, SAMP8 mice presented depression-like behavior that is dependent on senescence process, because it differs from SAMR1, senescence resistant strain.
Assuntos
Envelhecimento/genética , Envelhecimento/psicologia , Comportamento Animal , Depressão/epidemiologia , Depressão/psicologia , Camundongos Endogâmicos/genética , Camundongos Endogâmicos/psicologia , Animais , Antidepressivos Tricíclicos/uso terapêutico , Córtex Cerebral/metabolismo , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Dopamina/metabolismo , Imipramina/uso terapêutico , Incidência , Masculino , Camundongos , Receptores de Serotonina/metabolismo , Natação/psicologia , Resultado do Tratamento , Triptofano Hidroxilase/metabolismoRESUMO
The protein deacetylase, sirtuin 1, is suggested as a master regulator of exercise-induced beneficial effects. Sirtuin 1 modulates mitochondrial biogenesis, primarily via its ability to deacetylate and activate proliferator-activated receptor-γ coactivator-1α (PGC-1α), interacting with AMPK kinase. Redox cell status can also influence this regulatory axis and together they form an important convergence point in hormesis during the aging process. Here, we tested whether treadmill training (36weeks), as a paradigm of long-term moderate exercise, modifies the AMPK-sirtuin 1-PGC-1α axis and redox balance in rat gastrocnemius muscle, liver and heart. Physical activity induced increases in sirtuin 1 protein levels in all the aged rat tissues studied, as well as total PGC-1α levels. However, no changes in AMPK activation or significant differences in mitochondrial biogenesis (by measuring electron transport chain protein content) were found after exercise training. Parallel to these changes, we observed an improvement of oxidative stress defenses, mainly in muscle, with modification of the antioxidant enzyme machinery resulting in a reduction in lipid peroxidation and protein carbonylation. Thus, we demonstrate that moderate long-term exercise promotes tissue adaptations, increasing muscle, liver and heart sirtuin 1 protein content and activity and increasing PGC-1α protein expression. However, AMPK activation or mitochondrial biogenesis is not modified, but it cannot be discarded that its participation in the adaptive mechanism which prevents the development of the deleterious effects of age.
Assuntos
Estresse Oxidativo/fisiologia , Condicionamento Físico Animal/fisiologia , Sirtuína 1/biossíntese , Quinases Proteína-Quinases Ativadas por AMP , Animais , Fígado/metabolismo , Masculino , Renovação Mitocondrial/fisiologia , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Oxirredução , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Proteínas Quinases/metabolismo , Proteínas de Ligação a RNA/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Fatores de Transcrição/metabolismoRESUMO
AIMS: 3-Nitropropionic acid (3-NP) is a toxin that replicates most of the clinical and pathophysiological symptoms of Huntington's disease, inducing neurodegeneration in the striatum due to the inhibition of mitochondrial succinate dehydrogenase. Different pathways have been implicated in the cell death induced by 3-NP in rodents. One of them is the Jun-N-terminal kinase (JNK) pathway, which may play a role in the neurodegenerative process in different diseases. Moreover, the lack of one isoform of JNK (JNK3) has been associated with neuroprotection in different experimental models of neurodegeneration. Therefore, in the present study the role of JNK3 in the experimental Huntington's model induced by 3-NP administration was evaluated. METHODS: 3-NP was intraperitoneally administered once a day for 3 days to wild-type and Jnk3-null mice. Coronal brain sections were used to determine cell death and astrogliosis in striatum. Western blots were performed to determine the involvement of different pathways in both wild-type and Jnk3-null mice. RESULTS: Although JNK activation was observed following 3-NP administration, the results indicate that the lack of JNK3 does not confer neuroprotection against 3-NP toxicity. Thus, other pathways must be involved in the neurodegeneration induced in this model. One of the possible pathways towards 3-NP-induced apoptosis could involve the calpains, as their activity was increased in wild-type and Jnk3-null mice. CONCLUSION: Although JNK3 is a key protein involved in cell death in different neurodegenerative diseases, the present study demonstrates that the lack of JNK3 does not confer neuroprotection against 3-NP-induced neuronal death.
