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BACKGROUND: Dexmedetomidine (DEX) and low-dose ketamine (KET) present neuroprotective effects in acute ischemic stroke (AIS); however, to date, no studies have evaluated which has better protective effects not only on the brain but also lungs in AIS. METHODS: AIS-induced Wistar rats (390 ± 30 g) were randomized after 24-h, receiving dexmedetomidine (STROKE-DEX, n = 10) or low-dose S(+)-ketamine (STROKE-KET, n = 10). After 1-h protective ventilation, perilesional brain tissue and lungs were removed for histologic and molecular biology analysis. STROKE animals (n = 5), receiving sodium thiopental but not ventilated, had brain and lungs removed for molecular biology analysis. Effects of DEX and KET mean plasma concentrations on alveolar macrophages, neutrophils, and lung endothelial cells, extracted primarily 24-h after AIS, were evaluated. RESULTS: In perilesional brain tissue, apoptosis did not differ between groups. In STROKE-DEX, compared to STROKE-KET, tumor necrosis factor (TNF)-α and vascular cell adhesion molecule-1 (VCAM-1) expressions were reduced, but no changes in nuclear factor erythroid 2-related factor-2 (Nrf2) and super oxide dismutase (SOD)-1 were observed. In lungs, TNF-α and VCAM-1 were reduced, whereas Nrf2 and SOD-1 were increased in STROKE-DEX. In alveolar macrophages, TNF-α and inducible nitric oxide synthase (M1 macrophage phenotype) were lower and arginase and transforming growth factor-ß (M2 macrophage phenotype) higher in STROKE-DEX. In lung neutrophils, CXC chemokine receptors (CXCR2 and CXCR4) were higher in STROKE-DEX. In lung endothelial cells, E-selectin and VCAM-1 were lower in STROKE-DEX. CONCLUSIONS: In the current AIS model, dexmedetomidine compared to low-dose ketamine reduced inflammation and endothelial cell damage in both brain and lung, suggesting greater protection.
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Dexmedetomidina , Accidente Cerebrovascular Isquémico , Ketamina , Accidente Cerebrovascular , Ratas , Animales , Ketamina/metabolismo , Dexmedetomidina/uso terapéutico , Dexmedetomidina/farmacología , Accidente Cerebrovascular Isquémico/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Células Endoteliales/metabolismo , Molécula 1 de Adhesión Celular Vascular/metabolismo , Ratas Wistar , Pulmón/patología , Accidente Cerebrovascular/metabolismo , Encéfalo/metabolismoRESUMEN
PURPOSE: Motor function is restored by axonal sprouting in ischemic stroke. Mitochondria play a crucial role in axonal sprouting. Taurine (TAU) is known to protect the brain against experimental stroke, but its role in axonal sprouting and the underlying mechanism are unclear. METHODS: We evaluated the motor function of stroke mice using the rotarod test on days 7, 14, and 28. Immunocytochemistry with biotinylated dextran amine was used to detect axonal sprouting. We observed neurite outgrowth and cell apoptosis in cortical neurons under oxygen and glucose deprivation (OGD), respectively. Furthermore, we evaluated the mitochondrial function, adenosine triphosphate (ATP), mitochondrial DNA (mtDNA), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PCG-1α), transcription factor A of mitochondria (TFAM), protein patched homolog 1 (PTCH1), and cellular myelocytomatosis oncogene (c-Myc). RESULTS: TAU recovered the motor function and promoted axonal sprouting in ischemic mice. TAU restored the neuritogenesis ability of cortical neurons and reduced OGD-induced cell apoptosis. TAU also reduced reactive oxygen species, stabilized mitochondrial membrane potential, enhanced ATP and mtDNA content, increased the levels of PGC-1α, and TFAM, and restored the impaired levels of PTCH1, and c-Myc. Furthermore, these TAU-related effects could be blocked using an Shh inhibitor (cyclopamine). CONCLUSION: Taurine promoted axonal sprouting via Shh-mediated mitochondrial improvement in ischemic stroke.
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Proteínas Hedgehog , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Taurina , Animales , Ratones , Adenosina Trifosfato/metabolismo , ADN Mitocondrial/metabolismo , Proteínas Hedgehog/metabolismo , Accidente Cerebrovascular Isquémico/metabolismo , Mitocondrias , Oxígeno/metabolismo , Accidente Cerebrovascular/metabolismo , Factores de Transcripción/metabolismo , Taurina/farmacologíaRESUMEN
Stroke is one of the leading causes of death and long-term disabilities worldwide, resulting in a debilitating condition occasioned by disturbances in the cerebral vasculature. Primary damage due to metabolic collapse is a quick outcome following stroke, but a multitude of secondary events, including excitotoxicity, inflammatory response, and oxidative stress cause further cell death and functional impairment. In the present work, we investigated whether a primary ischemic damage into the dorsal striatum may cause secondary damage in the circumjacent corpus callosum (CC). Animals were injected with endothelin-1 and perfused at 3, 7, 14, and 30 post-lesion days (PLD). Sections were stained with Cresyl violet for basic histopathology and immunolabeled by antibodies against astrocytes (anti-GFAP), macrophages/microglia (anti-IBA1/anti MHC-II), oligodendrocytes (anti-TAU) and myelin (anti-MBP), and Anti-Nogo. There were conspicuous microgliosis and astrocytosis in the CC, followed by later oligodendrocyte death and myelin impairment. Our results suggest that secondary white matter damage in the CC follows a primary focal striatal ischemia in adult rats.
