Early Targeting of L-Selectin on Leukocytes Promotes Recovery after Spinal Cord Injury, Implicating Novel Mechanisms of Pathogenesis

ENEURO, 2018 · DOI: http://dx.doi.org/10.1523/ENEURO.0101-18.2018 · Published: August 13, 2018

Simple Explanation

Spinal cord injury (SCI) can lead to loss of motor and sensory function. This is often made worse by the body's own immune response, where certain immune cells release harmful substances that damage tissue. The study identifies L-selectin, a receptor involved in immune cell recruitment, as a potential target to improve recovery after SCI. The research uses both mice that lack L-selectin and a drug called diclofenac to reduce L-selectin's activity. Diclofenac, a common anti-inflammatory drug, was found to help improve recovery after spinal cord injury in mice, suggesting it could be repurposed for human treatment. The key finding is that reducing L-selectin's function, either through genetic modification or a drug, can improve outcomes after spinal cord injury. This suggests L-selectin plays a role in worsening the injury and that diclofenac's benefits may stem from its impact on L-selectin.

Study Duration

5-6 weeks

Participants

Adult male mice (approximately three to five months of age)

Evidence Level

Level II: Experimental study using L-selectin knock-out mice and diclofenac in a murine model of spinal cord injury (SCI)

Key Findings

1
L-selectin knockout (KO) mice showed improved long-term recovery with greater white matter sparing relative to wild-type (WT) mice and reduced oxidative stress in the injured cord at 72 h post-SCI.
2
Diclofenac administration to injured WT mice enhanced neurological recovery to a level comparable to that of KOs but did not improve recovery in KOs.
3
Diclofenac induced the shedding of L-selectin from the cell surface of myeloid subsets, specifically neutrophils and non-classical monocytes, in the blood and the injured spinal cord.

Research Summary

This study establishes L-selectin as a determinant of long-term recovery and tissue sparing after spinal cord injury (SCI). The research demonstrates that L-selectin contributes to secondary pathogenesis during acute inflammation, implicating it in roles beyond just immune cell recruitment. The study reports that diclofenac, by inducing L-selectin shedding, improves recovery in a murine model of SCI, suggesting its potential as an acute therapy for SCI in humans.

Practical Implications

Potential Therapeutic Target

L-selectin is a novel therapeutic target for mitigating secondary pathogenesis following spinal cord injury.

Drug Repurposing

Diclofenac, an FDA-approved NSAID, may be repurposed as an acute therapy to attenuate neurologic deficits following SCI in humans.

Timing of Intervention

There is a critical time window for anti-inflammatory intervention in SCI, as diclofenac was effective when administered within 3 hours of injury.

Study Limitations

1
Study was conducted exclusively on male mice, limiting generalizability.
2
The exact mechanisms by which L-selectin contributes to oxidative stress and secondary pathogenesis require further elucidation.
3
The long-term effects and safety of diclofenac treatment for SCI in humans need to be evaluated.

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