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

PLoS ONE, 2017 · DOI: 10.1371/journal.pone.0170512 · Published: January 25, 2017

Simple Explanation

This study investigates the role of a specific receptor, PAR-1, in spinal cord injuries. The researchers found that when PAR-1 is absent, the body's inflammatory response is reduced, leading to better recovery. The study also found that a protein called APC, which interacts with the same receptor, can help improve recovery after spinal cord injury. This suggests that targeting PAR-1 with APC could be a potential treatment. The diverse effects of thrombin and APC may reflect “biased agonism” whereby activation of PAR-1 by thrombin or APC involves distinct intracellular signaling cascades

Study Duration

42 days

Participants

100 adult male mice

Evidence Level

Level 2: Animal study using PAR-1 null and wild-type mice with contusive spinal cord injury

Key Findings

1
PAR-1 null mice showed reduced neutrophil infiltration and improved vascular integrity after spinal cord injury compared to wild-type mice.
2
PAR-1 null mice exhibited better locomotor recovery, greater white matter sparing, and reduced glial scarring compared to wild-type mice after spinal cord injury.
3
Treatment with APC improved locomotor recovery in wild-type mice but had no additional benefit in PAR-1 null mice, suggesting APC acts through PAR-1.

Research Summary

This study investigates the role of PAR-1 in wound healing and locomotor recovery after spinal cord injury. The research demonstrates a detrimental role for thrombin-activated PAR-1 in the healing process. The study's findings indicate that administering APC counteracts thrombin-PAR-1-induced adverse effects and provides protection after spinal cord injury. The research validates APC as a therapeutic target for spinal cord injury, showing that it has been independently validated in three species using different models of spinal cord injury.

Practical Implications

Therapeutic Target

PAR-1 is an effective target for therapeutic intervention after spinal cord injury, suggesting potential for new treatments.

Drug Development

APC can be further refined with the goal of optimizing long-term neurological outcomes and translating this effort to human clinical trials.

Biased Agonism Exploitation

Biased agonism can be favorably exploited to improve outcome after spinal cord injury.

Study Limitations

1
Limited numbers of animals died during the course of experiments.
2
Further studies are needed to investigate the protective mechanism of APC-PAR-1 downstream signaling.
3
Further studies are needed to evaluate the optimal therapeutic window and pharmokinetics of APC treatment for spinal cord injury.

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