NT-3 promotes proprioceptive axon regeneration when combined with activation of the mTor intrinsic growth pathway but not with reduction of myelin extrinsic inhibitors

Exp Neurol, 2016 · DOI: 10.1016/j.expneurol.2016.05.021 · Published: September 1, 2016

Neurology Genetics Regenerative Medicine & Stem Cells

Simple Explanation

This study investigates how to improve the regrowth of nerve fibers (axons) after spinal cord injuries, focusing on large, insulated axons that transmit position sense (proprioception). They tested whether reducing myelin, a substance that can inhibit axon growth, or activating an internal growth pathway called mTOR could enhance the effect of a growth factor called NT-3. The researchers found that simply removing myelin's inhibitory effect did not significantly improve axon regeneration. However, activating the mTOR pathway in combination with NT-3 treatment led to a substantial increase in the regrowth of sensory axons, including those responsible for proprioception. This combined approach also resulted in some functional recovery, as the treated animals showed improvement in a test that measured their ability to walk on a grid without making errors. The study suggests that activating the mTOR pathway can boost the regenerative potential of nerve fibers when combined with appropriate growth factors.

Study Duration

4 Weeks

Participants

Sixty adult female Sprague Dawley rats (175–200g)

Evidence Level

Not specified

Key Findings

1
Loss of myelin inhibitory proteins showed modest enhancement of sensory axon regeneration.
2
Expression of caRheb within adult DRG neurons in vitro increased S6 phosphorylation and doubled the overall length of neurite outgrowth.
3
Combined expression of caRheb in DRG neurons and NT-3 within the spinal cord increased regeneration of sensory axons almost 3 fold when compared to NT-3 alone.

Research Summary

The study examined whether eliminating myelin-associated inhibitors or activating intrinsic growth pathways could enhance NT-3-mediated regeneration of sensory axons through the dorsal root entry zone (DREZ). Results indicated that loss of myelin-associated inhibitors had a modest effect on enhancing regeneration in the presence of NT-3, whereas expression of ca-Rheb in DRG neurons induced greater than a 2 fold increase in NT-3 mediated regeneration. Proprioceptive assessment using a grid runway indicates functionally significant regeneration of large-diameter myelinated sensory afferents, suggesting that caRheb-induced increase in mTOR activation enhances neurotrophin-3 induced regeneration of large-diameter myelinated axons.

Practical Implications

Combination Therapy

Combining mTOR activation with neurotrophin supplementation shows promise for enhancing axonal regeneration.

Targeted Regeneration

Specifically targeting the mTOR pathway in DRG neurons can improve regeneration of myelinated sensory axons.

Functional Recovery

Enhanced regeneration leads to improved proprioceptive behavioral responses, indicating functional recovery.

Study Limitations

1
The molecular mechanism that stops axons at the DREZ is complicated and this regenerative failure maybe attributed to both growth-inhibitory molecules at the DREZ and lack of intrinsic growth capability by adult DRG neurons
2
Activating the mTOR signaling pathway might be necessary to induce regeneration through the DREZ but not sufficient, requiring activation of other signaling pathways to boost axon extension.
3
NT3+Rheb group showed a modest but statistically significant reduction of right foot slip errors when the animals walked on a horizontal ladder compared to NT3 and the lesion control group

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