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Repositorio Institucional PONTIFICIA UNIVERSIDAD JAVERIANA FACULTAD DE CIENCIAS EFECTO PROTECTOR DE LA TIBOLONA EN UN MODELO INFLAMATORIO DE MICROGLÍA ESTIMULADO POR PALMITATO OSCAR ALEJANDRO HIDALGO LANUSSA Trabajo para optar al título de MAESTRIA EN CIENCIAS BIOLOGICAS Tutor George Emilio Sampaio Barreto Co-tutor Luis Miguel García Segura BOGOTÁ, D.C. NOVIEMBRE DE 2016 NOTA DE ADVERTENCIA Artículo 23, Resolución N° 13 de Julio de 1946 “La Universidad no se hace responsable por los conceptos emitidos por sus alumnos en sus trabajos de tesis. Sólo velará porque no se publique nada contrario al dogma y a la moral católica y porque las tesis no contengan ataques personales contra persona alguna, antes bien se vean en ellas el anhelo de buscar la verdad y la justicia” EFECTO PROTECTOR DE LA TIBOLONA EN UN MODELO INFLAMATORIO DE MICROGLÍA ESTIMULADO POR PALMITATO Oscar Alejandro Hidalgo Lanussa George Emilio Barreto Director Sonia Luz Albarracín, PhD. Lisandro Giraldez, PhD. Jurado 1 Jurado 2 Rosa Margarita Gómez, PhD. Jurado 3 EFECTO PROTECTOR DE LA TIBOLONA EN UN MODELO INFLAMATORIO DE MICROGLÍA ESTIMULADO POR PALMITATO Oscar Alejandro Hidalgo Lanussa Concepción Judith Puerta Bula, Ph.D. Alba Alicia Trespalacios, Ph.D. Decana Directora de Posgrado Facultad de Ciencias Facultad de Ciencias DEDICATORIA A mi mamá siempre… AGRADECIMIENTOS Quiero agradecer a todas las personas que de una u otra manera me apoyaron durante este camino de investigación y formación, de manera muy especial agradezco a mis compañeros de laboratorio de Bioquímica de la Pontificia Universidad Javeriana. A Eliana Báez y Marco Ávila por todo lo que me enseñaron y colaboraron en este trabajo. De igual manera a mi tutor el profesor George Barreto por confiar siempre en mí y darme la oportunidad de trabajar con él. TABLA DE CONTENIDO RESUMEN ......................................................................................................................................... 1 1. INTRODUCCIÓN ...................................................................................................................... 3 1.1 Planteamiento del problema de investigación........................................................................... 3 1.2 Justificación .............................................................................................................................. 6 2. MARCO TEORICO .................................................................................................................... 8 2.1 Metabolismo de los ácidos grasos y mecanismo celular en condición de daño ....................... 8 2.2 Inflamación del sistema nervioso............................................................................................ 12 2.2.1 Ácidos grasos, neuroinflamación y neurodegeneración ............................................. 13 2.2.2 Rol de la microglía en el proceso inflamatorio ................................................................ 16 2.3 Estrógenos ............................................................................................................................... 17 2.3.1 Receptores de Estrógeno .................................................................................................. 17 2.4. Neuroesteroides y esteroides neuroactivos ........................................................................... 19 2.4.1 Rol de los compuestos estrogénicos en la inflamación .................................................... 20 2.5 Tibolona, un esteroide neuroactivo y regulador de la actividad estrogénica .......................... 22 2.5.1 Regulación estrogénica de la inflamación ........................................................................... 24 3. OBJETIVOS ................................................................................................................................. 26 3.1. Objetivo General .................................................................................................................... 26 3.2. Objetivos específicos ............................................................................................................. 26 4. METODOLOGÍA ......................................................................................................................... 27 4.1. MÉTODOS EXPERIMENTALES ........................................................................................ 27 4.1.1. Línea Celular ................................................................................................................... 27 4.1.2 Modelo de estimulación con ácido palmítico ................................................................... 28 4.1.3 Tratamientos farmacológicos ........................................................................................... 28 4.1.4. Determinación de parámetros en el modelo .................................................................... 29 4.1.5. Estimación celular de la intensidad media de fluorescencia ........................................... 32 4.1.6. Citometría de flujo .......................................................................................................... 32 4.1.7. Determinación de Citoquinas: ......................................................................................... 33 4.1.8. Determinación y cuantificación de proteínas por Western Blot ..................................... 33 4.1.9. Inmunofluorescencia ....................................................................................................... 34 4.1.10. Análisis estadístico ........................................................................................................ 35 5. RESULTADOS ............................................................................................................................ 36 5.1. Efecto del ácido palmítico sobre la viabilidad en el modelo microglial ................................ 36 5.1.1. Evaluación de la fragmentación nuclear, potencial de membrana mitocondrial y producción de especies reactivas de oxígeno en células insultadas con ácido palmítico ......... 38 5.2. Efecto de la tibolona sobre la fragmentación nuclear, las especies reactivas de oxígeno, el potencial de membrana mitocondrial y masa mitocondrial en el modelo inflamatorio de ácido palmítico ....................................................................................................................................... 40 5.2.1. Efecto de la tibolona sobre los parámetros celulares en el modelo ................................. 40 5.3. Efecto de los receptores alfa y beta de estrógeno sobre el modelo inflamatorio estimulado por ácido palmítico ....................................................................................................................... 48 5.3.1. Efecto de los agonistas y antagonistas de los receptores de estrógeno sobre el modelo inflamatorio de ácido palmítico ................................................................................................ 48 5.3.3. Evaluación del efecto de la tibolona sobre los parámetros de función celular asociados con el tratamiento con agonistas de los receptores de estrógeno. ............................................. 51 5.3.4. Caracterización de la respuesta asociada a proteínas del mecanismo antioxidante mediante el tratamiento con tibolona y agonistas-antagonistas de los receptores de estrógenos ................................................................................................................................................... 53 5.4. Efecto de la tibolona sobre el componente inflamatorio en células microglia bajo un insulto con ácido palmítico ....................................................................................................................... 62 5.4.1 Efecto de la tibolona sobre la expresión de citoquinas en el modelo inflamatorio de ácido palmítico .................................................................................................................................... 62 5.4.2. Efecto de la tibolona sobre la modulación de la subunidad p65 de factor de transcripción Kappa B (NF-κB) y su translocación al núcleo......................................................................... 64 5.4.3. Efecto de la tibolona y la modulación de receptor de estrógeno beta sobre la expresión de la subunidad p65 del factor transcripción Kappa B.............................................................. 65 6. DISCUSIÓN ................................................................................................................................. 69 6.1. Efecto del ácido palmítico sobre el modelo microglial ......................................................... 69 6.2. Efecto de la tibolona sobre la respuesta de las células BV-2 al ácido palmítico ................... 70 6.3 Mecanismo de acción de la tibolona sobre el modelo inflamatorio con palmitato ................. 72 6.4. Respuesta del modelo estimulado con tibolona en la expresión de proteínas de efecto antioxidante ................................................................................................................................... 75 6.4.1 Efecto de la tibolona sobre la expresión de la proteína neuroglobina en células sometidas a ácido palmítico ....................................................................................................................... 78 6.5 Respuesta inflamatoria del modelo a la estimulación con palmitato y tratamiento con tibolona ......................................................................................................................................................
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