Efecto antioxidante del trans- resveratrol y el ubiquinol en la función testicular de ratones cd1 sometidos a un ejercicio de natación forzada

• Autores: Antonia Lucía Sánchez de Medina
• Directores de la Tesis: Inmaculada Rodríguez Artiles (dir. tes.), Diana María Vaamonde Martín (codir. tes.)
• Lectura: En la Universidad de Córdoba (ESP) ( España ) en 2021
• Idioma: español
• Tribunal Calificador de la Tesis: Cristina Riber Pérez (presid.), Katiuska Satue Ambrojo (secret.), Julián Santiago Moreno (voc.)
• Programa de doctorado: Programa de Doctorado en Biociencias y Ciencias Agroalimentarias por la Universidad de Córdoba
• Materias:
  • Ciencias de la vida
    • Biología animal (zoología)
      • Patología animal
  • Ciencias agrarias
    • Ciencias veterinarias
      • Patología
• Enlaces
  • Tesis en acceso abierto en: Helvia
• Resumen

  • 1. Introducción o motivación de la tesis La realización de ejercicio es una práctica cada vez más común en la sociedad actual. La valoración de cómo la actividad física afecta a la salud ha tomado gran importancia en las últimas décadas. Se ha demostrado que el ejercicio practicado de forma moderada y continua aporta numerosos beneficios a la salud, reduciendo la probabilidad de padecer enfermedades cardiovasculares, diabetes y cáncer (Newton y Galvao, 2008; Agarwal y cols., 2012). La relación que existe entre ejercicio y fertilidad es también un tema de estudio en auge, debido a las altas tasas de problemas reproductivos encontrados en los atletas (Arce y cols., 1993, Jensen y cols., 1995; Gebreegziabher y cols., 2004; Vaamonde y cols., 2009; Wise y cols., 2011; Kipandula y Lampiao, 2015). Cuando revisamos los estudios publicados en esta línea observamos que los resultados encontrados son diversos. De un lado, en modelos de roedores, se ha observado que un ejercicio moderado, reduce los daños de inflamación y estrés oxidativo que acontecen con el envejecimiento en testículo (Zhao y cols., 2013), así como también produce un incremento de la capacidad antioxidante total del organismo (Kalantari y cols., 2017). En el hombre también se ha demostrado que el ejercicio moderado, tiene un efecto beneficioso en la fertilidad, mejorando parámetros del seminograma como cantidad de esperma, concentración, motilidad y morfología (Vaamonde y cols., 2012; Gaskins, y cols., 2015). De otro lado, cuando el ejercicio se practica de forma aguda o intensa y continua puede conducir a un estado de estrés oxidativo debido a que el incremento en el consumo de oxígeno incrementa la producción de especies reactivas de oxígeno (ERO), moléculas que se forman del metabolismo celular, provocando un desequilibrio de la homeostasis prooxidante-antioxidante intracelular (Kawamura y Muraoka, 2018). Las ERO son sustancias muy inestables y reactivas que pueden dañar a distintas clases de moléculas como proteínas, lípidos, ácidos nucleicos y azúcares presentes en las células, siendo la peroxidación de los lípidos uno de los daños más comúnmente asociados al incremento de las ERO. Los espermatozoides son células muy propensas a sufrir daño oxidativo debido a que tienen gran cantidad de ácidos grasos poliinsaturados en su membrana y por la baja concentración de enzimas antioxidantes presentes en su escaso citoplasma, lo que limita su capacidad de eliminar radicales y la capacidad de reparar su ADN (Lenzi y cols., 1996). Aunque pequeñas cantidades de ERO son necesarias para que los espermatozoides adquieran su capacidad fertilizante (capacitación, reacción del acrosoma y fusión del ovocito) (Aitken, 1997; de Lamirande y Gagnon, 1993 (a y b); Griveau y Le Lannou 1997); cuando estas exceden la capacidad antioxidante propia del testículo se induce un daño que puede causar alteraciones de la función testicular (Álvarez y cols., 1987; Aitken, 1995; Aziz y cols., 2004; Aitken, 2006; Agarwal y cols., 2008; Tremellen, 2008; Saki y cols., 2009, 2010; Jana y cols., 2010; Rodríguez y cols., 2016). Son escasos los estudios que valoran como el ejercicio, que practica la mayor parte de población, moderado y continuo, afecta a la fertilidad. Algunos estudios con programas de ejercicio moderados han observado alteraciones de seminograma afectándose incluso la fertilidad (Saki y cols., 2009, 2010; Rodríguez y cols., 2016) pudiendo ser la causa, al igual que en los casos de ejercicio intenso, de un desequilibrio en la homeostasis prooxidante-antioxidante.

