Santos-Nogueira, EvaLópez-Serrano, ClaraHernández, JoaquimLago, NataliaAstudillo, Alma MBalsinde, JesúsEstivill-Torrús, GuillermoRodríguez de Fonseca, FernandoChun, JeroldLópez-Vales, Rubèn2016-06-232016-06-232015-07-15Santos-Nogueira E, López-Serrano C, Hernández J, Lago N, Astudillo AM, Balsinde J, et al. Activation of Lysophosphatidic Acid Receptor Type 1 Contributes to Pathophysiology of Spinal Cord Injury. J. Neurosci.. 2015 ; 35(28):10224-350270-6474http://hdl.handle.net/10668/2219Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't;UNLABELLED 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. SIGNIFICANCE STATEMENT This study reveals that LPA signaling via LPA receptor type 1 activation causes demyelination and functional deficits after spinal cord injury.enDemyelinationLysophosphatidic acidMicrogriaNeuroprotectionOligodendrocytesSpinal cord injuryPotenciales evocados motoresLisofosfolípidosRatasratones consanguíneos C57BLRatones transgénicosMicroglíaActividad motoraOligodendroglíaReceptores de ácidos lisofosfatídicosMédula espinaltraumatismos de la médula espinalFactores de tiempoAnimales recién nacidosCélulas cultivadasMuerte celularCorteza cerebralEnfermedades desmielinizantesModelos de enfermedad en animalesMedical Subject Headings::Organisms::Eukaryota::Animals::Animal Population Groups::Animals, NewbornMedical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell DeathMedical Subject Headings::Anatomy::Cells::Cells, CulturedMedical Subject Headings::Anatomy::Nervous System::Central Nervous System::Brain::Prosencephalon::Telencephalon::Cerebrum::Cerebral CortexMedical Subject Headings::Diseases::Nervous System Diseases::Demyelinating DiseasesMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Animal::Disease Models, AnimalMedical Subject Headings::Phenomena and Processes::Physiological Phenomena::Electrophysiological Phenomena::Evoked PotentialsMedical Subject Headings::Check Tags::FemaleMedical Subject Headings::Chemicals and Drugs::Lipids::Membrane Lipids::PhospholipidsMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::MiceMedical Subject Headings::Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Laboratory::Animals, Inbred Strains::Mice, Inbred Strains::Mice, Inbred C57BLMedical Subject Headings::Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Genetically Modified::Mice, TransgenicMedical Subject Headings::Anatomy::Cells::Neuroglia::MicrogliaMedical Subject Headings::Phenomena and Processes::Musculoskeletal and Neural Physiological Phenomena::Musculoskeletal Physiological Phenomena::Musculoskeletal Physiological Processes::Movement::Motor ActivityMedical Subject Headings::Anatomy::Cells::Neuroglia::OligodendrogliaMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, G-Protein-Coupled::Receptors, Lysophospholipid::Receptors, Lysophosphatidic AcidMedical Subject Headings::Anatomy::Nervous System::Central Nervous System::Spinal CordMedical Subject Headings::Diseases::Wounds and Injuries::Spinal Cord InjuriesMedical Subject Headings::Phenomena and Processes::Physical Phenomena::Time::Time FactorsMedical Subject Headings::Organisms::Eukaryota::Animalsresearch article26180199open access10.1523/JNEUROSCI.4703-14.20151529-2401PMC4502263