Reviving the use of inhibitors of matrix metalloproteases in spinal cord injury: a case for specificity

Neural Regeneration Research, 2023 · DOI: https://doi.org/10.4103/1673-5374.367837 · Published: September 1, 2023

Spinal Cord Injury Immunology Physiology

Simple Explanation

Spinal cord injury lacks fully restorative treatments, focusing on symptomatic relief. Restorative therapies should protect neurons, neutralize inhibitors, and promote axon regeneration. Matrix metalloproteases (MMPs) participate in degradation of the blood-spinal cord barrier (BSCB), oxidative stress, demyelination, and progressive neuroinflammation after SCI. Selective MMP inhibition, particularly MMP-9 and MMP-12 with AZD1236, shows promise in alleviating edema, BSCB breakdown, neuropathic pain, and restoring sensory and locomotor function after spinal cord injury.

Study Duration

Not specified

Participants

Human and animal studies were screened

Evidence Level

Review

Key Findings

1
MMP-9 and MMP-2 are upregulated after SCI, contributing to BSCB breakdown, inflammation, and apoptosis.
2
Inhibition of MMP-9 and MMP-12 using AZD1236 attenuates edema, BSCB breakdown, neuropathic pain, and promotes functional recovery after SCI.
3
The reduction of SCI-induced edema was reliant on the combined suppression of both MMP-9 and MMP-12.

Research Summary

The review focuses on the role of matrix metalloproteases (MMPs) in spinal cord injury (SCI) and the potential of MMP inhibitors as a therapeutic strategy. MMPs contribute to several detrimental processes after SCI, including blood-spinal cord barrier breakdown, inflammation, and neuropathic pain. Next-generation MMP inhibitors, such as AZD1236, demonstrate promising results in preclinical studies by reducing edema, improving functional recovery, and suppressing inflammation after SCI.

Practical Implications

Therapeutic potential of MMP inhibitors

Specific MMP inhibitors, like AZD1236, could be a novel therapeutic approach for SCI, addressing multiple pathological drivers.

Importance of selectivity

The specificity of MMP inhibitors is crucial to avoid off-target effects and improve efficacy, paving the way for clinical translation.

Clinical translation

The findings support further investigation and clinical trials to assess the safety and efficacy of MMP inhibitors in human SCI patients.

Study Limitations

1
Limited human data on MMP expression after SCI.
2
Complexity of MMP roles, with both detrimental and beneficial effects depending on the phase of injury.
3
Challenges in designing highly selective MMP inhibitors with optimal pharmacokinetic profiles.

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