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Accidente Cerebrovascular , Sustancia Blanca , Animales , Cuerpo Calloso/patología , Vaina de Mielina/metabolismo , Oligodendroglía/metabolismo , Ratas , Accidente Cerebrovascular/metabolismoRESUMEN
There are no clinical interventions to prevent post-injury epilepsy, a common and devastating outcome after brain insults. Epileptogenic events that run from brain injury to epilepsy are poorly understood. Previous studies in our laboratory suggested Proechimys, an exotic Amazonian rodent, as resistant to acquired epilepsy development in post-status epilepticus models. The present comparative study was conducted to assess (1) stroke-related brain responses 24-h and 30 days after cortical photothrombosis and (2) post-stroke epilepsy between Proechimys rodents and Wistar rats, a traditional animal used for laboratory research. Proechimys group showed smaller volume of ischemic infarction and lesser glial activation than Wistar group. In contrast to Wistar rats, post-stroke decreased levels of pro-inflammatory cytokines and increased levels of anti-inflammatory mediators and growth factors were found in Proechimys. Electrophysiological signaling changes assessed by cortical spreading depression, in vitro and in vivo, showed that Wistar's brain is most severely affected by stroke. Chronic electrocorticographic recordings showed that injury did not lead to epilepsy in Proechimys whereas 88% of the Wistar rats developed post-stroke epilepsy. Science gains insights from comparative studies on diverse species. Proechimys rodents proved to be a useful animal model to study antiepileptogenic mechanisms after brain insults and complement conventional animal models.
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Epilepsia/metabolismo , Bosque Lluvioso , Estado Epiléptico/metabolismo , Accidente Cerebrovascular/metabolismo , Animales , Ratas , Ratas WistarRESUMEN
Post-stroke individuals presented deleterious changes in skeletal muscle and in the cardiovascular system, which are related to reduced oxygen uptake ([Formula: see text]) and take longer to produce energy from oxygen-dependent sources at the onset of exercise (mean response time, MTRON) and during post-exercise recovery (MRTOFF). However, to the best of our knowledge, no previous study has investigated the potential mechanisms related to [Formula: see text] kinetics response (MRTON and MRTOFF) in post-stroke populations. The main objective of this study was to determine whether the MTRON and MRTOFF are related to: 1) body composition; 2) arterial compliance; 3) endothelial function; and 4) hematological and inflammatory profiles in chronic post-stroke individuals. Data on oxygen uptake ([Formula: see text]) were collected using a portable metabolic system (Oxycon Mobile®) during the six-minute walk test (6MWT). The time to achieve 63% of [Formula: see text] during a steady state (MTRON) and recovery (MRTOFF) were analyzed by the monoexponential model and corrected by a work rate (wMRTON and wMRTOFF) during 6MWT. Correlation analyses were made using Spearman's rank correlation coefficient (rs) and the bias-corrected and accelerated bootstrap method was used to estimate the 95% confidence intervals. Twenty-four post-stroke participants who were physically inactive took part in the study. The wMRTOFF was correlated with the following: skeletal muscle mass (rs = -0.46), skeletal muscle mass index (rs = -0.45), augmentation index (rs = 0.44), augmentation index normalized to a heart rate of 75 bpm (rs = 0.64), reflection magnitude (rs = 0.43), erythrocyte (rs = -0.61), hemoglobin (rs = -0.54), hematocrit (rs = -0.52) and high-sensitivity C-reactive protein (rs = 0.58), all p < 0.05. A greater amount of oxygen uptake during post-walking recovery is partially related to lower skeletal muscle mass, greater arterial stiffness, reduced number of erythrocytes and higher systemic inflammation in post-stroke individuals.
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Oxígeno/metabolismo , Accidente Cerebrovascular/fisiopatología , Prueba de Paso/métodos , Adulto , Anciano , Anciano de 80 o más Años , Proteína C-Reactiva/metabolismo , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Consumo de Oxígeno , Proyectos Piloto , Accidente Cerebrovascular/metabolismoRESUMEN
Systems biology postulates the balance between energy production and conservation in optimizing locomotion. Here, we analyzed how mechanical energy production and conservation influenced metabolic energy expenditure in stroke survivors during treadmill walking at different speeds. We used the body center of mass (BCoM) and segmental center of mass to calculate mechanical energy production: external and each segment's mechanical work (Wseg). We also estimated energy conservation by applying the pendular transduction framework (i.e. energy transduction within the step; Rint). Energy conservation was likely optimized by the paretic lower-limb acting as a rigid shaft while the non-paretic limb pushed the BCoM forward at the slower walking speed. Wseg production was characterized by greater movements between the limbs and body, a compensatory strategy used mainly by the non-paretic limbs. Overall, Wseg production following a stroke was characterized by non-paretic upper-limb compensation, but also by an exaggerated lift of the paretic leg. This study also highlights how post-stroke subjects may perform a more economic gait while walking on a treadmill at preferred walking speeds. Complex neural adaptations optimize energy production and conservation at the systems level, and may fundament new insights onto post-stroke neurorehabilitation.This article has and associated First Person interview with the first author of the paper.
