Evaluación del potencial terapéutico del extracto vegetal Zanthoxylum martinicense asociado a la actividad agonista de LXR en el modelo murino de enfermedad de Alzheimer (3xTg-AD)

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dc.contributor.advisorArboleda Bustos, Gonzalo Humberto
dc.contributor.authorPérez Silva, Ana Milena
dc.contributor.cvlachttps://scienti.minciencias.gov.co/cvlac/visualizador/generarCurriculoCv.do?cod_rh=0001676218spa
dc.contributor.researchgroupMuerte Celular y Neurocienciasspa
dc.date.accessioned2023-06-07T14:12:33Z
dc.date.available2023-06-07T14:12:33Z
dc.date.issued2023
dc.descriptionilustraciones, fotografías principalmente a blanco y negrospa
dc.description.abstractEvaluación del potencial terapéutico del extracto vegetal Zanthoxylum martinicense asociado a la actividad agonista de LXR en el modelo murino de enfermedad de Alzheimer (3xTg-AD) La enfermedad de Alzheimer (EA) es un trastorno neurodegenerativo caracterizado por un deterioro cognitivo asociado patológicamente por la formación de placas amiloides y ovillos neurofibrilares. La hipótesis amiloide postula que el origen de la enfermedad comienza por la acumulación de péptidos Aβ, que desencadena procesos de neuroinflamación, desregulación de quinasas, incremento de especies reactivas de oxígeno, pérdida de espinas dendríticas y muerte neuronal. Estudios preliminares han demostrado que el extracto vegetal de Zanthoxylum martinicense presenta actividad agonista LXR, y la activación de estos receptores se relaciona con la modulación de biomarcadores de la EA (tales como la homeóstasis de colesterol, la agregación de depósitos amiloides y la neuroinflamación) para prevenir el desarrollo de la patología. Por tal motivo, se plantea como objetivo, evaluar el potencial terapéutico del extracto vegetal de Zanthoxylum martinicense con actividad agonista LXR en el modelo murino 3xTg-AD. Método: Se administró vía oral el extracto vegetal de raíz de Zanthoxylum martinicense durante 90 días, con dosis de 50mg/kg/día y 100mg/kg/día en ratones 3xTg-AD de 15 meses de edad, con el fin de evaluar: (1) cambios cognitivos a nivel comportamental empleando el laberinto acuático de Morris, (2) su efecto sobre la carga Aβ y la expresión de τ, GFAP e Iba-1 y (3) cambios en el nivel de expresión de proteína APOE y ABCA1 en lisados de hipocampo y corteza cerebral de ratones 3xTg-AD. Resultados: Se observó que el tratamiento con el extracto vegetal de Zanthoxylum martinicense redujo drásticamente el inmunomarcaje de la patología amiloide de manera dosis dependiente (p = 0.0002), tendió a disminuir el área de inmunoreactividad positiva de τ (p = 0.1619), generó una reversión en los procesos de neuroinflamación tanto a nivel morfológico como inmunohistoquímico para GFAP (p = 0.0857) e Iba-1 (p = 0.0286) y aumentó el nivel de expresión de algunos blancos transcripcionales de LXR: APOE y ABCA1 (p < 0.0001) en el hipocampo y corteza cerebral de ratones 3xTg-AD en comparación con los animales 3xTg-AD tratados con el vehículo (3xTg-AD VH), lo cual está asociado con una mejora en el proceso de consolidación de la memoria espacial y de aprendizaje de ratones 3xTg-AD, asemejando el comportamiento en el laberinto acuático de Morris a niveles similares del grupo control C57, el cual no presentó ningún tipo de daño cognoscitivo. Por tal motivo, la actividad agonista LXR presente en el extracto vegetal de Zanthoxylum martinicense ha demostrado tener un potencial terapéutico prometedor en modelos murinos con el fenotipo de la EA la cual ha sido asociada con una mejora a nivel cognitivo como resultado de una disminución en el inmunomarcaje de los principales biomarcadores histopatológicos de la enfermedad y un incremento en el nivel de expresión de sus blancos transcripcionales: APOE y ABCA1. Palabras clave: Alzheimer, Zanthoxylum martinicense, Aβ, τ, GFAP, Iba-1, APOE, ABCA1. (Texto tomado de la fuente)
dc.description.abstractEvaluation of the therapeutic potential of plant extract from Zanthoxylum martinicense associated with agonist activity of LXR in the murine model of Alzheimer's disease (3xTg-AD) Alzheimer's disease is a neurodegenerative disorder characterized by a cognitive impairment pathologically associated by the formation of amyloid plaques and neurofibrillary tangles. The amyloid hypothesis postulates that the origin of the disease begins with the accumulation of Aβ peptides, which trigger processes of neuroinflammation, deregulation of kinases, reactive oxygen species increase, loss of dendritic spines, and neuronal death. Preliminary studies have shown that the plant extract Zanthoxylum martinicense presents LXR agonist activity, and the activation of these receptors is related to the modulation of biomarkers of Alzheimer's