LPA1 and LPA2 receptors as new therapeutic targets for the treatment of central nervous system pathologies

Zusammenfassung

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...