Small-molecule-induced Rho-inhibition: NSAIDs after spinal cord injury

Cell Tissue Res., 2012 · DOI: 10.1007/s00441-012-1334-7 · Published: July 1, 2012

Spinal Cord Injury Pharmacology Regenerative Medicine

Simple Explanation

Following spinal cord injury, the central nervous system's limited ability to regrow axons hinders functional recovery. The RhoA pathway, a key inhibitory cascade, prevents axonal regrowth by integrating signals from the injury environment. Blocking RhoA activation can diminish the axon's sensitivity to these inhibitory signals, fostering axonal sprouting and enhanced plasticity. Ibuprofen, a common NSAID, has been found to inhibit RhoA activation, encourage axonal sprouting and regeneration, protect vulnerable tissue, and improve motor recovery in spinal cord injury models. This review examines the effects of small-molecule-induced RhoA inhibition on axonal plasticity and neurofunctional outcomes in CNS injury. The review also considers the potential for clinical translation of these findings, particularly focusing on ibuprofen's possible risks and benefits in acute spinal cord injury treatment.

Study Duration

Not specified

Participants

Not specified

Evidence Level

Not specified

Key Findings

1
Ibuprofen inhibits RhoA activation, enhancing axonal sprouting/regeneration.
2
Ibuprofen protects 'tissue at risk' (neuroprotection) after SCI.
3
Ibuprofen improves motor recovery in clinically relevant SCI models within realistic therapeutic time-frames.

Research Summary

The review focuses on the role of RhoA inhibition in promoting axonal plasticity and functional recovery after CNS injury, particularly spinal cord injury (SCI). It highlights how blocking RhoA activation can counteract growth-inhibitory signals, leading to enhanced axonal sprouting and regeneration. The review emphasizes the potential of non-steroidal anti-inflammatory drugs (NSAIDs), specifically ibuprofen, to inhibit RhoA activation and improve outcomes after SCI. It discusses preclinical evidence supporting ibuprofen's neuroprotective and plasticity-promoting effects. The authors address translational aspects, including CNS permeability of ibuprofen, dosage considerations, and implications for clinical use. They compare ibuprofen with other therapeutic approaches targeting the Rho pathway and discuss its potential benefits and risks in the context of acute SCI treatment.

Practical Implications

Clinical Translation Potential

Ibuprofen, an FDA-approved drug, could be repurposed for acute SCI treatment due to its RhoA-inhibiting effects, potentially improving neurological function recovery.

Combination Therapy

Ibuprofen's combined RhoA inhibition, anti-inflammatory, and PPARγ-activating effects might offer a multi-pronged approach to SCI treatment, potentially mitigating adverse effects of specific Rho/ROCK inhibitors.

Neuropathic Pain Management

Besides promoting neuronal plasticity, ibuprofen's anti-inflammatory properties could attenuate the development of neuropathic pain, a common complication after SCI.

Study Limitations

1
Functional outcome in the indomethacin trials has been assessed by using the Tarlov scale, which represents an earlier, less sensitive measurement tool compared with the BBB scale
2
A weakness of the study of Fu et al. (2007) is that the functional outcome has been statistically evaluated by using Student's t-test.
3
The study identifies a need for further research to consistently reproduce the Rho-inhibiting effects of indomethacin, as some studies have shown its efficacy while others have not.

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