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

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

Abstract

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.

MeSH terms

  • Animals
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Locomotion / drug effects
  • Locomotion / physiology*
  • Mice
  • Mice, Knockout
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Neutrophil Infiltration
  • Protein C / pharmacology
  • Receptor, PAR-1 / genetics
  • Receptor, PAR-1 / metabolism*
  • Recovery of Function / drug effects
  • Recovery of Function / physiology*
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism*
  • Spinal Cord / pathology
  • Spinal Cord / physiopathology
  • Spinal Cord Injuries / metabolism*
  • Spinal Cord Injuries / pathology
  • Spinal Cord Injuries / physiopathology
  • White Matter / drug effects
  • White Matter / metabolism
  • White Matter / pathology*

Substances

  • Protein C
  • Receptor, PAR-1

Grant support

This study was supported by the U.S. National Institutes of Health/National Institute of Neurological Disorders and Stroke (http://www.ninds.nih.gov) NS39278 (LN), NS43302 (WW), the Roman Reed Fund of California (http://romanreedfoundation.com/) (WW), and the Ministry of Science and Technology, Taiwan (https://www.most.gov.tw/en/public) 101-2320-B-006-008-MY3 (JYH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.