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Publication : Targeting the thrombin receptor modulates inflammation and astrogliosis to improve recovery after spinal cord injury.

First Author  Radulovic M Year  2016
Journal  Neurobiol Dis Volume  93
Pages  226-42 PubMed ID  27145117
Mgi Jnum  J:240849 Mgi Id  MGI:5896504
Doi  10.1016/j.nbd.2016.04.010 Citation  Radulovic M, et al. (2016) Targeting the thrombin receptor modulates inflammation and astrogliosis to improve recovery after spinal cord injury. Neurobiol Dis 93:226-42
abstractText  The deregulation of serine protease activity is a common feature of neurological injury, but little is known regarding their mechanisms of action or whether they can be targeted to facilitate repair. In this study we demonstrate that the thrombin receptor (Protease Activated Receptor 1, (PAR1)) serves as a critical translator of the spinal cord injury (SCI) proteolytic microenvironment into a cascade of pro-inflammatory events that contribute to astrogliosis and functional decline. PAR1 knockout mice displayed improved locomotor recovery after SCI and reduced signatures of inflammation and astrogliosis, including expression of glial fibrillary acidic protein (GFAP), vimentin, and STAT3 signaling. SCI-associated elevations in pro-inflammatory cytokines such as IL-1beta and IL-6 were also reduced in PAR1-/- mice and co-ordinate improvements in tissue sparing and preservation of NeuN-positive ventral horn neurons, and PKCgamma corticospinal axons, were observed. PAR1 and its agonist's thrombin and neurosin were expressed by perilesional astrocytes and each agonist increased the production of IL-6 and STAT3 signaling in primary astrocyte cultures in a PAR1-dependent manner. In turn, IL-6-stimulated astrocytes increased expression of PAR1, thrombin, and neurosin, pointing to a model in which PAR1 activation contributes to increased astrogliosis by feedforward- and feedback-signaling dynamics. Collectively, these findings identify the thrombin receptor as a key mediator of inflammation and astrogliosis in the aftermath of SCI that can be targeted to reduce neurodegeneration and improve neurobehavioral recovery.
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