Targeting the Thrombin Receptor Modulates Inflammation and Astrogliosis to Improve Recovery after Spinal Cord Injury

Neurobiol Dis., 2016 · DOI: 10.1016/j.nbd.2016.04.010 · Published: September 1, 2016

Simple Explanation

This study investigates how a specific protein, the thrombin receptor (PAR1), affects recovery after spinal cord injury (SCI). The researchers found that mice without PAR1 had better locomotor recovery, reduced inflammation, and less scarring (astrogliosis) in the spinal cord after injury. The study suggests that targeting PAR1 could be a new way to help people recover from SCI by reducing inflammation and promoting tissue repair.

Study Duration

30 days

Participants

Adult female PAR1+/+ or PAR1−/− mice

Evidence Level

Not specified

Key Findings

1
PAR1 knockout mice displayed improved locomotor recovery after SCI and reduced signatures of inflammation and astrogliosis.
2
SCI-associated elevations in pro-inflammatory cytokines such as IL-1β and IL-6 were also reduced in PAR1−/− mice.
3
PAR1 and its agonist’s thrombin and neurosin were expressed by perilesional astrocytes and each agonist increased the production of IL-6 and STAT3 signaling in primary astrocyte cultures in a PAR1-dependent manner.

Research Summary

The study demonstrates that the thrombin receptor (PAR1) is a critical regulator of inflammation and astrogliosis after traumatic SCI. Targeting PAR1 genetically improved neurobehavioral outcomes, reduced inflammation and astrogliosis, and improved preservation of corticospinal axons. In primary astrocytes, PAR1 activation increased IL-6 and STAT3 activity, and IL-6 drove increases in PAR1 and its agonists, establishing a positive feedback mechanism.

Practical Implications

Therapeutic Target

PAR1 is identified as a potential therapeutic target for modulating inflammation and astrogliosis to enhance recovery of locomotor function after SCI.

Clinical Relevance

Small molecule inhibitors of PAR1 are available, providing a rationale for determining their efficacy in improving outcomes after neurological injury.

Feedforward Signaling

The identification of a feedforward and feedback signaling circuit centered on PAR1 suggests new strategies for modulating the SCI microenvironment.

Study Limitations

1
The study used a global knockout of PAR1, which does not allow for the determination of cell-specific contributions of PAR1 in neurons, astrocytes, and microglia.
2
The roles of other SCI relevant serine proteases, including additional kallikreins, need to be considered to determine whether their actions likewise occur by activation of PAR(s).
3
Additional efforts are needed to determine the range of injury and repair parameters influenced by protease-signaling at PAR1.

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