ES2649038T3 - Método para identificar moduladores de p11 - Google Patents

Método para identificar moduladores de p11 Download PDF

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ES2649038T3
ES2649038T3 ES13163588.0T ES13163588T ES2649038T3 ES 2649038 T3 ES2649038 T3 ES 2649038T3 ES 13163588 T ES13163588 T ES 13163588T ES 2649038 T3 ES2649038 T3 ES 2649038T3
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modulators
sample
treating
useful
candidate
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Per Svenningsson
Paul Greengard
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Rockefeller University
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Rockefeller University
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Abstract

Un método para identificar los moduladores de la proteína p11 (también conocida como S100-A10) útiles para tratar o aliviar trastornos relacionados con el receptor p11/5-HT, comprendiendo el método: (A) identificar moduladores de p11, que comprende las etapas de proporcionar una primera muestra y una segunda muestra, en donde la muestra comprende células mononucleares de sangre periférica que contienen cantidades equivalentes de producto génico p11 (por ejemplo, proteína o ARNm); poner en contacto la primera muestra con el modulador de p11 candidato; y determinar si las cantidades de producto génico p11 en la primera muestra han cambiado, en donde una cantidad aumentada de producto génico indica que los moduladores candidatos pueden ser útiles para tratar o aliviar trastornos asociados a un nivel anormalmente bajo de p11 mientras que una cantidad disminuida indica que los moduladores candidatos pueden ser útiles para tratar o aliviar trastornos asociados a un nivel anormalmente alto de p11, o (B) identificar moduladores de p11, que comprende poner en contacto un modulador de p11 candidato con una muestra que comprende células mononucleares de sangre periférica que comprenden un gen indicador unido funcionalmente a un promotor p11 y usar el nivel de expresión génica del indicador como un proxy para la expresión de p11, en donde una cantidad aumentada del producto génico del indicador indica que los moduladores candidatos pueden ser útiles para tratar o aliviar trastornos asociados a un nivel anormalmente bajo de p11 mientras que una cantidad disminuida indica que los moduladores candidatos pueden ser útiles para tratar o aliviar trastornos asociados al nivel anormalmente alto de p11.

