RESUMO
The aggregation of ß-amyloid peptides is associated to neurodegeneration in Alzheimer's disease (AD) patients. Consequently, the inhibition of both oligomerization and fibrillation of ß-amyloid peptides is considered a plausible therapeutic approach for AD. Herein, the synthesis of new naphthalene derivatives and their evaluation as anti-ß-amyloidogenic agents are presented. Molecular dynamic simulations predicted the formation of thermodynamically stable complexes between the compounds, the Aß1-42 peptide and fibrils. In human microglia cells, these compounds inhibited the aggregation of Aß1-42 peptide. The lead compound 8 showed a high affinity to amyloid plaques in mice brain ex vivo assays and an adequate log Poct/PBS value. Compound 8 also improved the cognitive function and decreased hippocampal ß-amyloid burden in the brain of 3xTg-AD female mice. Altogether, our results suggest that 8 could be a novel therapeutic agent for AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Naftalenos/farmacologia , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Agregados Proteicos/efeitos dos fármacos , Agregação Patológica de Proteínas/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Relação Dose-Resposta a Droga , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Dinâmica Molecular , Estrutura Molecular , Naftalenos/síntese química , Naftalenos/química , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fragmentos de Peptídeos/metabolismo , Agregação Patológica de Proteínas/metabolismo , Relação Estrutura-Atividade , TermodinâmicaRESUMO
Neurodegenerative diseases have mainly been associated with neuronal death. Recent investigations have shown that astroglia may modulate neuroinflammation in the early and late stages of the disease. [11C]Deuterodeprenyl ([11C]DED) is a tracer that has been used for reactive astrocyte detection in Alzheimer's disease, Creutzfeldt-Jakob disease and amyotrophic lateral sclerosis, among others, with some limitations. To develop a new radiotracer for detecting astrocytosis and overcoming associated difficulties, we recently reported the synthesis of a sulfonamide derivative of Sulforhodamine 101 (SR101), labeled with 18F, namely SR101 N-(3-[18F]Fluoropropyl) sulfonamide ([18F]2B-SRF101). The red fluorescent dye SR101 has been used as a specific marker of astroglia in the neocortex of rodents using in vivo models. In the present work we performed a biological characterisation of the new tracer including biodistribution and micro-PET/computed tomography (CT) images. PET/CT studies with [11C]DED were also done to compare with [18F]2B-SRF101 in order to assess its potential as an astrocyte marker. Biodistribution studies with [18F]2B-SRF101 were carried out in C57BL6J black and transgenic (3xTg) mice. A hepatointestinal metabolization as well as the pharmacokinetic profile were determined, showing appropriate characteristics to become a PET diagnostic agent. Dynamic PET/CT studies were carried out with [18F]2B-SRF101 and [11C]DED to evaluate the distribution of both tracers in the brain. A significant difference in [18F]2B-SRF101 uptake was especially observed in the cortex and hippocampus, and it was higher in 3xTg mice than it was in the control group. These results suggested that [18F]2B-SRF101 is a promising candidate for more extensive evaluation as an astrocyte tracer. The difference observed for [18F]2B-SRF101 was not found in the case of [11C]DED. The comparative studies between [18F]2B-SRF101 and [11C]DED suggest that both tracers have different roles as astrocytosis markers in this animal model, and could provide different and complementary information at the same time. In this way, by means of a multitracer approach, useful information could be obtained for the staging of the disease.
RESUMO
BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia. Neuroimaging methods have widened the horizons for AD diagnosis and therapy. The goals of this work are the synthesis of 2-(3-fluoropropyl)-6-methoxynaphthalene (5) and its [18F]-radiolabeled counterpart ([18F]Amylovis), the in silico and in vitro comparative evaluations of [18F]Amylovis and [11C]Pittsburg compound B (PIB) and the in vivo preclinical evaluation of [18F]Amylovis in transgenic and wild mice. METHODS: Iron-catalysis cross coupling reaction, followed by fluorination and radiofluorination steps were carried out to obtain 5 and 18F-Amylovis. Protein/Aß plaques binding, biodistribution, PET/CT Imaging and immunohistochemical studies were conducted in healthy/transgenic mice. RESULTS: The synthesis of 5 was successful obtained. Comparative in silico studies predicting that 5 should have affinity to the Aß-peptide, mainly through π-π interactions. According to a dynamic simulation study the ligand-Aß peptide complexes are stable in simulation-time (ΔG = -5.31 kcal/mol). [18F]Amylovis was obtained with satisfactory yield, high radiochemical purity and specific activity. The [18F]Amylovis log Poct/PBS value suggests its potential ability for crossing the blood brain barrier (BBB). According to in vitro assays, [18F]Amylovis has an adequate stability in time. Higher affinity to Aß plaques were found for [18F]Amylovis (Kd 0.16 nmol/L) than PIB (Kd 8.86 nmol/L) in brain serial sections of 3xTg-AD mice. Biodistribution in healthy mice showed that [18F]Amylovis crosses the BBB with rapid uptake (7 %ID/g at 5 min) and good washout (0.11±0.03 %ID/g at 60 min). Comparative PET dynamic studies of [18F]Amylovis in healthy and transgenic APPSwe/PS1dE9 mice, revealed a significant high uptake in the mice model. CONCLUSION: The in silico, in vitro and in vivo results justify that [18F]Amylovis should be studied as a promissory PET imaging agent to detect the presence of Aß senile plaques.
