Publication: Efecto de la inhibición dual de GSK-3 y PDE-7 en un modelo murino de esclerosis lateral amiotrófica
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2016-03-14
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Universidad Complutense de Madrid
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Abstract
La Esclerosis Lateral Amiotrófica (ELA) es una enfermedad neurodegenerativa en la que mueren progresivamente las neuronas motoras de la corteza cerebral y la médula, con la consiguiente atrofia de los músculos inervados por ellas. Si bien últimamente han aparecido distintos modelos animales para el estudio de la ELA, los ratones que sobre-expresan el gen SOD1 humano con la mutación G93A, son los más utilizados. Estos son los animales que empleamos en nuestro estudio, en el cual evaluamos un inhibidor dual de las enzimas GSK-3 y PDE-7 llamado VP1.15. La Glucógeno Sintetasa Kinasa -3 (GSK-3) es una serina-treonina kinasa con múltiples funciones celulares y neurofisiológicas. En el Sistema Nervioso Central, la isoforma más abundante corresponde a GSK-3 β, cuya actividad está regulada negativamente por fosforilación en la Ser9. Su sobre-expresión se asocia con la muerte neuronal, la hiperfosforilación en Tau y la retracción de las neuritas en cultivos de neuronas. Por eso es vista como partícipe de la patofisiología de las enfermedades neurodegenerativas. En particular, su aumento ha sido detectado en la médula de los pacientes con ELAe. La superfamilia de las Fosfodiesterasas (PDEs) comprende enzimas ubicuas con capacidad de metalofosfohidrolasas que hidrolizan AMPc y/o GMPc llevándolos a sus respectivos monofosfatos inactivos. PDE-7 es una PDE específica para AMPc. Su inhibición actúa como neuroprotectora en cultivos celulares y en modelos de infarto experimental, disminuye la activación inflamatoria y la supervivencia de precursores de oligodendrocitos en cultivos primarios de neuronas, reduce los síntomas clínicos en el modelo murino de encefalomielitis autoinmune y la alteración cognitiva en el modelo murino de Enfermedad de Alzheimer (EA). Los mecanismos regulatorios y de señalización celular modulados por GSK-3 y PDE-7, involucran a CREB, β-catenina y los niveles de AMPc, moléculas que serán estudiadas en profundidad en esta investigación...
Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease where motor neurons die in the cerebral cortex and spinal cord, resulting in the weakness of muscles innervated by them. While recently it was appear different animal models that reproduced ALS, but mice that overexpressed human SOD1 with G93A mutation are the most used. These animals were used in our study, where we evaluated a dual inhibitor of GSK-3 and PDE-7 enzimes called VP1.15, that it was synthesized for Ana Martineźs group in Instituto de Química médica of CSIC. Glycogen synthase kinase-3 (GSK-3) is a serine–threonine kinase with diverse cellular and neurophysiological functions. In the Central nervous system, the isoform more expressed is GSK-3β. The activity is negatively regulated by phosphorylation at Ser9. GSK-3 is expressed at synaptic level in both mature and immature nerves. Several studies show the importance attached to growth and axonal polarity, axonal remodeling, neurogenesis, neuronal plasticity, neurotransmitter release and activity-dependent bulk endocytosis. GSK-3 overexpression has been associated with neuronal death, tau hyperphosphorylation, and neurite retraction in cultured neurons, then may be linked to the pathophysiology of neurodegenerative diseases. In particular, increased levels of GSK-3, have been detected in the spinal cord of patients with sporadic ALS. Phosphodiesterases (PDEs) are a large superfamily of ubiquitously metallophosphohydrolase enzymes that hydrolyze cAMP and/or cGMP to their respective inactive monophosphates. PDE7 is a cAMP-specific PDE. PDE7 inhibition acts as neuroprotective agent in cellular cultures and experimental stroke model, decrease inflammatory activation on primary neural cultures and survival of oligodendrocyte precursors, reduces clinical symptoms in the experimental autoimmune encephalomyelitis mouse model and cognitive impairment in a mouse model of Alzheimer disease. Overview of regulation and cell signaling modulated by GSK3 and PDE7 involve CREB, beta catenin and cAMP level, molecules that are deep studied in this work...
Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease where motor neurons die in the cerebral cortex and spinal cord, resulting in the weakness of muscles innervated by them. While recently it was appear different animal models that reproduced ALS, but mice that overexpressed human SOD1 with G93A mutation are the most used. These animals were used in our study, where we evaluated a dual inhibitor of GSK-3 and PDE-7 enzimes called VP1.15, that it was synthesized for Ana Martineźs group in Instituto de Química médica of CSIC. Glycogen synthase kinase-3 (GSK-3) is a serine–threonine kinase with diverse cellular and neurophysiological functions. In the Central nervous system, the isoform more expressed is GSK-3β. The activity is negatively regulated by phosphorylation at Ser9. GSK-3 is expressed at synaptic level in both mature and immature nerves. Several studies show the importance attached to growth and axonal polarity, axonal remodeling, neurogenesis, neuronal plasticity, neurotransmitter release and activity-dependent bulk endocytosis. GSK-3 overexpression has been associated with neuronal death, tau hyperphosphorylation, and neurite retraction in cultured neurons, then may be linked to the pathophysiology of neurodegenerative diseases. In particular, increased levels of GSK-3, have been detected in the spinal cord of patients with sporadic ALS. Phosphodiesterases (PDEs) are a large superfamily of ubiquitously metallophosphohydrolase enzymes that hydrolyze cAMP and/or cGMP to their respective inactive monophosphates. PDE7 is a cAMP-specific PDE. PDE7 inhibition acts as neuroprotective agent in cellular cultures and experimental stroke model, decrease inflammatory activation on primary neural cultures and survival of oligodendrocyte precursors, reduces clinical symptoms in the experimental autoimmune encephalomyelitis mouse model and cognitive impairment in a mouse model of Alzheimer disease. Overview of regulation and cell signaling modulated by GSK3 and PDE7 involve CREB, beta catenin and cAMP level, molecules that are deep studied in this work...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Biológicas, Departamento de Bioquímica y Biología Molecular, leída el 12-01-2016