Activation of lysophosphatidic acid receptor type 1 contributes to pathophysiology of spinal cord injury

Eva Santos-Nogueira, Clara López-Serrano, Joaquim Hernández, Natalia Lago, Alma M. Astudillo, Jesús Balsinde, Guillermo Estivill-Torrús, Fernando Rodriguez de Fonseca, Jerold Chun, Rubèn López-Vales

Research output: Contribution to journalArticleResearchpeer-review

58 Citations (Scopus)

Abstract

© 2015, the authors. 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 receptormediated 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.
Original languageEnglish
Pages (from-to)10224-102035
JournalJournal of Neuroscience
Volume35
DOIs
Publication statusPublished - 15 Jul 2015

Keywords

  • Demyelination
  • Lysophosphatidic acid
  • Microglia
  • Neuroprotection
  • Oligodendrocytes
  • Spinal cord injury

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