Assuntos
Corpo Estriado/enzimologia , Doença de Huntington/enzimologia , Proteína Quinase 10 Ativada por Mitógeno/metabolismo , Degeneração Neural/enzimologia , Animais , Western Blotting , Convulsivantes/toxicidade , Modelos Animais de Doenças , Ativação Enzimática , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Degeneração Neural/induzido quimicamente , Nitrocompostos/toxicidade , Propionatos/toxicidadeRESUMO
Hypoxia-inducible factor-1 alpha (HIF-1α) is a master transcription factor that regulates the response to hypoxia and ischemia and induces the expression of various genes, including vascular endothelial growth factor (VEGF) and erythropoietin (EPO). This study shows the systemic response of increased HIF-1α, EPO, and VEGF mRNA and protein. In addition, VEGF expression was increased in neurons and over-expressed in glial cells in a model of neuroexcitotoxicity in the hippocampus, in which rats were neonatally exposed to high glutamate concentrations. Simultaneous increases in HIF-1α, EPO and VEGF mRNA in peritoneal macrophages were also observed. Our study is consistent with the hypothesis that these genes exert a protective effect in response to neurotoxicity.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Hipocampo/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Macrófagos/metabolismo , Síndromes Neurotóxicas/patologia , Fatores Etários , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Eritropoetina/genética , Eritropoetina/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Ácido Glutâmico/toxicidade , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Macrófagos/efeitos dos fármacos , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Síndromes Neurotóxicas/etiologia , Neurotoxinas/toxicidade , Gravidez , RNA Mensageiro , Ratos , Ratos Wistar , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Exercise enhances general health. However, its effects on neurodegeneration are controversial, and the molecular pathways in the brain involved in this enhancement are poorly understood. Here, we examined the effect of long-term moderate treadmill training on adult male rat cortex and hippocampus to identify the cellular mechanisms behind the effects of exercise. We compared three animal groups: exercised (30 min/day, 12 m/min, 5 days/wk, 36 wk), handled but nonexercised (treadmill handling procedure, 0 m/min), and sedentary (nonhandled and nonexercised). Moderate long-term exercise induced an increase in IGF-1 levels and also in energy parameters, such as PGC-1α and the OXPHOS system. Moreover, the sirtuin 1 pathway was activated in both the exercised and nonexercised groups but not in sedentary rats. This induction could be a consequence of exercise as well as the handling procedure. To determine whether the long-term moderate treadmill training had neuroprotective effects, we studied tau hyperphosphorylation and GSK3ß activation. Our results showed reduced levels of phospho-tau and GSK3ß activation mainly in the hippocampus of the exercised animals. In conclusion, in our rodent model, exercise improved several major brain parameters, especially in the hippocampus. These improvements induced the upregulation of sirtuin 1, a protein that extends life, the stimulation of mitochondrial biogenesis, the activation of AMPK, and the prevention of signs of neurodegeneration. These findings are consistent with other reports showing that physical exercise has positive effects on hormesis.
Assuntos
Córtex Cerebral/metabolismo , Hipocampo/metabolismo , Fármacos Neuroprotetores/metabolismo , Condicionamento Físico Animal/fisiologia , Quinases Proteína-Quinases Ativadas por AMP , Animais , Peso Corporal/fisiologia , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Mitocôndrias/metabolismo , Doenças Neurodegenerativas/prevenção & controle , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Proteínas Quinases/metabolismo , Proteínas de Ligação a RNA/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Sirtuína 1/metabolismo , Fatores de Transcrição/metabolismo , Proteínas tau/metabolismoRESUMO
Taurine, 2-aminoethanesulfonic acid, is present at high concentrations in many invertebrate and vertebrate systems, and it has several biological functions. In addition, it has been related to a neuroprotective role against several diseases, such as epilepsy. It has been reported that taurine induces a decrease of calbindin-D28k, calretinin, and parvalbumin protein levels in the hippocampus 3 days after administration. In the present work we hypothesized that the decrease of these proteins could alter the action of kainic acid (KA) and make mice more susceptible to excitotoxicity. Therefore, we treated mice with taurine and after 3 days treated them with KA. The results showed that taurine pretreatment did not induce a major susceptibility to KA. Moreover, neurodegeneration was reduced in pretreated mice. However, astrogliosis was similar to that observed in mice treated only with KA. The immunohistochemistries for calbindin-D28k, calretinin, and parvalbumin showed that these proteins were reduced as a consequence of KA treatment and of taurine treatment. However, mice pretreated with taurine prior to KA administration presented the same reduction in these proteins as mice treated with only taurine or only KA.
Assuntos
Proteínas de Ligação ao Cálcio/antagonistas & inibidores , Resistência a Medicamentos/efeitos dos fármacos , Ácido Caínico/agonistas , Neurotoxinas/agonistas , Parvalbuminas/antagonistas & inibidores , Proteína G de Ligação ao Cálcio S100/antagonistas & inibidores , Taurina/toxicidade , Animais , Calbindina 1 , Calbindina 2 , Calbindinas , Proteínas de Ligação ao Cálcio/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Resistência a Medicamentos/fisiologia , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Degeneração Neural/tratamento farmacológico , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Parvalbuminas/metabolismo , Proteína G de Ligação ao Cálcio S100/metabolismo , Taurina/metabolismoRESUMO
Senescence-accelerated mice (SAM) represent an aging model establish by selective inbreeding of the AKR/J strain. SAMP8 is a suitable model to study the genetics or proteics fundamental mechanisms of aging, in physiological or pathological conditions, because SAMP8 develop neuropathological markers also found in neurodegenerative diseases like Alzheimer. Melatonin is known as sleep hormone because its action controlling the sleep/awake circadian rhythm. Moreover, melatonin has antioxidant properties and may have an important anti-aging role. The chronic treatment with melatonin in the SAMP8 model was able to reduce oxidative stress and the neurodegenerative calpain/Cdk5 pathway and primed phosphorylation of GSK3beta and tau hiperphosphorylation markers of cerebral aging and neurodegeneration in SAMP8 brains, indicating the neuroprotective and anti-aging effect of melatonin.