Assuntos
Radioisótopos de Carbono/química , Radioisótopos de Flúor/química , Radioisótopos de Flúor/farmacologia , Naftalenos/química , Neuroimagem/métodos , Placa Amiloide/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Radioquímica/métodos , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacologia , Animais , Simulação por Computador , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Distribuição TecidualRESUMO
Introducción: La hipertensión arterial contribuye al 80 por ciento de las muertes por enfermedad cardiovascular y cerebrovascular en la población de 65 años y más. Objetivo: Determinar la prevalencia de hipertensión arterial, adhesión al tratamiento y su control en adultos mayores. Métodos: Se realizó un estudio observacional descriptivo de corte transversal en 1 216 adultos mayores de 4 áreas de salud seleccionadas pertenecientes a los municipios Marianao y La Lisa, en el período de septiembre de 2008 a septiembre de 2009. Resultados: La prevalencia de hipertensión arterial ajustada fue de 74,3 (IC 95 por ciento 71,7-76,9), con mayor prevalencia en las mujeres. La detección previa de hipertensión arterial resultó superior al 70 por ciento en todos los policlínicos seleccionados, pero la adhesión al tratamiento osciló entre 47 y 68 por ciento, y menos de la mitad de los hipertensos se encontraban controlados. Conclusiones: Fortalecer la atención primaria de salud para mejorar la atención y el control de la hipertensión arterial es clave en la reducción de la morbilidad y la mortalidad por enfermedades cardiovasculares
Introduction: The high blood pressure accounts for the 80 percent of death from cardiovascular and cerebrovascular disease in persons aged 65 and over. Objective: To determine the prevalence of the high blood pressure, the adherence to treatment and its control in elderly patients. Methods: A cross-sectional, descriptive and observational study was conducted in 1 216 elderly in four health areas selected from the Marianao and La Lisa municipalities from September, 2008 to September, 2009. Results: The adjusted high blood pressure prevalence was of 74,3 percent (95 percent CI 71,7-76,9) greater in female patients. The early detection of high blood pressure was higher to 70 percent in all polyclinics selected, but the adherence to treatment fluctuates between 47 and 68 percent and les than half of hypertensive ones were under control. Conclusions: To strength the primary health care to improve the high blood pressure care and control is the key in reduction of morbidity and mortality from cardiovascular diseases
RESUMO
Se presenta una propuesta de evaluación geriátrica para su aplicación en las Fuerzas Armadas Revolucionarias, ante la carencia de una metodología uniforme para la atención del adulto mayor. Se sugiere la aplicación de la Valoración Geriátrica Integral a los jubilados de nuestras Fuerzas Armadas Revolucionarias y a los miembros de la Asociación de Combatientes de la Revolución Cubana que se atienden en nuestras instituciones médicas, esta valoración incluye: evaluación biomédica (se refiere a la historia clínica, valoración nutricional, prueba de Tinetti y un examen oftalmológico y auditivo detallado), evaluación psicológica (se debe destacar demencia y depresión según los criterios del Diagnóstico and Statistical Manual of Desorders IV, con el apoyo del mini-examen del estado mental y de la escala de depresión geriátrica respectivamente), evaluación social (recoge información sobre la situación socio-económica, familiar, de la vivienda y de soporte asistencial) y la evaluación funcional (explora la capacidad de realizar las actividades de la vida diaria a través de los índices de Katz, Lawton y de las ejecuciones prácticas)
Assuntos
Humanos , Masculino , Feminino , Idoso , Avaliação Geriátrica/métodos , Saúde do Idoso , Hospitais Militares , Aposentadoria/psicologiaRESUMO
Se estudiaron 45 pacientes con diagnostico de demencia senil tipo Alzheimer, los cuales se dividieron aleatoriamente en 3 grupos de tratamiento: ozonoterapia rectal, magnetoterapia y tratamiento combinado. Se definieron 3 tipos de respuestas: regresion o mejoria, progresion y sin cambios, de acuerdo con la escala de deterioro global dependiente de la edad y de la enfermedad de Alzheimer, el miniexamen del estado mental de Folstein, el criterio familiar y de observacion del equipo medico de mejoria en manifestaciones psiquiatricasy conductuales, asi como otros indicadores que miden calidad de vida. Se obtuvo una respuesta de regresion o mejoria en el 60 por ciento de los casos con campo magnetico y ozonoterapia combinados al mes de tratamiento, siendo mantenida en el 46,6 por ciento de los pacientes, aun a los 6 meses de tratamiento, respuestasque no se obtuvo con el empleo del campo magnetico o del ozono, como metodos aislados. No se presentaron manifestaciones de toxicidad en los pacientes