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Metabolismo Energético , Marcha , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/fisiopatología , Adaptación Fisiológica , Anciano , Fenómenos Biomecánicos , Prueba de Esfuerzo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Consumo de Oxígeno , Accidente Cerebrovascular/complicaciones , Rehabilitación de Accidente Cerebrovascular , CaminataRESUMEN
We hypothesized that knowledge of cerebral autoregulation (CA) status during recanalization therapies could guide further studies aimed at neuroprotection targeting penumbral tissue, especially in patients that do not respond to therapy. Thus, we assessed CA status of patients with acute ischemic stroke (AIS) during intravenous r-tPA therapy and associated CA with response to therapy. AIS patients eligible for intravenous r-tPA therapy were recruited. Cerebral blood flow velocities (transcranial Doppler) from middle cerebral artery and blood pressure (Finometer) were recorded to calculate the autoregulation index (ARI, as surrogate for CA). National Institute of Health Stroke Score was assessed and used to define responders to therapy (improvement of ≥ 4 points on NIHSS measured 24-48 h after therapy). CA was considered impaired if ARI < 4. In 38 patients studied, compared to responders, non-responders had significantly lower ARI values (affected hemisphere: 5.0 vs. 3.6; unaffected hemisphere: 5.4 vs. 4.4, p = 0.03) and more likely to have impaired CA (32% vs. 62%, p = 0.02) during thrombolysis. In conclusion, CA during thrombolysis was impaired in patients who did not respond to therapy. This variable should be investigated as a predictor of the response to therapy and to subsequent neurological outcome.
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Circulación Cerebrovascular/efectos de los fármacos , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Terapia Trombolítica/métodos , Administración Intravenosa/métodos , Anciano , Anciano de 80 o más Años , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/fisiopatología , Circulación Cerebrovascular/fisiología , Femenino , Fibrinólisis , Homeostasis/fisiología , Humanos , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/fisiopatología , Masculino , Persona de Mediana Edad , Arteria Cerebral Media/fisiopatología , Índice de Severidad de la Enfermedad , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/fisiopatología , Resultado del Tratamiento , Ultrasonografía Doppler Transcraneal/métodosRESUMEN
Stroke survivors are at substantial risk of recurrent cerebrovascular event or cardiovascular disease. Exercise training offers nonpharmacological treatment for these subjects; however, the execution of the traditional exercise protocols and adherence is constantly pointed out as obstacles. Based on these premises, the present study investigated the impact of an 8-week dynamic resistance training protocol with elastic bands on functional, hemodynamic, and cardiac autonomic modulation, oxidative stress markers, and plasma nitrite concentration in stroke survivors. Twenty-two patients with stroke were randomized into control group (CG, n = 11) or training group (TG, n = 11). Cardiac autonomic modulation, oxidative stress markers, plasma nitrite concentration, physical function and hemodynamic parameters were evaluated before and after 8 weeks. Results indicated that functional parameters (standing up from the sitting position (P = 0.011) and timed up and go (P = 0.042)) were significantly improved in TG. Although not statistically different, both systolic blood pressure (Δ = -10.41 mmHg) and diastolic blood pressure (Δ = -8.16 mmHg) were reduced in TG when compared to CG. Additionally, cardiac autonomic modulation (sympathovagal balance-LF/HF ratio) and superoxide dismutase were improved, while thiobarbituric acid reactive substances and carbonyl levels were reduced in TG when compared to the CG subjects. In conclusion, our findings support the hypothesis that dynamic resistance training with elastic bands may improve physical function, hemodynamic parameters, autonomic modulation, and oxidative stress markers in stroke survivors. These positive changes would be associated with a reduced risk of a recurrent stroke or cardiac event in these subjects.
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Estrés Oxidativo , Entrenamiento de Fuerza , Rehabilitación de Accidente Cerebrovascular/métodos , Accidente Cerebrovascular/patología , Anciano , Presión Sanguínea , Enfermedad Crónica , Femenino , Fuerza de la Mano , Hemodinámica , Humanos , Masculino , Persona de Mediana Edad , NADPH Oxidasas/metabolismo , Nitritos/sangre , Carbonilación Proteica , Accidente Cerebrovascular/metabolismo , Superóxido Dismutasa/metabolismo , SobrevivientesRESUMEN
Amniotic fluid has been investigated as new cell source for stem cells in the development of future cell-based transplantation. This study reports isolation of viable human amniotic fluid-derived stem cells, labeled with multimodal iron oxide nanoparticles, and its effect on focal cerebral ischemia-reperfusion injury in Wistar rats. Middle cerebral artery occlusion of 60 min followed by reperfusion for 1 h, 6 h, and 24 h was employed in the present study to produce ischemia and reperfusion-induced cerebral injury in rats. Tests were employed to assess the functional outcome of the sensorimotor center activity in the brain, through a set of modified neurological severity scores used to assess motor and exploratory capacity 24 h, 14, and 28 days after receiving cellular therapy via tail vein. In our animal model of stroke, transplanted cells migrated to the ischemic focus, infarct volume decreased, and motor deficits improved. Therefore, we concluded that these cells appear to have beneficial effects on the ischemic brain, possibly based on their ability to enhance endogenous repair mechanisms.
