Publication: Los receptores LPA₁ y LPA₂, como nuevas dianas terapéuticas para el tratamiento de patologías del sistema nervioso central
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2018-08-28
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Universidad Complutense de Madrid
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Abstract
Los lisofosfolípidos son derivados lípidicos con funciones tanto estructurales como de señalización, por lo que juegan un papel fundamental en humanos y otros mamíferos. El análisis de lisofosfolípidos en fluidos humanos de pacientes con diferentes condiciones patológicas revela no sólo la importancia de los lisofosfolípidos y de sus receptores en enfermedades humanas, sino también sus potenciales aplicaciones como biomarcadores y/o dianas terapéuticas.1,2 Entre ellos, destaca el ácido lisofosfatídico (LPA) debido a su implicación en la regulación de procesos fisiológicos y patológicos de importancia a través de la activación de sus receptores correspondientes LPA1–6,3-5 todos ellos pertenecientes a la superfamilia de los receptores acoplados a proteínas G (GPCRs). El LPA regula una amplia variedad de actividades biológicas, especialmente en el desarrollo y el funcionamiento del sistema nervioso.6,7 Considerando los numerosos efectos producidos por el LPA en diferentes tipos celulares del sistema nervioso y la sobreexpresión de los receptores de LPA como consecuencia de un daño neuronal observado tanto en ratones como en humanos, es probable que el LPA regule aspectos esenciales en la reorganización celular después de un trauma neuronal.8 Entre todas las neuropatologías donde el LPA juega un papel importante, el dolor neuropático9-13 y el daño medular14-16 son condiciones con una elevada incidencia y altamente incapacitantes, que actualmente carecen de terapias específicas. En este contexto, los receptores LPA1 y LPA2 se han relacionado con estas patologías,17,18 pero la falta de agonistas y antagonistas potentes y selectivos ha dificultado el estudio de sus funciones específicas. Por tanto, en este trabajo, hemos abordado el desarrollo de ambos tipos de compuestos para así tratar de esclarecer la función de los receptores LPA1 y LPA2 en el dolor neuropático y en el daño medular...
Lysophospholipids (LPs) are cell membrane lipid derivatives that also act as extracellular signals and play important roles in humans and other mammals. Analysis of LPs in human body fluids from subjects with different pathophysiological conditions reveal not only the relevance of LPs and their receptors in human diseases, but also their potential application as biomarkers and/or therapeutic targets.1,2 Among them, lysophosphatidic acid (LPA) stands out as a molecule that elicits a plethora of biological effects by binding to specific G protein-coupled receptors: LPA1–6 receptors.3-5 LPA regulates a wide variety of biological activities, notably within the developing and adult nervous system.6,7 Considering the pleiotropic effects of LPA on many nervous system cell types, together with data showing localized up-regulation of LPA receptors after injury in mice and humans, it is likely that LPA regulates essential aspects of the cellular reorganization after neural trauma.8 Among all neuropathologies where LPA plays an important role, neurophatic pain (NP)9-13 and spinal cord injury (SCI)14-16 are high incidence and seriously disabling conditions which currently lack specific pharmacological therapies. In this context, LPA1 and LPA2 receptor subtypes have been functionally linked to many neural processes associated to these pathologies,17,18 but the lack of potent and selective agonists and antagonists has impaired the delineation of their specific role. Hence, we have focused our efforts on the development of such agents to clarify the biological role of LPA1 and LPA2 receptors in NP and SCI...
Lysophospholipids (LPs) are cell membrane lipid derivatives that also act as extracellular signals and play important roles in humans and other mammals. Analysis of LPs in human body fluids from subjects with different pathophysiological conditions reveal not only the relevance of LPs and their receptors in human diseases, but also their potential application as biomarkers and/or therapeutic targets.1,2 Among them, lysophosphatidic acid (LPA) stands out as a molecule that elicits a plethora of biological effects by binding to specific G protein-coupled receptors: LPA1–6 receptors.3-5 LPA regulates a wide variety of biological activities, notably within the developing and adult nervous system.6,7 Considering the pleiotropic effects of LPA on many nervous system cell types, together with data showing localized up-regulation of LPA receptors after injury in mice and humans, it is likely that LPA regulates essential aspects of the cellular reorganization after neural trauma.8 Among all neuropathologies where LPA plays an important role, neurophatic pain (NP)9-13 and spinal cord injury (SCI)14-16 are high incidence and seriously disabling conditions which currently lack specific pharmacological therapies. In this context, LPA1 and LPA2 receptor subtypes have been functionally linked to many neural processes associated to these pathologies,17,18 but the lack of potent and selective agonists and antagonists has impaired the delineation of their specific role. Hence, we have focused our efforts on the development of such agents to clarify the biological role of LPA1 and LPA2 receptors in NP and SCI...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, Departamento de Química Orgánica, leída el 05-05-2017