Description

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estímulos individuales (0,1 ms de duración) cada 15 s a una intensidad que arroja el 50-70 % de respuesta máxima evaluada por una curva estímulo/respuesta establecida para cada corte examinado midiendo la amplitud del potencial de campo provocado por intensidad de estímulo creciente. Para evaluar el efecto de la activación del receptor de serotonina en la transmisión sináptica glutamatérgica, se aplica serotonina en la solución de perfusión mientras se mide la amplitud de fEPSP/PS. La serotonina (50 µM; en presencia de 10 µM fluoxetina) reduce la amplitud de la fEPSP/PS en cortes de ratones WT (72 □ 2,7 % de valor de base) y su efecto se suprime en cortes de ratones p11 KO (98 □ 3,6 % de valor de base). Los valores numéricos se expresan mediante □SEM. Se aplican fármacos en la solución de perfusión cambiando una llave de tres conductos.
La serotonina, a través de receptores 5-HT1B, reduce la liberación de glutamato en terminales de neuronas que se originan en la corteza cerebral e inhiben la transmisión sináptica en las sinapsis corticoestriatales. Se monitoriza la amplitud de potenciales postsinápticos excitatorios (fEPSP, en inglés) provocada por la breve estimulación eléctrica de fibras glutamatérgicas y registrada extracelularmente en el núcleo accumbens. El fEPSP es mediado por receptores AMPA activados por el glutamato endógeno liberado por la estimulación eléctrica del corte tanto en ratones de tipo salvaje como en ratones p11 KO [f EPSP / reducción de 77 y 81 % de pico de población (PS, en inglés) respectivamente, comparado con la base, 15 min tras el antagonista del receptor AMPA 6-ciano-7nitroquinoxalina-2,3-diona (CNQX)]. Cuando se aplica en la solución de perfusión, la serotonina reduce la amplitud del f EPSP/PS en los cortes de ratones de tipo salvaje, pero no de ratones p11 KO.
Contenido tisular de monoaminas y metabolitos. Se sacrifican ratones tipo salvaje, heterocigotos p11 y p11 KO macho (n= 8 por genotipo) mediante irradiación de microondas concentrada y se diseccionan el hipocampo, las cortezas y striata y se congelan en hielo seco. A continuación, las muestras tisulares son sonicadas en 10 volúmenes de 0,1N TCA, se agitan y centrifugan a 12.000 g durante 2 min. Los sobrenadantes se recogen y analizan para detectar serotonina y el metabolito de serotonina ácido 5-hidroxiindolacético (5-HIAA) usando HPLC junto con detección electroquímica (HPLC-EC). Se separa la serotonina y 5-HIAA con una columna analítica C18 Hypersil 5µm de sílice desactivada para bases (4,6 x 150 mm) con una fase móvil que consta de 75mM fosfato de sodio monobásico, 350 mg/L ácido 1-octanosulfónico sal sódica, 0,5 mM EDTA, 0,8 % tetrahidrofurano (grado HPLC, sin inhibidor) y 8 % acetonitrilo, pH 3 (ajustado con ácido fosfórico), a una velocidad de flujo de 1,2 ml/min. Se usa un detector electroquímico con electrodos de carbono vítreo duales (electrodo 1 = 680 mV, intervalo, 0,5 nA; electrodo 2 = -100 mV, intervalo, 0,2 nA). Se recogen los datos usando software EZChrom que calculó las alturas de picos y concentraciones de muestras. La sensibilidad para serotonina y 5-HIAA es 0,1 pmol/ml.
Los receptores 5-HT1B actúan como autorreceptores e inhiben la liberación de serotonina. Puesto que p11 se expresa en los núcleos del rafe, las cantidades de serotonina y su metabolito principal ácido 5-hidroxiindolacético (5-HIAA) se miden en áreas de proyección, a saber, corteza, striatum e hipocampo en ratones de tipo salvaje y p11 KO. Según una regulación de la renovación de 5-HT y/o metabolismo por receptores 5-HT1B, y un papel potenciador de p11 en la función del receptor 5-HT1B, los ratones p11 KO presentan niveles aumentados de metabolismo y/o renovación de serotonina.
Análisis de comportamiento -Análisis de campo abierto. Se miden las actividades horizontales durante 30 minutos (se analizan los resultados cada periodo de 5 min) durante el día en un sistema de detección del movimiento sensible a infrarrojos y a luz roja, multijaula y computerizado. Los valores de actividad periférica se dividen 13 por los valores de actividad horizontal totales para determinar la tigmotaxis. En los experimentos con anpirtolina (5 mg/kg, i.p.), se somete a pruebas a animales 15 min tras la inyección. Algunos ratones tratados con anpirtolina habían recibido inyecciones diarias con imipramina (10 mg/kg, i.p.) durante 4 semanas hasta el día antes del experimento.
Análisis de comportamiento -Prueba de suspensión por la cola. La prueba de suspensión por la cola, un modelo de actividad similar al antidepresivo, se lleva a cabo como se ha descrito (S11) y es una versión modificada de la validada para ratones C57B16 (S12) y NMRI (S13). Los ratones son suspendidos individualmente por la cola en una barra horizontal (la distancia al suelo es de 35 cm) usando cinta adhesiva (la distancia desde la punta de la cola es de 2 cm). Normalmente, los ratones mostraron diversos comportamientos orientados a escapar intercalados con ratos temporalmente crecientes de inmovilidad. Se graba en vídeo una sesión de prueba de 6 min y se puntúa por un observador que desconoce el genotipo. El parámetro registrado es el número de segundos que estuvo inmóvil. En los experimentos con anpirtolina (5 mg/kg) e imipramina (10 mg/kg), se somete a pruebas a los animales 15 minutos tras la inyección.
Análisis de comportamiento -Prueba de consumo de sacarosa. Se usa un procedimiento de una sola botella en ratones de tipo salvaje y ratones p11 KO alojados de manera individual para analizar el consumo de sacarosa. Se mide el consumo de una solución de sacarosa al 2 % en agua durante un periodo de 96 horas. En un experimento posterior, se mide el consumo de agua durante el mismo periodo de tiempo.
Para evaluar los efectos del comportamiento de deleción de p11, se compara la tigmotaxis en ratones de tipo salvaje y ratones p11 KO en condiciones basales y en respuesta a anpirtolina en ratones que no han recibido fármaco y en ratones que han sido tratados a largo plazo con imipramina. En animales tratados con imipramina, la anpirtolina causa una reducción significativa en tigmotaxis en ratones de tipo salvaje, pero no en ratones p11 KO (Fig. 4G).
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