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Líquido Amniótico/metabolismo , Conducta Animal , Isquemia Encefálica , Trasplante de Células Madre , Células Madre/metabolismo , Accidente Cerebrovascular , Adulto , Animales , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Isquemia Encefálica/fisiopatología , Isquemia Encefálica/terapia , Modelos Animales de Enfermedad , Femenino , Xenoinjertos , Humanos , Embarazo , Ratas , Ratas Wistar , Células Madre/patología , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/fisiopatología , Accidente Cerebrovascular/terapiaRESUMEN
Objective: The aim of this research is to study skin autofluorescence and the associations between skin glycated proteins and clinical characteristics of healthy and unhealthy subjects for noninvasive screening of diabetes and cardiovascular disease (CVD) risks. Background data: Accumulated advanced glycation endproducts (AGEs) promote increased oxidative stress and inflammation, as well as cross-linking of proteins leading to tissue damage and several diseases, including diabetes. Materials and methods: One hundred and four subjects with or without diabetes and stroke aged 20-80 years and with Fitzpatrick skin type (I to IV) participated in this study. The fluorescence spectrometer was used to illuminate a skin surface of 1 cm2. The skin of forearm was positioned on the spectrometer to assess skin AGEs. Anthropometric data and body composition also were evaluated. Results: Elevated skin autofluorescence was found in subjects >50 years old, as well as in patients with insulin resistance (IR), diabetes, and stroke. There was a positive correlation between the skin autofluorescence and age (r = 0.7, p = 0.0001), body mass index (BMI) (r = 0.5, p = 0.001), body fat (r = 0.5, p = 0.0001), waist circumference (r = 0.45, p = 0.001), and systolic blood pressure (BP) (r = 0.45, p = 0.0001). Conclusions: Elevated skin autofluorescence can provide a noninvasive screening of diabetes and CVD risks.
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Diabetes Mellitus/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , Piel/metabolismo , Accidente Cerebrovascular/metabolismo , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Estudios de Casos y Controles , Diabetes Mellitus/diagnóstico por imagen , Humanos , Persona de Mediana Edad , Imagen Óptica , Estrés Oxidativo/fisiología , Piel/diagnóstico por imagen , Espectrometría de Fluorescencia , Accidente Cerebrovascular/diagnóstico por imagen , Adulto JovenRESUMEN
Stroke is one of the main causes of human disability worldwide. Ischemic stroke is mostly characterized by metabolic collapse and fast tissue damage, followed by secondary damage in adjacent regions not previously affected. Heavy metals intoxication can be associated with stroke incidence, because of their damaging action in the vascular system. Mercury, in particular, possesses a high tropism by metabolically active regions, such as the brain. In the present study we sought to evaluate whether methylmercury (MeHg) intoxication can aggravate the tissue damage caused by an ischemic stroke induced by microinjections of endothelin-1 (ET-1) into the motor cortex of adult rats. Following MeHg intoxication by gavage (0.04â¯mg/kg/day) during 60 days, the animals were injected with ET-1 (1⯵l, 40â¯pmol/µl) or vehicle (1⯵l). After 7 days, all animals were submitted to behavioral tests and then their brains were processed to biochemical and immunohistochemical analyses. We observed that long-term MeHg intoxication promoted a significant Hg deposits in the motor cortex, with concomitant increase of microglial response, followed by reduction of the neuronal population following ischemia and MeHg intoxication, as well as disturbance in the antioxidant defense mechanisms by misbalance of oxidative biochemistry with increase of both lipid peroxidation and nitrite levels, associated to behavioral deficits. MeHg exposure and cortical ischemia demonstrated that both injuries are able of causing significant neurobehavioural impairments in motor coordination and learning accompanied of an exacerbated microglial activation, oxidative stress and neuronal loss in the motor cortex, indicating that MeHg as a source of metabolic disturbance can act as an important increasing factor of ischemic events in the brain.
