Inmunolocalización De La Sustancia Py Del Receptor

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Inmunolocalización De La Sustancia Py Del Receptor UNIVERSIDAD DE SEVILLA FACULTAD DE MEDICINA DEPARTAMENTO DE CIRUGÍA TESIS DOCTORAL INMUNOLOCALIZACIÓN DE LA SUSTANCIA P Y DEL RECEPTOR NK1 EN LAS ESTRUCTURAS DEL SISTEMA NERVIOSO CENTRAL IMPLICADAS EN LA ENFERMEDAD DE ALZHEIMER-KRAEPELIN Amparo Murciano Rosado Sevilla 2015 Agradecimientos Mi más profundo agradecimiento a mis directores de tesis. Al Dr. D. Miguel Muñoz Sáezpor su amor por el conocimiento, su necesidad de transmitir su saber y entusiasmo a todoel que esté dispuesto a recibirlo. A la Dra. Dña. Inmaculada Bueno Rodríguez por su dedicación, paciencia y disponibilidad. Por su Amistad desde la infancia y por liarme en este mundo de la investigación. A mi bisabuelo Ramón, mi abuelo Gabriel, mi tía Carmen y mi tío y padrino Ramón, a mis hermanos Antonio y Montserrat y a mi sobrina Mª Paz, tronco y sabia antigua y nueva del amor por la medicina familiar. A todos mis compañeros y amigos que me han facilitado la realización de este trabajo. A Dña Ana Moreno, responsable de Doctorado de la Universidad de Sevilla, por sus consejos y orientación que han sido claves. A Dña Isabel Mª Rodríguez del Nodo coordinador del Biobanco del SSPA, Dña Carolina Castilla, del Nodo de Biobanco de Sevilla y a Dña Carmen Pérez del Nodo de Biobanco de Córdoba, por su interés y disponibilidad en la gestión de las muestras. A D. Andrés Carranza, Patólogo de Hospital UniversaitaioVirgen del Rocío y DñaMaría García Martos, Patóloga del Hospital Universitario del Sureste de Madrid, por su disponibilidad y colaboración en el proceso de inmunohistoquímica. A mi padre, por los consejos y por el amor que me han brindado siempre, por ser un ejemplo de generosidad, trabajo, honradez y por estar ahí. A mis hermanos, que me han ofrecido siempre suayuda sus palabras de ánimo y su ejemplo. A mis sobrinos, en especial a Javier, con los que he compartido horas de estudio. A Manu, mi marido, por su apoyo y paciencia, y por haber padecido mi ausencia. Espero que este trabajo aporte un grano de arena, un poco de luz a la ciencia en la búsqueda de la mejoradel manejo terapéutico y pronóstico de los pacientes con Alzheimer, por todos nuestros pacientes, sus familias y los venideros. Tengo presente a Dios en todo lo que hago, que me acompaña y me da fuerzas. Mi fe enDios me guía y me ayuda en los momentos difíciles, es el pilar de mi vida. A mamá, luz y guía de todos mis pasos. Y voy apaciguando las palabras, las acaricio, las ordeno y, dueño, las reparto y las lanzo, bien maduras, a la cara del hombre de mi tiempo Antonio Murciano Índice general 1. Introducción ................................................................................................................... 17 1.1. Justificación ........................................................................................................... 17 1.2. Enfermedad de alzheimer o demencia tipo alzheimer –kraepelin .......................... 17 1.2.1. Definición .................................................................................................. 17 1.2.2. Historia ..................................................................................................... 20 1.2.3. Epidemiología............................................................................................ 22 1.2.4 Características clínicas de la EA .................................................................. 23 1.2.5. Neuropatología en la EA: ........................................................................... 24 1.2.6. Genética en la EA ...................................................................................... 31 1.2.7. Fisiopatología de la EA ............................................................................... 34 1.2.8. Clasificación de EA ..................................................................................... 60 1.2.9. Criterios diagnósticos de la EA ................................................................... 61 1.2.10. DIANAS TERAPEÚTICAS .............................................................................. 64 1.3. SUSTANCIA P Y RECEPTOR NK-1 ............................................................................. 69 1.3.1 NEUROTRANSMISIÓN ................................................................................ 69 1.3.2. NEUROPÉPTIDOS ....................................................................................... 72 1.3.3. COEXISTENCIA-COTRANSMISIÓN ............................................................... 75 1.3.4. TAQUICININAS ........................................................................................... 76 1.3.5. RECEPTORES TAQUICINÉRGICOS ................................................................ 