Abstract Information


Targeting the thrombin receptor to improve recovery of function after spinal cord injury

1Yoon H, 2Radulovic M, 3Scarisbrick I
1Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, Minnesota, USA; 2Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, Minnesota, USA; 3Rehabilitation Medicine Research Center, Department of Physiology and Biomedical Engineering, Neurobiology of Disease Program, Mayo Clinic, Rochester, Minnesota, USA

Objective: A significant number of neurological conditions involve deregulation of thrombin activity including hemorrhagic, infectious and traumatic injuries, however little is known regarding roles in spinal cord injury (SCI), mechanisms of action, or the utility of therapeutic modulation. Thrombin is well known for its ability to cleave soluble fibrinogen releasing fibrin monomers that support hemostasis and a high affinity agonist for Protease Activated Receptor 1 (PAR1), also referred to as the thrombin receptor. PAR1 is a seven transmembrane G-protein-coupled receptor that is activated by extracellular N-terminal cleavage. Here we critically evaluated the role of PAR1 as a regulator of the SCI microenvironment by examining cellular, molecular and neurobehavioral outcomes after experimental contusion-compression spinal cord injury in PAR1+/+ or PAR1‐/‐ mice.
Design/Methods: The regulatory role of PAR1 in neurobehavioral recovery after traumatic SCI was examined in 12w old adult female PAR1+/+ or PAR1‐/‐ mice, which involved both contusion and compression using modified aneurysm clip (FEJOTA™,8g closing force). Sensorimotor outcomes were determined after injury such as gait ad motor coordination. Cellular and molecular correlates of changes in locomotor recovery were assessed by examination of spinal cord segments at the injury epicenter as well as segments above and below the site of injury at early(7dpi) and more chronic time points after SCI(30dpi).
Results: PAR1-/- mice resulted in significant improvements in recovery of gait, motor coordination, and strength following SCI. Improvements in sensorimotor function were accompanied by reductions in signatures of inflammation and astrogliosis, including lower levels of expression of GFAP, vimentin, and STAT3 signaling. SCI-associated elevations in pro-inflammatory cytokines were also reduced in PAR1‐/‐ mice and coordinate improvements in tissue sparing were observed. Moreover, PAR1‐/‐ mice showed increased NeuN-positive ventral horn neurons as well as PKCγ-positive corticospinal axons. Also, we investigated the possible significance of the thrombin signaling system to astrogliosis using a primary astrocyte cell culture platform. In response to elevated thrombin, astrocytes showed PAR1-dependent increases in the expression and secretion of IL-6, and elevated levels of intracellular STAT3 signaling. In turn, IL-6-stimulated astrocytes increased expression of both PAR1 and thrombin. Together these findings point to a model in which PAR1 activation contributes to increased astrogliosis by both feedforward- and feedback-signaling dynamics.
Conclusion: These studies suggest that PAR1 sits at the interface of the proteolytic microenvironment and cellular responses that contribute to astrogliosis, pro-inflammatory events and neurodegeneration accompanying traumatic SCI. Given the significant improvements in neurobehavioral outcomes observed in PAR1‐/‐ mice, these studies also suggest that PAR1 may serve as a new target to modulate astrogliosis, reduce neural injury and promote an environment favorable to repair and recovery of function after spinal cord trauma.
Support: NIH R01 NS052741, Mayo Clinic Rehabilitation Medicine Research Center, Craig H. Neilsen Foundation.


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