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Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatología , Compuestos de Metilmercurio/toxicidad , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/fisiopatología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Isquemia Encefálica/patología , Comorbilidad , Peroxidación de Lípido/efectos de los fármacos , Masculino , Compuestos de Metilmercurio/farmacocinética , Corteza Motora/efectos de los fármacos , Corteza Motora/metabolismo , Neuronas/efectos de los fármacos , Estrés Oxidativo , Ratas , Ratas Wistar , Accidente Cerebrovascular/patologíaRESUMEN
BACKGROUND: Acute cerebral infarction (ACI) and intracerebral hemorrhage (ICH) are potentially lethal cerebrovascular diseases that seriously impact public health. ACI and ICH share several common clinical manifestations but have totally divergent therapeutic strategies. A poor diagnosis can affect stroke treatment. OBJECTIVE: To screen for biomarkers to differentiate ICH from ACI, we enrolled 129 ACI and 128 ICH patients and 65 healthy individuals as controls. METHODS: Patients with stroke were diagnosed by computed tomography/magnetic resonance imaging, and their blood samples were obtained by fingertip puncture within 2-12 h after stroke initiation. We compared changes in metabolites between ACI and ICH using dried blood spot-based direct infusion mass spectrometry technology for differentiating ICH from ACI. RESULTS: Through multivariate statistical approaches, 11 biomarkers including 3-hydroxylbutyrylcarnitine, glutarylcarnitine (C5DC), myristoylcarnitine, 3-hydroxypalmitoylcarnitine, tyrosine/citrulline (Cit), valine/phenylalanine, C5DC/3-hydroxyisovalerylcarnitine, C5DC/palmitoylcarnitine, hydroxystearoylcarnitine, ratio of sum of C0, C2, C3, C16, and C18:1 to Cit, and propionylcarnitine/methionine were screened. An artificial neural network model was constructed based on these parameters. A training set was evaluated by cross-validation method. The accuracy of this model was checked by an external test set showing a sensitivity of 0.8400 (95% confidence interval [CI], 0.7394-0.9406) and specificity of 0.7692 (95% CI, 0.6536-0.8848). CONCLUSION: This study confirmed that metabolomic analysis is a promising tool for rapid and timely stroke differentiation and prediction based on differential metabolites.
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Hemorragia Cerebral/diagnóstico , Infarto Cerebral/diagnóstico , Metabolómica/métodos , Accidente Cerebrovascular/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Estudios de Casos y Controles , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/fisiopatología , Infarto Cerebral/metabolismo , Infarto Cerebral/fisiopatología , Diagnóstico Diferencial , Pruebas con Sangre Seca , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Redes Neurales de la Computación , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/fisiopatología , Tomografía Computarizada por Rayos X/métodosRESUMEN
BACKGROUND AND PURPOSE: Dysregulation of the miR-15a/16-1 cluster in plasma has been reported in patients with stroke as a potential biomarker for diagnostic and prognostic use. However, the essential role and therapeutic potential of the miR-15a/16-1 cluster in ischemic stroke are poorly understood. This study is aimed at investigating the regulatory role of the miR-15a/16-1 cluster in ischemic brain injury and insight mechanisms. METHODS: Adult male miR-15a/16-1 knockout and wild-type mice, or adult male C57 BL/6J mice injected via tail vein with the miR-15a/16-1-specific inhibitor (antagomir, 30 pmol/g), were subjected to 1 hour of middle cerebral artery occlusion and 72 hours of reperfusion. The neurological scores, brain infarct volume, brain water content, and neurobehavioral tests were then evaluated and analyzed. To explore underlying signaling pathways associated with alteration of miR-15a/16-1 activity, major proinflammatory cytokines were measured by quantitative polymerase chain reaction or ELISA and antiapoptotic proteins were examined by Western blotting. RESULTS: Genetic deletion of the miR-15a/16-1 cluster or intravenous delivery of miR-15a/16-1 antagomir significantly reduced cerebral infarct size, decreased brain water content, and improved neurological outcomes in stroke mice. Inhibition of miR-15a/16-1 significantly decreased the expression of the proinflammatory cytokines interleukin-6, monocyte chemoattractant protein-1, vascular cell adhesion molecule 1, tumor necrosis factor alpha, and increased Bcl-2 and Bcl-w levels in the ischemic brain regions. CONCLUSIONS: Our data indicate that pharmacological inhibition of the miR-15a/16-1 cluster reduces ischemic brain injury via both upregulation of antiapoptotic proteins and suppression of proinflammatory molecules. These results suggest that the miR-15a/16-1 cluster is a novel therapeutic target for ischemic stroke.
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Antagomirs/farmacología , Isquemia Encefálica/tratamiento farmacológico , MicroARNs/antagonistas & inhibidores , Accidente Cerebrovascular/tratamiento farmacológico , Animales , Antagomirs/administración & dosificación , Isquemia Encefálica/inmunología , Isquemia Encefálica/metabolismo , Modelos Animales de Enfermedad , Infarto de la Arteria Cerebral Media , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Accidente Cerebrovascular/inmunología , Accidente Cerebrovascular/metabolismoRESUMEN
