期刊
JOURNAL OF NEUROSCIENCE
卷 35, 期 28, 页码 10224-10235出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4703-14.2015
关键词
demyelination; lysophosphatidic acid; microglia; neuroprotection; oligodendrocytes; spinal cord injury
资金
- National Institutes of Health [NS084398]
- Wings for Life Foundation
- Marie-Curie International Reintegration Program Grant [MC IRG 249274]
- Spanish Ministry of Economy and Competitiveness [SAF2013-48431-R]
- Health Research Fund of Spain [Cell Therapy Network and Center for Biomedical Research in Neurodegenerative Diseases Network (CIBERNED)]
- FPU fellowship
Lysophosphatidic acid (LPA) is an extracellular lipid mediator involved in many physiological functions that signals through six known G-protein-coupled receptors (LPA(1)-LPA(6)). 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 LPA(1) 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 LPA(1) antagonist or mice lacking LPA(1) linked receptor-mediated signaling to demyelination, which was in part mediated by microglia. Finally, we demonstrate that selective blockade of LPA(1) after spinal cord injury results in reduced demyelination and improvement in locomotor recovery. Overall, these results support LPA-LPA(1) signaling as a novel pathway that contributes to secondary damage after spinal cord contusion in mice and suggest that LPA(1) antagonism might be useful for the treatment of acute spinal cord injury.
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