title: Protease-Activated Receptor-1 Supports Locomotor Recovery by Biased Agonist Activated Protein C after Contusive Spinal Cord Injury.
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.
authors.affiliation: Department of Emergency Medicine, University of California, San Francisco, California, United States of America.
authors.forename: William D
authors.initials: WD
authors.lastname: Whetstone
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, California, United States of America.
authors.forename: Breset
authors.initials: B
authors.lastname: Walker
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, California, United States of America.
authors.forename: Alpa
authors.initials: A
authors.lastname: Trivedi
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, California, United States of America.
authors.forename: Sangmi
authors.initials: S
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Noble-Haeusslein
authors.affiliation: Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan City, Taiwan.
authors.forename: Jung-Yu C
authors.initials: JC
authors.lastname: Hsu
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008124:Locomotion / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020556:Neutrophil Infiltration; D011486:Protein C / Q000494:pharmacology; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism*; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D066127:White Matter / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*
chemical_list: D011486:Protein C; D044463:Receptor, PAR-1