STUDY QUESTION: What is the impact of chronic hypertension on placental development, fetal growth and maternal outcome in the stroke-prone spontaneously hypertensive rat (SHRSP)? SUMMARY ANSWER: SHRSP showed an impaired remodeling of the spiral arteries and abnormal pattern of trophoblast invasion during placentation, which were associated with subsequent maternal glomerular injury and increased baseline hypertension as well as placental insufficiency and asymmetric fetal growth restriction (FGR). WHAT IS KNOWN ALREADY: A hallmark in the pathogenesis of preeclampsia (PE) is abnormal placentation with defective remodeling of the spiral arteries preceding the onset of the maternal syndrome. Pregnancies affected by chronic hypertension display an increased risk for PE, often associated with poor maternal and fetal outcomes. However, the impact of chronic hypertension on the placentation process as well as the nature of the factors promoting the development of PE in pregnant hypertensive women remain elusive. STUDY DESIGN, SIZE, DURATION: Timed pregnancies [n = 5] were established by mating 10-12-week-old SHRSP and Wistar Kyoto (WKY, normotensive controls) females with congenic males. Maternal systolic blood pressures (SBPs) were recorded pre-mating, throughout pregnancy (GD1-19) and post-partum by the tail-cuff method. On selected dates, 24 h urine- and blood samples were collected, and animals were euthanized for isolation of implantation sites and kidneys for morphometrical analyses. PARTICIPANTS/MATERIALS, SETTING, METHODS: The 24 h proteinuria and the albumin:creatinine ratio were used for evaluation of maternal renal function. Renal injury was assessed on periodic acid Schiff, Masson's trichrome and Sirius red stainings. Placental and fetal weights were recorded on gestation day (GD)18 and GD20, followed by determination of fetal cephalization indexes and developmental stage, according to the Witschi scale. Morphometric analyses of placental development were conducted on hematoxylin-eosin stained tissue sections collected on GD14 and GD18, and complemented with immunohistochemical evaluation of isolectin B4 binding for assessment of placental vascularization. Analyses of vascular wall alpha actin content, perforin-positive natural killer (NK) cells and cytokeratin expression by immunohistochemistry were used for evaluation of spiral artery remodeling and trophoblast invasion. MAIN RESULTS AND THE ROLE OF CHANCE: SHRSP females presented significantly increased SBP records from GD13 to GD17 (SBPGD13 = 183.9 ± 3.9 mmHg, P < 0.005 versus baseline) and increased proteinuria at GD18 (P < 0.01 versus WKY). Histological examination of GD18 kidneys revealed glomerular enlargement and mesangial matrix expansion, which were not evident in pregnant WKY or age-matched virgin SHRSP. At GD20, SHRSP displayed a significant reduction of placental mass (P < 0.01 versus WKY) and signs of placental insufficiency (i.e. hypertrophy and reduced branching morphogenesis of the labyrinth layer), associated with decreased offspring weights and increased cephalization index (both P < 0.001 versus WKY) indicating asymmetric FGR. Notably, SHRSP placentas displayed an incomplete remodeling of spiral arteries starting as early as GD14, with luminal narrowing and reduced densities of perivascular NK cells followed by decreased infiltration of endovascular trophoblasts at GD18. LARGE SCALE DATA: n/a. LIMITATIONS, REASONS FOR CAUTION: A pitfall of the present study is the differences in the blood pressure profiles between rats and humans (i.e. unlike pregnancies affected by PE, blood pressure in SHRSP and other hypertensive rat models decreases pre-delivery), which limits extrapolation of the results. WIDER IMPLICATIONS OF THE FINDINGS: Our findings provide new insights on the role of chronic hypertension as a risk factor for PE by interfering with early events during the placentation process. The SHRSP strain represents an attractive model for further studies aimed at addressing the relative contribution of intrinsic (i.e. placental) and extrinsic (i.e. decidual/vascular) factors to defective spiral artery remodeling in pregnancies affected by PE. STUDY FUNDING AND COMPETING INTEREST(S): This work was supported by research grants from Fundación Florencio Fiorini to G.B., from Charité Stiftung to S.M.B. and University of Buenos Aires (UBACyt) to J.T. The authors have no competing interests to declare.
Asunto(s)
Retardo del Crecimiento Fetal/fisiopatología , Preeclampsia/fisiopatología , Proteinuria/fisiopatología , Accidente Cerebrovascular/fisiopatología , Trofoblastos/patología , Actinas/genética , Actinas/metabolismo , Animales , Biomarcadores , Decidua/metabolismo , Decidua/patología , Decidua/fisiopatología , Femenino , Retardo del Crecimiento Fetal/metabolismo , Retardo del Crecimiento Fetal/patología , Feto , Expresión Génica , Queratinas/genética , Queratinas/metabolismo , Riñón/metabolismo , Riñón/patología , Riñón/fisiopatología , Placentación , Preeclampsia/metabolismo , Preeclampsia/patología , Embarazo , Proteinuria/metabolismo , Proteinuria/patología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/patología , Trofoblastos/metabolismo , Arteria Uterina/metabolismo , Arteria Uterina/patología , Arteria Uterina/fisiopatología , Remodelación VascularRESUMEN
Post-stroke cognitive impairment is a major cause of long-term neurological disability. The prevalence of post-stroke cognitive deficits varies between 20% and 80% depending on brain region, country, and diagnostic criteria. The biochemical mechanisms underlying post-stroke cognitive impairment are not known in detail. Cyclin-dependent kinase 5 is involved in neurodegeneration, and its dysregulation contributes to cognitive disorders and dementia. Here, we administered cyclin-dependent kinase 5-targeting gene therapy to the right hippocampus of ischemic rats after transient right middle cerebral artery occlusion. Cyclin-dependent kinase 5 RNA interference prevented the impairment of reversal learning four months after ischemia as well as neuronal loss, tauopathy, and microglial hyperreactivity. Additionally, cyclin-dependent kinase 5 silencing increased the expression of brain-derived neurotrophic factor in the hippocampus. Furthermore, deficits in hippocampal long-term potentiation produced by excitotoxic stimulation were rescued by pharmacological blockade of cyclin-dependent kinase 5. This recovery was blocked by inhibition of the TRKB receptor. In summary, these findings demonstrate the beneficial impact of cyclin-dependent kinase 5 reduction in preventing long-term post-ischemic neurodegeneration and cognitive impairment as well as the role of brain-derived neurotrophic factor/TRKB in the maintenance of normal synaptic plasticity.
