Feb. 04, 2022
Led by Isobel A. Scarisbrick, Ph.D., a team of Mayo Clinic researchers has conducted multiple studies demonstrating that the thrombin receptor known as protease-activated receptor 1 (PAR1) plays an integral role in central nervous system (CNS) repair. The research was spearheaded by Erin M. Triplet, an M.D.-Ph.D candidate in the Medical Scientist Training Program at Mayo Clinic College of Medicine and Science.
Role of protease-activated receptor 1 (PAR1) thrombin receptor
The studies have revealed that PAR1 helps regulate neurite growth via a mechanism involving a growth factor and cholesterol. Although it's now understood that the ability to block the function of PAR1 may be associated with improved outcomes after neural injuries, Dr. Scarisbrick and her team continue to strive to learn more about the molecular mechanisms involved and their potential to impact repair.
Delving further into the CNS regeneration processes, Dr. Scarisbrick and colleagues conducted a study demonstrating that functional recovery and signs of neural repair increased after spinal cord injury in mice with PAR1 gene knockout, while the tumor gene phosphatase and tensin homolog pseudogene 1 (PTEN) was decreased. This is significant since PTEN can inhibit axon regeneration. Signs of neural repair observed included increased expression of cholesterol biosynthesis machinery and markers of axonal and synaptic integrity. The results of this study were published in Neurobiology of Disease in 2021.
Additional key findings and implications
- PAR1 differentially regulates a gene encoding a rate-limiting enzyme in cholesterol production (HMGCS1) across the neuronal and astroglial compartments of the intact adult spinal cord.
- Inhibiting cortical neuron PAR1 pharmacologically using the FDA-approved drug vorapaxar in vitro also decreased PTEN and promoted neurite outgrowth. These changes, including those driven by suboptimal brain-derived neurotrophic factor (BDNF), were cholesterol dependent.
- Use of vorapaxar to inhibit PAR1 also caused murine cortical neurons, human SH-SY5Y neurons and induced pluripotent stem cell-derived human spinal cord neurons to show increased HMGCS1 and cholesterol production in response to BDNF.
"These findings build on our previous work and further highlight for the first time a link between the thrombin receptor PAR1, cholesterol and BDNF," says Dr. Scarisbrick. "And they provide additional evidence that PAR1-linked neurotrophic coupling mechanisms involved in neuronal cholesterol metabolism are an important part of the CNS repair machinery. We are hopeful that this information will guide us in our attempts to identify new strategies to enhance neural resiliency and regeneration after injury."
Role of statin use in reduced motor recovery after spinal cord injury
Concerns about whether statin therapy has negative effects on patients' neurological health are relatively new and still being debated by experts. In a study published in Spinal Cord Series and Cases in 2021, Mayo Clinic researchers sought to establish the prevalence of cholesterol-lowering agent use in patients with SCI and determine if use of this therapy impacts patients' recovery of motor function.
To address this question, the researchers conducted a retrospective analysis of statin use in adults with neurologically significant SCI. Relevant data from patients in Olmsted County, Minnesota, from 2005 to 2018 were obtained from the Rochester Epidemiology Project.
Researchers recorded demographics and cholesterol-lowering agent use in 83 individuals with SCI meeting all criteria. A total of 68 of the 83 individuals were then assessed for change in function over the first two months after spinal cord injury using the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) motor subscore. Researchers then performed statistical comparisons between the control and statin groups and a generalized regression to assess associations between independent variables and functional outcomes.
Results
- Approximately 30% of individuals with SCI had a prescription for a cholesterol-lowering agent at the time of SCI. No significant differences were observed in severity of injury or demographic composition between the statin and control groups.
- The change in motor subscore in the statin group was smaller than the change noted in the control group (p = 0.03).
- Severity of injury and statin use were significant predictors of reduced motor recovery (p = 0.001 and p = 0.04, respectively).
"These findings indicate that both severity of SCI and statin use among patients were significant predictors of reduced motor recovery," explains Dr. Scarisbrick. "Additional larger-scale studies will help us assess the role of serum lipids in modulating CNS recovery after injury and provide further information on whether statins and other cholesterol-lowering agents affect the body's response to spinal cord injury or its ability to heal during the acute period following traumatic injury."
For more information
Triplet EM, et al. The thrombin receptor links brain derived neurotrophic factor to neuron cholesterol production, resiliency and repair after spinal cord injury. Neurobiology of Disease. 2021;152:105294.
Triplet EM, et al. Statin use is associated with reduced motor recovery after spinal cord injury. Spinal Cord Series and Cases. 2021;7:8.
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