    Para combatir el estatus de estrés oxidativo, durante años se ha valorado el incremento de la capacidad antioxidante del organismo, administrando antioxidantes exógenos. Por ello, son cada vez más las investigaciones que estudian el efecto que tiene la suplementación de la dieta con antioxidantes, tanto a nivel reproductivo como a otros niveles (Agarwal y cols., 2003; Tremellen, 2008). Su uso en modelos de ejercicio y fertilidad también han sido valorado (Jana y cols., 2014; Kalantari y cols., 2017; Minaii y cols., 2014; Moayeri y cols., 2018; Rodríguez y cols., 2016; Vijayprasad y cols., 2014).

    El trans-resveratrol es un estilbenoide, ampliamente consumido en alimentos como la uva roja y el vino. Actúa reduciendo la peroxidación lipídica, oxidación y nitración proteica (Olas y Wachowicz, 2005), mejorando el funcionamiento de las mitocondrias. Presenta un amplio rango de funciones biológicas demostradas en estudios previos, como antiinflamatoria, antioxidante, antiviral, antitumoral, cardioprotectiva y neuroprotectiva (Fremont, 2000; Wensel y cols., 2005). A nivel reproductivo, su efecto es controvertido, así se ha usado en modelos de animales donde se ha visto que eleva la concentración de gonadotropinas y testosterona en sangre, incrementando la producción de espermatozoides del epidídimo (Juan y cols., 2005) y revirtiendo los daños testiculares producidos por diversos agentes oxidantes (Yuluğ y cols., 2013) y por el estrés (Bitgul y cols., 2013); de otro lado se ha visto que a altas dosis el trans-resveratrol presenta un efecto pro-oxidante incrementando marcadores de estrés oxidativo y provocando alteraciones del seminograma, como la concentración de espermatozoides y la motilidad (Ranawat y cols., 2013). En modelos de ejercicio ha sido usado previamente, observándose que revierte los efectos deletéreos que el ejercicio provoca sobre la morfología espermática en ratones CD-1 sometidos a tres minutos de natación forzada durante cincuenta días (Rodríguez y cols., 2016) y protege del daño oxidativo producido por el ejercicio intenso (Guo y cols., 2019).

    El ubiquinol (QH), forma reducida de la coenzima Q10 (CoQ10), es una sustancia liposoluble, similar a las vitaminas. Está presente en la mayoría de los tejidos del organismo y tiene dos funciones principales; bioenergética mejorando la actividad de la mitocondria en la síntesis de ATP, y antioxidante. Como antioxidante actúa a nivel de la mitocondria y membranas lipídicas, donde ejerce las funciones de transportador redox (Bentinger y cols., 2007); elimina los radicales libres, y previene la iniciación y propagación de la peroxidación lipídica en las membranas celulares, ayudando además a la regeneración de otros antioxidantes como el tocoferol y el ascorbato (Crane y cols., 2001); también disminuye la producción de citoquinas proinflamatorias y del factor α de necrosis tumoral (Fouad y cols., 2011). Su actividad como antioxidante se está estudiando en diferentes campos, existiendo numerosos estudios que han demostrado su capacidad para disminuir los efectos deletéreos que las ERO producen en distintos tejidos (Litarru, 2007), entre ellos el testicular (Ognjanovic y cols., 2010; Fouad y cols., 2011; Nadjarzadeh, 2014). Pese a su baja solubilidad, se ha demostrado que la administración exógena oral de ubiquinol produce un incremento en los niveles de CoQ10 y ubiquinol en plasma seminal y células espermáticas (Balercia y cols., 2009, Safarinejad y cols., 2009, 2012). Usado como suplemento oral en la dieta en pacientes con problemas de fertilidad mejora algunos parámetros del seminograma (Safarinejad y cols., 2009, 2012). No obstante, su efectividad respecto a los parámetros reproductivos no ha sido probada en sujetos sometidos a ejercicio, ni en modelos animales ni en el hombre.