disease (such as cholesterol homeostasis, the aggregation of amyloid deposits and neuroinflammation) to prevent the development of the pathology. Therefore, the objective is to evaluate the therapeutic potential of the plant extract Zanthoxylum martinicense with LXR agonist activity in the 3xTg-AD murine model. Method: The plant extract Zanthoxylum martinicense was administered orally for 90 days, with doses of 50mg/kg/day and 100mg/kg/day in 3xTg-AD mice of 15 months of age, in order to evaluate: (1) cognitive changes at the behavioral level using the Morris water maze, (2) its effect on Aβ load and the expression of τ, GFAP and Iba-1 and (3) changes in the level of expression of APOE and ABCA1 protein in the hippocampus and cerebral cortex of 3xTg-AD mice. Results: It was shown that the treatment with the plant extract Zanthoxylum martinicense reduced the immunolabeling of the amyloid pathology in a dose-dependent manner (p = 0.0002), it tended to decrease the area of positive immunoreactivity of τ (p = 0.1619), followed by a reversion in neuroinflammation processes at a morphological and immunohistochemical level for GFAP (p = 0.0857) and Iba-1 (p = 0.0286) and increased the expression level of some LXR transcriptional targets: APOE and ABCA1 (p < 0 0001) in the hippocampus and cerebral cortex of 3xTg-AD mice compared to 3xTg-AD animals treated with the vehicle (3xTg-AD VH), which it is associated with an improvement in the consolidation process of spatial memory and learning of 3xTg-AD mice, resembling this behavior to C57 control group in the Morris water maze, which did not present any type of cognitive damage. For this reason, the LXR agonist activity in the Zanthoxylum martinicense plant extract has shown promising therapeutic potential in murine models with the Alzheimer's disease phenotype, which has been associated with an improvement at a cognitive level as a result of a decrease in the immunolabeling of the main histopathological biomarkers of the disease and an increase in the level of expression of its transcriptional targets: APOE and ABCA1. Keywords: Alzheimer´s disease, Zanthoxylum martinicense, Aβ, τ, GFAP, Iba-1, APOE, ABCA1eng
dc.description.degreelevelMaestríaspa
dc.description.degreenameMagíster en Ciencias - Bioquímicaspa
dc.description.researchareaEnfermedades neurodegenerativasspa
dc.format.extent101 páginasspa
dc.format.mimetypeapplication/pdfspa
dc.identifier.instnameUniversidad Nacional de Colombiaspa
dc.identifier.reponameRepositorio Institucional Universidad Nacional de Colombiaspa
dc.identifier.repourlhttps://repositorio.unal.edu.co/spa
dc.identifier.urihttps://repositorio.unal.edu.co/handle/unal/83985
dc.language.isospaspa
dc.publisherUniversidad Nacional de Colombiaspa
dc.publisher.branchUniversidad Nacional de Colombia - Sede Bogotáspa
dc.publisher.facultyFacultad de Cienciasspa
dc.publisher.placeBogotá,Colombiaspa
dc.publisher.programBogotá - Ciencias - Maestría en Ciencias - Bioquímicaspa
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dc.rights.accessrightsinfo:eu-repo/semantics/openAccessspa
dc.rights.licenseAtribución-NoComercial-SinDerivadas 4.0 Internacionalspa
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/spa
dc.subject.ddc610 - Medicina y saludspa
dc.subject.decsExtractos vegetalesspa
dc.subject.decsPlant Extractseng
dc.subject.decsEnfermedad de Alzheimerspa
dc.subject.decsAlzheimer Diseaseeng
dc.subject.decsMedicamentos similaresspa
dc.subject.decsSimilar Drugseng
dc.subject.proposalPatología amiloidespa
dc.subject.proposalEnfermedad de Alzheimerspa
dc.subject.proposalReceptores X hepáticos (LXR)spa
dc.subject.proposalZanthoxylum martinicenseother
dc.subject.proposalTaupatíasspa
dc.titleEvaluación del potencial terapéutico del extracto vegetal Zanthoxylum martinicense asociado a la actividad agonista de LXR en el modelo murino de enfermedad de Alzheimer (3xTg-AD)spa
dc.title.translatedEvaluation of the therapeutic potential of plant extract from Zanthoxylum martinicense associated with agonist activity of LXR in the murine model of Alzheimer's disease (3xTg-AD)eng
dc.typeTrabajo de grado - Maestríaspa
dc.type.coarhttp://purl.org/coar/resource_type/c_bdccspa
dc.type.coarversionhttp://purl.org/coar/version/c_ab4af688f83e57aaspa
dc.type.contentTextspa
dc.type.driverinfo:eu-repo/semantics/masterThesisspa
dc.type.redcolhttp://purl.org/redcol/resource_type/TMspa
dc.type.versioninfo:eu-repo/semantics/acceptedVersionspa
dcterms.audience.professionaldevelopmentInvestigadoresspa
dcterms.audience.professionaldevelopmentPúblico generalspa
dcterms.audience.professionaldevelopmentReceptores de fondos federales y solicitantesspa
oaire.accessrightshttp://purl.org/coar/access_right/c_abf2spa

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