Inhibition of microtubule detyrosination by parthenolide facilitates functional CNS axon regeneration

eLife, 2023 · DOI: https://doi.org/10.7554/eLife.88279 · Published: October 17, 2023

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

Injured axons in the central nervous system (CNS) usually fail to regenerate, causing permanent disabilities. The beneficial hIL-6 and Pten knockout effects on axon growth are limited by the induction of tubulin detyrosination in axonal growth cones. Systemic application of the prodrug dimethylamino-parthenolide (DMAPT) facilitates axon regeneration in the injured optic nerve and spinal cord.

Study Duration

8 weeks

Participants

Adult mice and human retinal cells

Evidence Level

Not specified

Key Findings

1
Parthenolide significantly enhanced neurite extension concentration-dependently with maximum effects at 0.5 and 1 nM.
2
hIL-6 treatment increased tubulin detyrosination, while par blocked this effect.
3
DMAPT significantly enhanced hIL-6-induced optic nerve regeneration.

Research Summary

Here we demonstrate that the systemic application of DMAPT facilitates axon regeneration in the injured optic nerve and accelerates functional recovery after severe spinal cord injury. Parthenolide’s effects on CNS regeneration in vivo were confirmed in cell culture using primary RGCs from adult mice and humans. Consistently, effective parthenolide concentrations reduce detyrosination levels in hIL-6-treated, and Pten-/- RGCs, and combined treatment leads to more substantial neurite growth than each treatment alone.

Practical Implications

Therapeutic Potential for CNS Injuries

DMAPT shows promise as a drug candidate for treating CNS injuries by facilitating functional CNS regeneration and reducing the limiting effects of pro-regenerative treatments.

Combination Therapy Enhancement

Parthenolide can be used as an ideal cotreatment to accelerate axon regeneration and functional recovery in combination with other treatment strategies.

Overcoming Limitations of Regenerative Treatments

DMAPT neutralizes the hIL-6-mediated limiting effect of decreased microtubule dynamics and synergistically accelerates CNS regeneration.

Study Limitations

1
Possibility that other known activities of parthenolide/DMAPT, such as oxidative stress or NF-kB inhibition, could have contributed to the observed effects
2
DMAPT-induced long-distance RpST regeneration might not be essential for its beneficial effects on functional recovery
3
Whether DMAPT treatment can also improve functional recovery in more clinically relevant injury models

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