82 1.3.6. SUSTANCIA P ............................................................................................. 89 1.3.7. Distribución y funciones de las taquicininas ............................................... 92 1.3.7.1. Distribución y funciones de las taquicininas en el sistema nervioso central: SNC.................................................................. 92 1.3.7.2. Distribución y funciones de las Taquicininas en tejidos periféricos: ................................................................................. 95 1.3.8. Fisiopatología relacionada con la SP y NK1R .............................................. 98 1.3.9. ANTAGONISTAS DE LOS RECEPTORES NK1 .................................................. 112 1.3.9.1. ANTAGONISTAS PEPTÍDICOS ....................................................... 113 1.3.9.2. ANTAGONISTAS NO PEPTÍDICOS ................................................. 114 1.3.9.3. USOS TERAPÉUTICOS DE LOS ANTAGONISTAS RNK1 .................... 116 2. Hipótesis y objetivos del trabajo .................................................................................. 125 3. Material y método ........................................................................................................ 127 3.1. Metodología y plan de trabajo ............................................................................. 127 3.2. Datos clínicos de los pacientes ............................................................................. 127 3.3. Metodología del estudio inmunohistoquímico de la SP y el RNK1........................ 131 4. RESULTADOS ................................................................................................................ 135 5. DISCUSIÓN .................................................................................................................... 149 6. RESUMEN ..................................................................................................................... 179 7. CONCLUSIONES............................................................................................................. 181 8. BIBLIOGRAFÍA ............................................................................................................... 183 Índice de figuras Figura 1. Zonas afectadas en EA en relación con su función .......................................................... 19 Figura 2. Progresión en el deterioro de las actividades cotidianas................................................. 23 Figura 3. Sucesión de parámetros biológicos y clínicos en la enfermedad de Alzheimer. DCL: deterioro cognitivo leve; SPCD: síntomas psicológicos y conductuales de demencia (López-Álvarez J et al, 2015). ............................................................................................ 24 Figura 4. Cerebro normal y EA ........................................................................................................ 25 Figura 5. Factores genéticos asociados a la EA ............................................................................... 33 Figura 6. Los procesos causados por Aβ y las intervenciones terapéuticas disponibles. (T. Jiang et al.2012) ............................................................................................................... 35 Figura 7. Vías amiloidogénica y no amiliodogénica, lugar de acción de posibles terapias modificadoras de enfermedad. ........................................................................................ 37 Figura 8. Placa beta-amiloide en preparación post-mortem de tehido cerebral de un paciente con EA ................................................................................................................ 37 Figura 9. Estructura y procesamiento del APP ................................................................................ 38 Figura 10. Neuronas que contienen ovillos neurofibrilares .............................................................. 40 Figura 11. Representación esquemática de un hemisferio de un sujeto normal (izquierda) y un hemisferio de una persona afectada por EA (derecha). ............................................. 41 Figura 12. Esaquema de la patogénesis de la EA en el que la proteína tau juega un papel central .............................................................................................................................. 42 Figura 13. Diagrama de un receptor nicotínico cerebral (nAchR) ..................................................... 44 Figura 14. disfunciones mitocondriales en la EA. (Hroudová J et al, 2014) ...................................... 47 Figura 15. Cascada inflamatoria mediada por la glía ........................................................................ 49 Figura 16. La microglia y la neuroinflamación .................................................................................. 50 Figura 17.
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