Publication: La esfingosina-1-fosfato liasa como herramienta terapéutica para modular los niveles de esfingosina-1- fosfato y reducir los déficits funcionales causados por la lesión medular
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2018-09-12
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Universidad Complutense de Madrid
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Abstract
Las lesiones traumáticas de la médula espinal son causa de discapacidad en más de cien mil personasen todo el mundo cada año. La lesión medular (LME) tiene una compleja fisiopatología que incluyemúltiples eventos, respuestas y procesos interrelacionados que afectan a los sistemas nervioso,vascular e inmune y que cambian a lo largo del tiempo. Al inicio del curso temporal de la LME, eltrauma inicial desencadena una serie de alteraciones vasculares, cambios bioquímicos y respuestascelulares secundarias que exacerban el daño inicial. El pronóstico de la LME depende estrechamentede las características de esta fase secundaria, incluyendo el incremento de la apoptosis, la infiltraciónde células inmunes y la respuesta inflamatoria, las alteraciones en la permeabilidad de la barrerahemato-medular, los procesos de degeneración Walleriana y desmielinización, la reactividad glial yla cicatriz glial, así como las respuestas neuroregenerativas. La caracterización de las vías deseñalización y los mecanismos subyacentes a todos estos procesos implicados en el daño secundarioresulta fundamental para identificar nuevas dianas sobre las cuales desarrollar estrategiasterapéuticas efectivas enfocadas a reducir los déficits funcionales inducidos por la lesión LME.Recientes evidencias sugieren que los esfingolípidos juegan un papel activo tras el daño en el SistemaNervioso Central (SNC) así como en diferentes patologías neurodegenerativas. Los esfingolípidos sonuna clase de lípidos basados en un esqueleto de esfingosina a partir del cual se generan una granvariedad de familias de esfingolípidos mediante fosforilación (v.g.: esfingosina-1-fosfato), acilación(v.g.: ceramidas), así como por adición de fosfocolina (esfingomielinas) o de residuos de azúcar (v.g.:cerebrósidos y gangliósidos). Aunque conocidos principalmente por papel como lípidos estructuralesen la biología de membranas, algunos esfingolípidos actúan como moléculas de señalización enprocesos de proliferación, supervivencia, apoptosis, migración y diferenciación celular. A pesar desu potencial, aún no se han desarrollado análisis detallados sobre el sistema de esfingolípidos en lamédula lesionada. Los escasos estudios existentes indican que varios esfingolípidos podrían participaren procesos clave de la LME. En particular, análisis en modelos de lesión medular han establecidoque la esfingosina-1-fosfato (S1P), un esfingolípido con numerosas funciones en el SNC, promuevela migración de células madre neurales hacia el sitio de la lesión. Estudios adicionales empleandoun análogo funcional de S1P sugieren que la concentración de este lípido bioactivo podría ser claveen la modulación de la respuesta inmune, la permeabilidad vascular o la reactividad glial tras la LME.Estas evidencias señalan a la S1P como una prometedora diana terapéutica para el tratamiento dela lesión medular. La señalización de S1P puede ser modificada mediante análogos funcionales, comomencionamos anteriormente, pero también actuando sobre las diferentes enzimas de la rutametabólica de los esfingolípidos. En este sentido, algunos estudios han demostrado el potencialterapéutico de modular la expresión o actividad de la S1P liasa (SPL), la enzima responsable de ladegradación irreversible de S1P...