Asunto(s)
Disfunción Cognitiva/prevención & control , Quinasa 5 Dependiente de la Ciclina/antagonistas & inhibidores , Plasticidad Neuronal/fisiología , Accidente Cerebrovascular/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Disfunción Cognitiva/etiología , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/patología , Quinasa 5 Dependiente de la Ciclina/genética , Modelos Animales de Enfermedad , Fenómenos Electrofisiológicos , Técnicas de Silenciamiento del Gen , Masculino , Aprendizaje por Laberinto/fisiología , Ratones Endogámicos C57BL , ARN Interferente Pequeño/genética , Ratas Wistar , Aprendizaje Inverso/fisiología , Prueba de Desempeño de Rotación con Aceleración Constante , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/patologíaRESUMEN
La posibilidad de que los exosomas funcionen como una nueva forma de comunicación intercelular para establecer y mantener circuitos cerebrales está comenzando a ser explorada. Los exosomas son liberados desde células e interactúan con otras células receptoras para mediar cambios fisiológicos. Todas las células cerebrales liberan exosomas incluyendo las celulas madre neuronales, las neuronas, astrocitos, microglia, oligodendrocitos y las celulas endoteliales. El objetivo de esta revisión es reunir evidencia actualizada sobre las funciones de protección, antiinflamación y regeneración de los exosomas en el ataque cerebrovascular (ACV) isquémico en ratas. Se realizó una búsqueda sistemática de la literatura sensible y específica en base de datos Medline, EMBASE, Web of Science, Scopus, TRIP database, SciELO y LILACS con términos libres y meSH. Los exosomas generados de CSMs pueden ser utilizados para el tratamiento del ACV. Los exosomas de oligodendrocitos también ejercen una variedad de efectos sobre las neuronas receptoras e influencian un amplio espectro de la fisiología neuronal. En conjunto estos resultados sugieren que los exosomas de las CSMs mediados con miR-133b se transfieren a astrocitos y neuronas, las que regulan la expresión génica, beneficiando tanto la remodelación de neuritas, como la recuperación funcional despues de un ACV. Sería importante en el futuro desarrollar métodos para cuantificar y caracterizar los exosomas en el cerebro con isquemia. Esto permitiría correlacionar entre la cantidad de exosomas en el cerebro y la recuperación funcional entregando información sobre sus mecanismos de acción.
The possibility that exosomes function as a new form of inter cellular communication to establish and maintain brain circuits is beginning to be investigated. Exosomes are released from cells and interact with other receptor cells to mediate physiological changes. All brain cells release exosomes including neural stem cells, neurons, astrocytes, microglia, oligodendrocytes and endothelial cells. The aim of this review is to gather current evidence on the protective, anti-inflammatory and regenerative functions of exosomes in ischemic stroke in rats. A systematic search of sensitive and specific literature was carried out in the following database search engines: Medline, EMBASE, Web of Science, Scopus, TRIP database, SciELO and LILACS with free and MeSH terms data. MSC generated exosomes can be used in the treatment of stroke. Oligodendrocyte exosomes also exert a variety of effects on receptor neurons and influence a wide spectrum of neuronal physiology. Together these results suggest that MSC exosome-mediated transfer of miR-133b to astrocytes and neurons, thus regulating gene expression, benefiting both neurite remodeling, such as functional recovery following a stroke. It would be important in the future to develop methods to quantify and characterize exosomes in brain ischemia. This would allow correlation between the amount of exosomes in the brain and functional recovery providing information relevant to its action mechanisms.
Asunto(s)
Animales , Ratas , Exosomas/metabolismo , Isquemia/metabolismo , Neuroprotección , Accidente Cerebrovascular/metabolismoRESUMEN
The search for molecules capable of restoring altered hippocampal plasticity in psychiatric and neurological conditions is one of the most important tasks of modern neuroscience. It is well established that neural plasticity, such as the ability of the postnatal hippocampus to continuously generate newly functional neurons throughout life, a process called adult hippocampal neurogenesis (AHN), can be modulated not only by pharmacological agents, physical exercise, and environmental enrichment, but also by "nutraceutical" agents. In this review we focus on resveratrol, a phenol and phytoalexin found in the skin of grapes and red berries, as well as in nuts. Resveratrol has been reported to have antioxidant and antitumor properties, but its effects as a neural plasticity inducer are still debated. The current review examines recent evidence implicating resveratrol in regulating hippocampal neural plasticity and in mitigating the effects of various disorders and diseases on this important brain structure. Overall, findings show that resveratrol can improve cognition and mood and enhance hippocampal plasticity and AHN; however, some studies report opposite effects, with resveratrol inhibiting aspects of AHN. Therefore, further investigation is needed to resolve these controversies before resveratrol can be established as a safe coadjuvant in preventing and treating neuropsychiatric conditions.
