Nonsteroidal Anti-Inflammatory Drugs Promote Axon Regeneration via RhoA Inhibition

The Journal of Neuroscience, 2007 · DOI: 10.1523/JNEUROSCI.4353-06.2007 · Published: April 11, 2007

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

After a spinal cord injury, axons (nerve fibers) in the central nervous system have limited ability to regrow, due to factors that inhibit their growth. This study shows that certain nonsteroidal anti-inflammatory drugs (NSAIDs) can overcome these growth restrictions. Specifically, ibuprofen and indomethacin, common pain relievers, can inhibit a signaling pathway called RhoA, which is activated by myelin and proteoglycans, substances that inhibit axon growth after CNS injury. By inhibiting RhoA, these NSAIDs promote the regrowth of axons and improve functional recovery in rodents with spinal cord injuries.

Study Duration

6 weeks

Participants

Sprague Dawley rats

Evidence Level

Level III, Experimental Study

Key Findings

1
Ibuprofen and indomethacin reverse RhoA activation induced by CNS myelin, CSPGs, or spinal cord lesion.
2
Ibuprofen and indomethacin stimulate neurite growth of dorsal root ganglion neurons on inhibitory substrates in vitro.
3
Systemic administration of ibuprofen promotes corticospinal and serotonergic axonal growth in rat spinal cord after dorsal hemisection and contusion injuries, leading to improved locomotor functional recovery.

Research Summary

This study identifies that the nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen and indomethacin overcome neuronal growth inhibitions from CNS myelin and CSPGs via repressing the activity of intracellular RhoA signal. Ibuprofen attenuates CNS myelin and CSPG inhibitions of axonal growth stimulating a significant axonal sprouting of descending fiber tracts in the distal spinal cord after a transection or a contusion injury. Ibuprofen promotes a remarkable locomotor functional recovery, even when delivered 1 week after trauma.

Practical Implications

Therapeutic Potential

RhoA-inhibiting NSAIDs may be an effective treatment in clinical conditions characterized by failure of axonal regeneration, including spinal cord injury.

Drug Repurposing

The common use of ibuprofen and indomethacin in patients makes them attractive candidates for repurposing to treat spinal cord injuries.

Target for CNS Axonal Regeneration

Regulation of RhoA activity represents an important target for overcoming axon growth inhibition and for developing potent agents for CNS axonal injury treatment.

Study Limitations

1
The molecular mechanism of RhoA inactivation by some NSAIDs remains unclear.
2
NSAIDs are dose-dependently associated with several side effects, particularly on the gastrointestine and kidney.
3
The study primarily focuses on ibuprofen and indomethacin; the effects of other NSAIDs on axonal regeneration may vary.

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