    Para facilitar la capacidad de absorción del ubiquinol, se han usado diferentes compuestos entre ellos el ácido ascórbico. El ácido ascórbico también conocido como Vit C, es una vitamina hidrosoluble, esencial para el correcto funcionamiento del cuerpo. Durante muchos años se ha relacionado su déficit con problemas de fertilidad, demostrándose que es esencial para el correcto desarrollo de la espermatogénesis debido en parte a su capacidad de reducir el α tocoferol y mantener este antioxidante en un estado activo (Aitken y Roman, 2008), protege la integridad de la membrana (Vijayprasad y cols., 2014) y en roedores y humanos, añadido como suplemento en la dieta, estimula la producción de espermatozoides y secreción de testosterona (Okon y Utuk, 2016; Sönmez y cols., 2005) mejorando algunos parámetros del seminograma (Akmal, y cols.,. 2006).

    Queremos comprobar si un programa de ejercicio moderado continuo provocará un incremento en las especies reactivas de oxígeno provocando daños sobre la función testicular, y que dichos daños podrán ser revertidos con la suplementación oral en la dieta de antioxidantes exógenos (ubiquinol o trans- resveratrol)  2.contenido de la investigación Con el fin de estudiar cómo el ejercicio moderado prolongado afecta a la función testicular del ratón, se ha planteado en este estudio un modelo de ejercicio consistente en un programa de natación forzada de 3 minutos diarios, en tanques de agua a temperatura controlada, durante 50 días. Como antioxidantes se han empleado el trans-resveratrol, previamente usado por nuestro grupo a una dosis menor de la utilizada en este trabajo y el ubiquinol, no utilizado previamente en modelos de ejercicio. Ambos antioxidantes se han administrado por vía oral. Se han utilizado 75 ratones CD-1, machos, de 65 días de edad que fueron distribuidos de forma aleatoria en cada uno de los siguientes grupos: grupo control (GC), grupo que no practicaba ejercicio ni recibía antioxidantes; grupo ejercicio (EJERC), grupo que practicaba ejercicio pero no recibía antioxidantes; grupo trans-resveratrol (EJ-Resv), grupo que practicaba ejercicio y recibía 100mg/Kg de trans-resveratrol; grupo ubiquinol (EJ-Ubiq), grupo que practicaba ejercicio y recibia 200mg/Kg de un compuesto elaborado por la empresa Kaneka que facilita la absorción del ubiquinol y que presenta además del ubiquinol un excipiente compuesto de 73,93 % de goma arábica, 20,44% de dextrina y 4,63% de vitamina C, y grupo excipiente (EJ-Excp), grupo que practicaba ejercicio y recibía el excipiente correspondiente a 200 mg /Kg del compuesto de Kaneka. Tras los 50 días de ejercicio de natación forzada, los animales fueron sacrificados, se extrajeron los epidídimos y testículos para el estudio de morfología y vitalidad espermática, valoración de estrés oxidativo (peroxidación lipídica, actividad antioxidante total, niveles de Q9, Q10 y enzimas antioxidantes) y valoración tanto de la espermatogénesis como de la histomorfometría testicular.

    3.Conclusiones 1º.- El modelo de ejercicio de 3 minutos de natación forzada diaria durante 50 días provoca alteraciones similares a las observadas en nuestro estudio anterior, incrementando el porcentaje de morfoanomalías de los espermatozoides epididimarios y el diámetro del núcleo de las espermatogonias de la pared de los túbulos, sin alteración de la vitalidad de los espermatozoides del epidídimo.

    2ª.- El modelo de ejercicio planteado produce un descenso, aunque no de forma significativa, de las enzimas antioxidantes glutatión peroxidasa y glutatión reductasa, además de un descenso de malondialdehido y de la ratio CoQ9/Q10 junto con un incremento de la actividad antioxidante total.

    3ª.- La administración de los antioxidantes ubiquinol y el trans-resveratrol, de forma diaria como suplemento en la dieta, protege frente a los efectos nocivos que el ejercicio planteado produce sobre la morfología espermática, disminuyendo el número de anomalías, a la vez que incrementa la vitalidad espermática; además reduce el diámetro de los núcleos de las espermatogonias y el número de células inmaduras en la luz del túbulo.

    5ª.- El ubiquinol es el antioxidante que mejor protege frente a los daños en la morfología de los espermatozoides epididimarios y el trans-resveratrol es el que mayor reducción presenta del diámetro de los núcleos de las espermatogonias y el que mejor preserva la espermatogénesis al disminuir la presencia de células inmaduras en la luz de los túbulos.

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