Asunto(s)
Hipocampo/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Estilbenos/farmacología , Envejecimiento , Animales , Modelos Animales de Enfermedad , Fatiga/tratamiento farmacológico , Fatiga/metabolismo , Fatiga/patología , Hipocampo/metabolismo , Neurogénesis/efectos de los fármacos , Resveratrol , Estilbenos/uso terapéutico , Estrés Fisiológico/efectos de los fármacos , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/patologíaRESUMEN
Neuromodulators, such as antidepressants, may contribute to neuroprotection by modulating growth factor expression to exert anti-inflammatory effects and to support neuronal plasticity after stroke. Our objective was to study whether early treatment with venlafaxine, a serotonin-norepinephrine reuptake inhibitor, modulates growth factor expression and positively contributes to reducing the volume of infarcted brain tissue resulting in increased functional recovery. We studied the expression of BDNF, FGF2 and TGF-ß1 by examining their mRNA and protein levels and cellular distribution using quantitative confocal microscopy at 5 days after venlafaxine treatment in control and infarcted brains. Venlafaxine treatment did not change the expression of these growth factors in sham rats. In infarcted rats, BDNF mRNA and protein levels were reduced, while the mRNA and protein levels of FGF2 and TGF-ß1 were increased. Venlafaxine treatment potentiated all of the changes that were induced by cortical stroke alone. In particular, increased levels of FGF2 and TGF-ß1 were observed in astrocytes at 5 days after stroke induction, and these increases were correlated with decreased astrogliosis (measured by GFAP) and increased synaptophysin immunostaining at twenty-one days after stroke in venlafaxine-treated rats. Finally, we show that venlafaxine reduced infarct volume after stroke resulting in increased functional recovery, which was measured using ladder rung motor tests, at 21 days after stroke. Our results indicate that the early oral administration of venlafaxine positively contributes to neuroprotection during the acute and late events that follow stroke.
Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Fármacos Neuroprotectores/farmacología , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/metabolismo , Clorhidrato de Venlafaxina/farmacología , Animales , Antidepresivos/farmacología , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Astrocitos/patología , Encéfalo/patología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Endotelina-1 , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Gliosis/tratamiento farmacológico , Gliosis/metabolismo , Gliosis/patología , Masculino , ARN Mensajero/metabolismo , Distribución Aleatoria , Ratas Sprague-Dawley , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/fisiología , Accidente Cerebrovascular/patología , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Stroke is a leading cause of death and neurological disability worldwide and striatal ischemic stroke is frequent in humans due to obstruction of middle cerebral artery. Several pathological events underlie damage progression and a comprehensive description of the pathological features following experimental stroke in both acute and chronic survival times is a necessary step for further functional studies. Here, we explored the patterns of microglial activation, astrocytosis, oligodendrocyte damage, myelin impairment, and Nogo-A immunoreactivity between 3 and 30 postlesion days (PLDs) after experimental striatal stroke in adult rats induced by microinjections of endothelin-1 (ET-1). The focal ischemia induced tissue loss concomitant with intense microglia activation between 3 and 14 PLDs (maximum at 7 PLDs), decreasing afterward. Astrocytosis was maximum around 7 PLDs. Oligodendrocyte damage and Nogo-A upregulation were higher at 3 PLDs. Myelin impairment was maximum between 7 and 14 PLDs. Nogo-A expression was higher in the first week in comparison to control. The results add important histopathological features of ET-1 induced stroke in subacute and chronic survival times. In addition, the establishment of the temporal evolution of these neuropathological events is an important step for future studies seeking suitable neuroprotective drugs targeting neuroinflammation and white matter damage.
Asunto(s)
Microglía/metabolismo , Accidente Cerebrovascular/patología , Animales , Astrocitos/citología , Astrocitos/metabolismo , Encéfalo/patología , Isquemia Encefálica/patología , Modelos Animales de Enfermedad , Endotelina-1/toxicidad , Inmunohistoquímica , Masculino , Microglía/citología , Microscopía , Proteína Básica de Mielina/inmunología , Proteína Básica de Mielina/metabolismo , Proteínas Nogo/metabolismo , Oligodendroglía/citología , Oligodendroglía/metabolismo , Ratas , Ratas Wistar , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Sustancia Blanca/metabolismoRESUMEN
The dorsal raphe nucleus (DRN) is a key structure of the endogenous pain inhibitory system. Although the DRN is rich in serotoninergic neurons, cholinergic neurons are also found in that nucleus. Both ictal and inter-ictal states are followed by post-ictal analgesia. The present study investigated the role of cholinergic mechanisms in postictal antinociceptive processes using microinjections of atropine and mecamylamine, muscarinic and nicotinic cholinergic receptor antagonists, respectively, in the DRN of rats. Intraperitoneal injection of pentylenetetrazole (PTZ) (at 64mg/kg) caused tonic and tonic-clonic seizures. The convulsive motor reactions were followed by an increase in pain thresholds, a phenomenon known as post-ictal analgesia. Pre-treatment of the DRN with atropine or mecamylamine at 1µg, 3µg and 5µg/0.2µL decreased the post-ictal antinociceptive phenomenon. The present results showed that the post-ictal analgesia was mediated by muscarinic and nicotinic cholinergic receptors in the DRN, a structure crucially involved in the neural network that organises post-ictal hypoalgesia.