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PLoS One. 2017 Jan 25;12(1):e0170512. doi: 10.1371/journal.pone.0170512. eCollection 2017.

Protease-Activated Receptor-1 Supports Locomotor Recovery by Biased Agonist Activated Protein C after Contusive Spinal Cord Injury.

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Department of Emergency Medicine, University of California, San Francisco, California, United States of America.
Department of Neurological Surgery, University of California, San Francisco, California, United States of America.
Department of Physical Therapy and Rehabilitation Science, University of California, San Francisco, California, United States of America.
Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan City, Taiwan.


Thrombin-induced secondary injury is mediated through its receptor, protease activated receptor-1 (PAR-1), by "biased agonism." Activated protein C (APC) acts through the same PAR-1 receptor but functions as an anti-coagulant and anti-inflammatory protein, which counteracts many of the effects of thrombin. Although the working mechanism of PAR-1 is becoming clear, the functional role of PAR-1 and its correlation with APC in the injured spinal cord remains to be elucidated. Here we investigated if PAR-1 and APC are determinants of long-term functional recovery after a spinal cord contusive injury using PAR-1 null and wild-type mice. We found that neutrophil infiltration and disruption of the blood-spinal cord barrier were significantly reduced in spinal cord injured PAR-1 null mice relative to the wild-type group. Both locomotor recovery and ability to descend an inclined grid were significantly improved in the PAR-1 null group 42 days after injury and this improvement was associated with greater long-term sparing of white matter and a reduction in glial scarring. Wild-type mice treated with APC acutely after injury showed a similar level of improved locomotor recovery to that of PAR-1 null mice. However, improvement of APC-treated PAR-1 null mice was indistinguishable from that of vehicle-treated PAR-1 null mice, suggesting that APC acts through PAR-1. Collectively, our findings define a detrimental role of thrombin-activated PAR-1 in wound healing and further validate APC, also acting through the PAR-1 by biased agonism, as a promising therapeutic target for spinal cord injury.

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