Trauma to the spinal cord causes permanent and incurable disabilities in more than a hundredthousand people every year worldwide. The pathophysiology of the spinal cord injury (SCI) is acomplex intermingled set of events, responses, and processes that affect the nervous, vascular andimmune systems during the days and months that follow the damage. The initial trauma triggers aseries of secondary vascular alterations, biochemical disturbances and cellular responses thatexacerbate the initial damage. The functional outcome from SCI largely depends on prominentfeatures of this secondary phase, including increased apoptosis, immune cell infiltration andinflammatory responses, alterations in blood-spinal cord barrier permeability, Walleriandegeneration and demyelination, glial reactivity and glial scar, as well as neuro-regenerativeresponses. Characterizing the pathways and the mechanisms underlying the secondary damage isbasic to identify targets on which to develop effective therapeutic strategies aimed to restrict thefunctional deficits induced by the SCI.Recent evidences suggest that sphingolipids play an active role following injury to the Central NervousSystem (CNS) as well as in different neurodegenerative diseases. Sphingolipids are a class of bioactivelipids characterized by a sphingosine backbone upon which a large and complex network of familiesis built up by phosphorylation (vg. Sphingosine-1-phosphate), acylation (vg. ceramides), addition ofphosphocoline headgroup (sphingomyelins) or sugar residues (cerebrosides and gangliosides, i.e.glycosphingolipids). Best known for their crucial roles in membrane biology, several sphingolipidmetabolites function as signalling molecules in proliferation, survival, apoptosis, motility, anddifferentiation pathways. The few existing studies indicate that sphingolipid metabolites can playactive roles in different processes of the SCI. Studies in SCI models have established that sphingosine-1-phosphate (S1P), a sphingolipid metabolite with pleiotropic effects in the CNS, promotes themigration of neural stem cells towards the injury site. Additional studies using S1P analogues suggestthat the concentration of this bioactive lipid may be also key for the immune response, the vascularpermeability and the glial reactivity occurring after SCI. Altogether, these evidences identify S1P asa promising therapeutic target for the treatment of spinal cord injury. S1P signalling can be modifiedusing analogues as previously mentioned but also acting on different enzymes of the sphingolipidpathway. In this respect, several studies have demonstrated the therapeutic potential of modulatingthe expression or activity of S1P lyase (SPL), the enzyme responsible for the irreversible degradationof S1P. Despite their potential, detailed analyses on the sphingolipid system and its modulation inSCI are still lacking...
Trauma to the spinal cord causes permanent and incurable disabilities in more than a hundredthousand people every year worldwide. The pathophysiology of the spinal cord injury (SCI) is acomplex intermingled set of events, responses, and processes that affect the nervous, vascular andimmune systems during the days and months that follow the damage. The initial trauma triggers aseries of secondary vascular alterations, biochemical disturbances and cellular responses thatexacerbate the initial damage. The functional outcome from SCI largely depends on prominentfeatures of this secondary phase, including increased apoptosis, immune cell infiltration andinflammatory responses, alterations in blood-spinal cord barrier permeability, Walleriandegeneration and demyelination, glial reactivity and glial scar, as well as neuro-regenerativeresponses. Characterizing the pathways and the mechanisms underlying the secondary damage isbasic to identify targets on which to develop effective therapeutic strategies aimed to restrict thefunctional deficits induced by the SCI.Recent evidences suggest that sphingolipids play an active role following injury to the Central NervousSystem (CNS) as well as in different neurodegenerative diseases. Sphingolipids are a class of bioactivelipids characterized by a sphingosine backbone upon which a large and complex network of familiesis built up by phosphorylation (vg. Sphingosine-1-phosphate), acylation (vg. ceramides), addition ofphosphocoline headgroup (sphingomyelins) or sugar residues (cerebrosides and gangliosides, i.e.glycosphingolipids). Best known for their crucial roles in membrane biology, several sphingolipidmetabolites function as signalling molecules in proliferation, survival, apoptosis, motility, anddifferentiation pathways. The few existing studies indicate that sphingolipid metabolites can playactive roles in different processes of the SCI. Studies in SCI models have established that sphingosine-1-phosphate (S1P), a sphingolipid metabolite with pleiotropic effects in the CNS, promotes themigration of neural stem cells towards the injury site. Additional studies using S1P analogues suggestthat the concentration of this bioactive lipid may be also key for the immune response, the vascularpermeability and the glial reactivity occurring after SCI. Altogether, these evidences identify S1P asa promising therapeutic target for the treatment of spinal cord injury. S1P signalling can be modifiedusing analogues as previously mentioned but also acting on different enzymes of the sphingolipidpathway. In this respect, several studies have demonstrated the therapeutic potential of modulatingthe expression or activity of S1P lyase (SPL), the enzyme responsible for the irreversible degradationof S1P. Despite their potential, detailed analyses on the sphingolipid system and its modulation inSCI are still lacking...
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Tesis de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, Departamento de Bioquímica y Biología Molecular I, leída el 19-05-2017