Oct. 23, 2018
There's ample evidence that neurological injury is commonly accompanied by dysregulated serine protease activity. Signaling at protease-activated receptor 1 (PAR1), also known as the thrombin receptor, is the focus of a Mayo study published in 2016 in Neurobiology of Disease.
"We know PAR1 serves as an important translator of the extracellular proteolytic microenvironment into cellular responses that contribute to tissue injury, remodeling and regeneration," says Isobel A. Scarisbrick, Ph.D., director of Mayo Clinic's Neuroregeneration and Neurorehabilitation Program in Rochester, Minnesota. "PAR1 clearly plays an important role, but our research seeks to learn more about the mechanisms of action or whether this receptor can be targeted to facilitate repair," says Dr. Scarisbrick.
In this study, Mayo researchers sought to examine PAR1's role as a translator within the microenvironment present after spinal cord injury, and its impact on pro-inflammatory events that contribute to astrogliosis and functional decline.
Mayo researchers found that PAR1 gene deletion is associated with a number of improved outcomes, including:
- Improved locomotor recovery in PAR1 -/- mice after spinal cord injury and reductions in other measures of inflammation and astrogliosis, including expression of glial fibrillary acidic protein (GFAP), vimentin and signal transducer and activator of transcription 3 (STAT3) signaling
- Reductions in pro-inflammatory cytokines in PAR1 -/- mice
- Observable preservation of specific types of ventral horn neurons and corticospinal axons
Mayo researchers also noted that astrocytes located near spinal lesions express PAR1 and its agonists thrombin and neurosin. These agonists increased the production of interleukin-6 (IL-6), proteins involved in inflammation, and STAT3, a transcription factor.
"These findings add to the growing body of evidence that identifies the thrombin receptor as a key mediator of inflammation and astrogliosis in the aftermath of spinal cord injury that can be targeted to reduce neurodegeneration and improve neurobehavioral recovery," explains Dr. Scarisbrick.
Dr. Scarisbrick notes that additional research is needed to determine the range of injury and repair parameters influenced by protease signaling at PAR1. Further examination of responses in mice where PAR1 is targeted in a cell-specific manner may provide a more complete understanding of the mechanism involved in reducing neural injury, astrogliosis and inflammation. "The fact that small-molecule inhibitors of PAR1 are currently in use for targeting thrombolytic disease suggests that our findings hold promise for clinical applications related to the promotion of neural resiliency and repair after spinal cord trauma," says Dr. Scarisbrick.
For more information
Radulovic M, et al. Targeting the thrombin receptor modulates inflammation and astrogliosis to improve recovery after spinal cord injury. Neurobiology of Disease. 2016;93:226.