ABSTRACT
Introducción: La esclerosis lateral amiotrófica (ELA) es una enfermedad neurodegenerativa, progresiva y de etiología desconocida caracterizada por la degeneración de motoneuronas superiores e inferiores. Aproximadamente el 90% de los casos de ELA son esporádicos, mientras que el 10% restante se consideran familiares. Independientemente de si son familiares o esporádicas, los pacientes desarrollan una debilidad progresiva, atrofia muscular con espasticidad y contracturas. Por lo general, la esperanza de vida en los pacientes de ELA es de 2 a 5 años. Desarrollo: Los modelos in vivo han ayudado a explicar la etiología y la patogénesis, así como los mecanismos de la ELA. Sin embargo, estos mecanismos no están del todo esclarecidos aún, por lo que los modelos experimentales son fundamentales para continuar con el estudio de los mismos, así como para la búsqueda de posibles dianas terapéuticas. A pesar de que el 90% de los casos son esporádicos, la mayoría de los modelos utilizados hasta la actualidad para estudiar la patogénesis están basados en las mutaciones genéticas asociadas a la enfermedad familiar, lo que provoca que la patogénesis de la ELA esporádica no sea aún conocida. Por tanto, sería fundamental el estudio de la enfermedad en modelos basados en la enfermedad esporádica. Conclusión: En el presente artículo se han revisado los principales modelos experimentales, tanto genéticos como esporádicos, utilizados en el estudio de esta enfermedad, enfocándonos en los que se han desarrollado utilizando el roedor como plataforma experimental.(AU)
Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease whose aetiology is unknown. It is characterised by upper and lower motor neuron degeneration. Approximately 90% of cases of ALS are sporadic, whereas the other 10% are familial. Regardless of whether the case is familial or sporadic, patients will develop progressive weakness, muscle atrophy with spasticity, and muscle contractures. Life expectancy of these patients is generally 25 years after diagnosis. Development: In vivo models have helped to clarify the aetiology and pathogenesis of ALS, as well as the mechanisms of the disease. However, as these mechanisms are not yet fully understood, experimental models are essential to the continued study of the pathogenesis of ALS, as well as in the search for possible therapeutic targets. Although 90% of cases are sporadic, most of the models used to study ALS pathogenesis are based on genetic mutations associated with the familial form of the disease; the pathogenesis of sporadic ALS remains unknown. Therefore, it would be critical to establish models based on the sporadic form. Conclusion: This article reviews the main genetic and sporadic experimental models used in the study of this disease, focusing on those that have been developed using rodents.(AU)
Subject(s)
Humans , Animals , Male , Female , Mice , Amyotrophic Lateral Sclerosis/diagnosis , Amyotrophic Lateral Sclerosis/drug therapy , Neurodegenerative Diseases , Cerebrospinal Fluid , Neurology , Nervous System DiseasesABSTRACT
INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease whose aetiology is unknown. It is characterised by upper and lower motor neuron degeneration. Approximately 90% of cases of ALS are sporadic, whereas the other 10% are familial. Regardless of whether the case is familial o sporadic, patients will develop progressive weakness, muscle atrophy with spasticity, and muscle contractures. Life expectancy of these patients is generally 2 to 5 years after diagnosis. DEVELOPMENT: In vivo models have helped to clarify the aetiology and pathogenesis of ALS, as well as the mechanisms of the disease. However, as these mechanisms are not yet fully understood, experimental models are essential to the continued study of the pathogenesis of ALS, as well as in the search for possible therapeutic targets. Although 90% of cases are sporadic, most of the models used to study ALS pathogenesis are based on genetic mutations associated with the familial form of the disease; the pathogenesis of sporadic ALS remains unknown. Therefore, it would be critical to establish models based on the sporadic form. CONCLUSIONS: This article reviews the main genetic and sporadic experimental models used in the study of this disease, focusing on those that have been developed using rodents.
