Epidermal growth factor receptor inhibitor ameliorates excessive astrogliosis and improves the regeneration microenvironment and functional recovery in adult rats following spinal cord injury

Journal of Neuroinflammation, 2014 · DOI: 10.1186/1742-2094-11-71 · Published: April 5, 2014

Spinal Cord Injury Regenerative Medicine Immunology

Simple Explanation

Astrogliosis, a common occurrence after spinal cord injury (SCI), can hinder neuronal repair despite some positive effects on axon regeneration. The epidermal growth factor receptor (EGFR) pathway regulates reactive astrogliosis, making it a potential therapeutic target. This study investigates whether blocking EGFR signaling with a specific inhibitor can reduce reactive astrogliosis and improve functional recovery following traumatic SCI. The study found that inhibiting EGFR with PD168393 can lessen excessive reactive astrogliosis, creating a more favorable environment for axon regeneration after SCI, suggesting EGFR inhibitors could be a promising therapeutic strategy for CNS injuries.

Study Duration

Not specified

Participants

96 adult female Sprague-Dawley rats

Evidence Level

Level 2: Animal study

Key Findings

1
EGFR phosphorylation parallels astrocyte activation, and the EGFR inhibitor PD168393 effectively inhibited scratch-induced reactive astrogliosis and proinflammatory cytokine/mediator secretion of reactive astrocytes in vitro.
2
Local administration of PD168393 suppressed CSPGs production and glial scar formation, which correlated with remarkable hindlimb motor function and bladder improvement in SCI rats.
3
PD168393 can ameliorate excessive reactive astrogliosis and facilitate a more favorable environment for axonal regeneration after SCI.

Research Summary

This study investigated the effect of the specific EGFR inhibitor PD168393 on reactive astrogliosis and proinflammatory cytokine secretion of reactive astrocytes in a scratch injury in vitro model and on glial scar formation and microenvironment for axonal regeneration and recovery in a spinal cord contusion rat model. The results showed that administration of PD168393 markedly inhibited scratch-induced reactive astrogliosis and secretion of proinflammatory cytokines/mediators by reactive astrocytes in culture, as well as suppressing glial scar formation, attenuating myelin loss, promoting the survival of VH motor neurons and more importantly, ameliorating hind limb motor functional and bladder recovery in SCI rats. The study concludes that attenuation of astrogliosis, reduction of CSPG expression, suppression of proinflammatory cytokine production, and decreasing myelin loss may be potential key mechanisms of EGFR inhibitor effect on improving outcome after SCI.

Practical Implications

Therapeutic Potential

EGFR inhibitors may represent a promising therapeutic intervention for central nervous system (CNS) injuries, particularly spinal cord injury.

Microenvironment Improvement

Modulating astrogliosis and CSPG production can create a more favorable microenvironment for axonal regeneration after SCI.

Functional Recovery

Targeting EGFR signaling may improve motor function and bladder control in individuals with spinal cord injuries.

Study Limitations

1
The discrepancies between studies using EGFR inhibitors in SCI may be explained by different conditions in animal model procedures, drug delivery manner and data processing methods.
2
The exact mechanism of how EGFR inhibitors promote axon regeneration in the spinal cord remains debated.
3
It cannot be excluded that the impairment of astrogliosis by EGFR inhibitor may be mediated through blocking ErbB2 receptor signaling.

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