期刊
NEUROBIOLOGY OF DISEASE
卷 66, 期 -, 页码 28-42出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2014.02.005
关键词
Type 4 disintegrin and metalloproteinase with thrombospondin motifs; Tissue plasminogen activator; Spinal cord injury; Chondroitin sulfate proteoglycans; Neurocan; Neuroplasticity; Neurite growth; Serotoninergic fibers; Type 1 plasminogen activator inhibitor
资金
- INSERM (French National Institute for Health and Medical Research)
- Regional Council of Lower Normandy
- IRME (Institut pour la Recherche sur la Moelle epiniere et l'Encephale)
- ALARME (Association Libre d'Aide a la Recherche sur la Moelle Epiniere)
Although tissue plasminogen activator (tPA) is known to promote neuronal remodeling in the CNS, no mechanism of how this plastic function takes place has been reported so far. We provide here in vitro and in vivo demonstrations that this serine protease neutralizes inhibitory chondroitin sulfate proteoglycans (CSPGs) by promoting their degradation via the direct activation of endogenous type 4 disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-4). Accordingly, in a model of compression-induced spinal cord injury (SCI) in rats, we found that administration of either tPA or its downstream effector ADAMTS-4 restores the tPA-dependent activity lost after the SCI and thereby, reduces content of CSPGs in the spinal cord, a cascade of events leading to an improved axonal regeneration/sprouting and eventually long term functional recovery. This is the first study to reveal a tPA ADAMTS-4 axis and its function in the CNS. It also raises the prospect of exploiting such cooperation as a therapeutic tool for enhancing recovery after acute CNS injuries. (C) 2014 Elsevier Inc. All rights reserved.
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