Subject(s)
Amyotrophic Lateral Sclerosis , Neurodegenerative Diseases , Humans , Animals , Mice , Amyotrophic Lateral Sclerosis/pathology , DNA-Binding Proteins/genetics , MutationABSTRACT
Zinc is found in synaptic vesicles in a large number of glutamatergic systems. Its involvement in neurotransmission and neurological disorders has been suggested. There are methods for tracing these circuits, but they do not fill the dendritic tree. In this study, extracellular selenite injections in vivo were combined with intracellular injection of fluorochromes in fixed tissue to reveal the morphology of these zinc-rich neurones. Intraperitoneal and intracerebral injections of sodium selenite alone or intracerebral injections of selenite combined with bisbenzimide were made in the visual cortex of the rat in order to locate the somata of zinc-rich neurones. After 24 h of retrograde transport, animals were killed and fluorescent markers were injected intracellularly into fixed slices to show neuronal morphology: (a) Lucifer Yellow (LY) followed by biocytin, (b) LY coupled to biocytin or (c) micro-ruby (MR) (dextranamines bound to rhodamine and biotin). Double-labelled somata (selenite+fluorochrome) were plotted. Details of the dendritic morphology were then revealed by incubation in avidin-biotin complex and development in 3,3'-diaminobenzidine and H(2)O(2). Camera lucida drawings showed that zinc-rich neurones in layers II-III involved in cortico-cortical visual projections were typical pyramidal neurones. This technique is noteworthy for its analysis of the morphology (and connections) of zinc-rich neurones.
Subject(s)
Dextrans/metabolism , Extracellular Space/metabolism , Lysine/analogs & derivatives , Neuroanatomy/methods , Neurons/cytology , Rhodamines/metabolism , Sodium Selenite/metabolism , Zinc/metabolism , Animals , Biotin/metabolism , Cell Count , Drug Administration Routes/veterinary , Injections, Intraperitoneal/methods , Injections, Jet/methods , Iontophoresis/methods , Isoquinolines/metabolism , Male , Microscopy, Confocal/instrumentation , Microscopy, Confocal/methods , Neural Pathways/anatomy & histology , Neural Pathways/metabolism , Neurons/metabolism , Rats , Rats, Inbred WKY , Rats, Wistar , Silver Staining/methods , Somatosensory Cortex/cytology , Somatosensory Cortex/metabolism , Visual Cortex/metabolismABSTRACT
Apart from iron, zinc is the most abundant oligoelement in the nervous tissue. Although the majority of zinc constitutes a stable fraction that is tightly bound to molecules and molecular complexes (structural or metabolic zinc), a small proportion (10 15% of cerebral zinc) remains as an ion and it is stored inside membranous compartments (ionic vesicular zinc). In neurons, most of this ionic zinc can be found inside synaptic vesicles and it is released outside the neuron during synaptic transmission: this is the synaptic zinc. In the surroundings of the synapse, zinc acts over a variety of neuronal receptors and ionic channels, playing a modulatory role that is not yet fully understood. The prolonged presence of zinc in the vicinity of the synapse allows its translocation to postsynaptic neurons, which lack the defensive mechanisms (membrane transporters that store zinc into vesicles). In this case, zinc acts as a neurotoxic and it can induce neuronal cell death. Neurons and glial cells have very efficient, although not well known, cleaning mechanisms that eliminate synaptic zinc from the extracellular space; it probably is simultaneous with glutamate clearance. It is feasible that dysfunction of these zinc cleaning systems could induce compensatory mechanisms (precipitation induced by amyloid precursor protein) which in turn could potentiate ethiologic factors of Alzheimer s disease.
Subject(s)
Alzheimer Disease/metabolism , Brain/metabolism , Synapses/metabolism , Zinc/metabolism , Amyloid beta-Protein Precursor/metabolism , Hippocampus/metabolism , Humans , ImmunohistochemistryABSTRACT
Después del hierro, el zinc es el oligoelemento más abundante en el tejido nervioso; aunque la mayor parte del zinc forma una fracción estable, fuertemente unida a moléculas y complejos moleculares (zinc estructural o metabólico), una pequeña proporción, 10-15 por ciento del zinc total en cerebro, permanece en forma iónica y se concentra en el interior de compartimentos membranosos (zinc vesicular-iónico). En neuronas, la mayor parte del zinc vesicular-iónico está en el interior de vesículas sinápticas y se vierte al exterior durante la trasmisión sináptica: es el zinc sináptico. En las inmediaciones, el zinc actúa sobre una gran variedad de neurorreceptores y canales iónicos ejerciendo una función moduladora no del todo conocida. Pero su permanencia prolongada permite su translocación a neuronas postsinápticas que carecen de mecanismos defensivos específicos, i.e., transportadores de membrana que lo encierren en vesículas. En tales casos, el zinc actúa como neurotóxico y puede provocar muerte neuronal. Neuronas y células gliales poseen mecanismos de limpieza que eliminan el zinc sináptico del espacio extracelular, probablemente de forma simultánea a lo que ocurre con el neurotransmisor (glutamato). Es muy posible que la disfunción de estos sistema de limpieza desencadene mecanismos compensatorios de precipitación por la proteína extracelular preamiloide, que a la larga, potencien factores etiológicos de la enfermedad de Alzheimer. (AU)
