title: Activation of Lysophosphatidic Acid Receptor Type 1 Contributes to Pathophysiology of Spinal Cord Injury.
abstract: Lysophosphatidic acid (LPA) is an extracellular lipid mediator involved in many physiological functions that signals through six known G-protein-coupled receptors (LPA1-LPA6). A wide range of LPA effects have been identified in the CNS, including neural progenitor cell physiology, astrocyte and microglia activation, neuronal cell death, axonal retraction, and development of neuropathic pain. However, little is known about the involvement of LPA in CNS pathologies. Herein, we demonstrate for the first time that LPA signaling via LPA1 contributes to secondary damage after spinal cord injury. LPA levels increase in the contused spinal cord parenchyma during the first 14 d. To model this potential contribution of LPA in the spinal cord, we injected LPA into the normal spinal cord, revealing that LPA induces microglia/macrophage activation and demyelination. Use of a selective LPA1 antagonist or mice lacking LPA1 linked receptor-mediated signaling to demyelination, which was in part mediated by microglia. Finally, we demonstrate that selective blockade of LPA1 after spinal cord injury results in reduced demyelination and improvement in locomotor recovery. Overall, these results support LPA-LPA1 signaling as a novel pathway that contributes to secondary damage after spinal cord contusion in mice and suggest that LPA1 antagonism might be useful for the treatment of acute spinal cord injury.
  
  
  CONCLUSIONS
  This study reveals that LPA signaling via LPA receptor type 1 activation causes demyelination and functional deficits after spinal cord injury.
authors.affiliation: Department of Cellular Biology, Physiology, and Immunology, Institute of Neurosciences, Center for Biomedical Research in Neurodegenerative Diseases Network (CIBERNED), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
authors.forename: Eva
authors.identifier: http://orcid.org/0000-0002-5917-3534
authors.initials: E
authors.lastname: Santos-Nogueira
authors.affiliation: Department of Cellular Biology, Physiology, and Immunology, Institute of Neurosciences, Center for Biomedical Research in Neurodegenerative Diseases Network (CIBERNED), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
authors.forename: Clara
authors.identifier: http://orcid.org/0000-0001-7597-262X
authors.initials: C
authors.lastname: López-Serrano
authors.affiliation: Department of Cellular Biology, Physiology, and Immunology, Institute of Neurosciences, Center for Biomedical Research in Neurodegenerative Diseases Network (CIBERNED), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Hernández
authors.affiliation: Neuroinflammation and Gene Therapy Laboratory, Pasteur Institute of Montevideo, 11400 Montevideo, Uruguay.
authors.forename: Natalia
authors.initials: N
authors.lastname: Lago
authors.affiliation: Institute of Biology and Molecular Genetics, Spanish National Research Council, 47003 Valladolid, Spain.
authors.forename: Alma M
authors.initials: AM
authors.lastname: Astudillo
authors.affiliation: Institute of Biology and Molecular Genetics, Spanish National Research Council, 47003 Valladolid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Balsinde
authors.affiliation: Research Laboratories, Interdepartmental Neuroscience and Mental Health Clinical Management Units, Institute for Biomedical Research of Málaga, Regional University Hospital of Málaga and Virgen de la Victoria, 29009 Málaga, Spain, and.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Estivill-Torrús
authors.affiliation: Research Laboratories, Interdepartmental Neuroscience and Mental Health Clinical Management Units, Institute for Biomedical Research of Málaga, Regional University Hospital of Málaga and Virgen de la Victoria, 29009 Málaga, Spain, and.
authors.forename: Fernando Rodriguez
authors.initials: FR
authors.lastname: de Fonseca
authors.affiliation: Molecular and Cellular Neuroscience Department, Dorris Neuroscience Center, Scripps Research Institute, La Jolla, California 92037.
authors.forename: Jerold
authors.identifier: http://orcid.org/0000-0003-3964-0921
authors.initials: J
authors.lastname: Chun
authors.affiliation: Department of Cellular Biology, Physiology, and Immunology, Institute of Neurosciences, Center for Biomedical Research in Neurodegenerative Diseases Network (CIBERNED), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain, ruben.lopez@uab.cat.
authors.forename: Rubèn
authors.initials: R
authors.lastname: López-Vales
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003711:Demyelinating Diseases / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D004195:Disease Models, Animal; D019054:Evoked Potentials, Motor / Q000187:drug effects / Q000235:genetics; D005260:Female; D008246:Lysophospholipids / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D049368:Receptors, Lysophosphatidic Acid / Q000172:deficiency / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000150:complications* / Q000209:etiology / Q000473:pathology*; D013997:Time Factors
chemical_list: D008246:Lysophospholipids; D049368:Receptors, Lysophosphatidic Acid; C032881:lysophosphatidic acid
keywords: demyelination; lysophosphatidic acid; microglia; neuroprotection; oligodendrocytes; spinal cord injury