Overcoming Macrophage-Mediated Axonal Dieback Following CNS Injury

The Journal of Neuroscience, 2009 · DOI: 10.1523/JNEUROSCI.1151-09.2009 · Published: August 12, 2009

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

Trauma to the adult CNS initiates processes that negatively affect neuronal regeneration. After spinal cord injury, the infiltration of macrophages coincides with axonal retraction from the injury site, known as axonal dieback. The researchers hypothesized that treatments thought to increase neuronal regeneration might partially work by inhibiting macrophage-mediated axonal retraction. They analyzed the effects of protease inhibition, substrate modification, and neuronal preconditioning on macrophage-axon interactions using an in vitro model.

Study Duration

Not specified

Participants

Adult female Sprague Dawley rats

Evidence Level

In vitro and in vivo study

Key Findings

1
General inhibition of matrix metalloproteinases and specific inhibition of MMP-9 prevented macrophage-induced axonal retraction.
2
Chondroitinase ABC-mediated digestion of the aggrecan substrate also prevented macrophage-induced axonal retraction.
3
A conditioning lesion to stimulate intrinsic neuronal growth potential prevented macrophage-induced axonal retraction in vitro and in vivo.

Research Summary

This study investigates how to prevent macrophage-induced retraction of dystrophic adult sensory neurons after CNS injury, using an in vitro model of the glial scar. The researchers found that protease inhibition (specifically MMP-9), substrate modification with chondroitinase ABC, and stimulating intrinsic neuronal growth capacity can all improve outcomes after macrophage attack. The results suggest that some treatments promoting neuronal regeneration after spinal cord injury may function by inhibiting macrophage-induced axonal retraction, rather than solely by promoting regeneration directly.

Practical Implications

Therapeutic Targets

MMP-9 inhibition could be a therapeutic target to reduce axonal dieback after CNS injury.

Combination Therapies

Combining substrate modification (ChABC) with other regenerative strategies may enhance axon regeneration.

Preconditioning Strategies

Enhancing intrinsic neuronal growth capacity through preconditioning lesions can help axons withstand macrophage attack.

Study Limitations

1
The study relies on an in vitro model, which may not fully replicate the complex in vivo environment.
2
The inhibitors used have activity against ADAMs, membrane-anchored enzymes, which could influence the results.
3
MMP-9's effect in vivo could be indirect, potentially activating other proteases.

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