Publication: Avances en la creación de un modelo experimental de ELA esporádica en rata mediante el tratamiento con ß-N-metilamino-L-alanina (L-BMAA)
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2014-11-17
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Universidad Complutense de Madrid
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Abstract
"Introducción": El L-BMAA es un aminoácido altamente neurotóxico que ha sido relacionado con la aparición de la Esclerosis Lateral Amiotrófica (ELA) esporádica. La ELA es una enfermedad neurodegenerativa caracterizada la degeneración de las motoneuronas. La mayoría de los casos de ELA son esporádicos, pero hasta el momento no existe un modelo validado para su estudio. "Objetivo" Desarrollo de un modelo in vivo de ELA esporádica en ratas mediante la administración de L-BMAA. "Resultados y discusión" El tratamiento más adecuado con L-BMAA para la aparición de los síntomas neurológicos es con dosis i.p. de 300 mg/kg/día durante 5 días consecutivos en ratas al destete. Los efectos neurológicos evolucionan en una fase inicial rápida, seguida de una fase más progresiva. Los animales tratados con L-BMAA presentan una serie de características similares a la ELA: fallos en la coordinación y el control motor, disminución del volumen muscular, adelgazamiento selectivo de la corteza motora, agrandamiento de los ventrículos laterales, alteración de núcleos bulbares implicados en la deglución, alteración del N-acetilaspartato y sus cocientes relacionados, y alteración de los niveles de glutamato, GABA y taurina. El tratamiento con L-BMAA causa daños en los orgánulos celulares, y provoca la activación de la autofagia y la apoptosis. Además, provoca un incremento de los niveles de GSK3β activo y la formación de acúmulos de TDP-43 ubiquitinados. Se comprobó la efectividad del modelo para el ensayo de moléculas terapéuticas mediante el tratamiento con el inhibidor de GSK3 VP2.51, consiguiéndose la recuperación de los síntomas neurológicos de los animales tratados con L-BMAA"Conclusiones":Las ratas tratadas con L-BMAA presentan las principales características de la ELA, por lo que son un buen modelo experimental de ELA esporádica. Éste puede ser de gran utilidad para conocer los mecanismos fisiopatológicos de la enfermedad y para el estudio de fármacos para su tratamiento.
"Introduction":L-BMAA is an amino acid, highly neurotoxic, which has been associated with the appearance of sporadic Amyotrophic Lateral Sclerosis (ALS). ALS is a neurodegenerative disease characterized by degeneration of motor neurons. Most ALS cases are sporadic, but there is not an animal model accepted so far for its study. "Objectives":The development of a sporadic ALS in vivo model in rats by means of L-BMAA administration."Results and discussion":The most suitable L-BMAA treatment in order to obtain neurological effects is inyected i.p. with doses of 300 mg/kg/day for 5 consecutive days with 21 days old rats (at weaning time). The effects evolve in a fast initial phase, followed by a more stable phase in which symptoms are developed progressively. Animals treated with L-BMAA present a series of features mimicking ALS, namely: deficient coordination and motor control, muscle volume decrease, selective thinning of the motor cortex, enlarged lateral ventricles, impaired bulbar nuclei involved in swallowing, alteration of N-acetylaspartate and related ratios, and altered levels of glutamate, GABA and taurine. L-BMAA treatment causes damage in cellular organelles, and causes activation of autophagy and apoptosis. Furthermore, causes increased levels of active GSK3 and the formation of ubiquitinated accumulations of TDP-43. The effectiveness of the model for testing therapeutic molecules was tested by treatment with GSK3 inhibitor VP2.51, achieving the recovery of neurological symptoms of the animals treated with L-BMAA. "Conclusions":Rats treated with L-BMAA present the main ALS features, so they are a good experimental model of sporadic ALS. It can be very useful to learn about the pathophysiological mechanisms of the disease and for the study of drugs for its treatment.
"Introduction":L-BMAA is an amino acid, highly neurotoxic, which has been associated with the appearance of sporadic Amyotrophic Lateral Sclerosis (ALS). ALS is a neurodegenerative disease characterized by degeneration of motor neurons. Most ALS cases are sporadic, but there is not an animal model accepted so far for its study. "Objectives":The development of a sporadic ALS in vivo model in rats by means of L-BMAA administration."Results and discussion":The most suitable L-BMAA treatment in order to obtain neurological effects is inyected i.p. with doses of 300 mg/kg/day for 5 consecutive days with 21 days old rats (at weaning time). The effects evolve in a fast initial phase, followed by a more stable phase in which symptoms are developed progressively. Animals treated with L-BMAA present a series of features mimicking ALS, namely: deficient coordination and motor control, muscle volume decrease, selective thinning of the motor cortex, enlarged lateral ventricles, impaired bulbar nuclei involved in swallowing, alteration of N-acetylaspartate and related ratios, and altered levels of glutamate, GABA and taurine. L-BMAA treatment causes damage in cellular organelles, and causes activation of autophagy and apoptosis. Furthermore, causes increased levels of active GSK3 and the formation of ubiquitinated accumulations of TDP-43. The effectiveness of the model for testing therapeutic molecules was tested by treatment with GSK3 inhibitor VP2.51, achieving the recovery of neurological symptoms of the animals treated with L-BMAA. "Conclusions":Rats treated with L-BMAA present the main ALS features, so they are a good experimental model of sporadic ALS. It can be very useful to learn about the pathophysiological mechanisms of the disease and for the study of drugs for its treatment.
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Biológicas, Departamento de Fisiología (Fisiología Animal II), leída el 29-05-2014