Nerve axon regeneration and improved motor function
The cancer drug epothilone B reduced the formation of scar tissue in injuries to the spinal cord and stimulated growth in damaged nerve cells in rats. Both effects promoted neuronal regeneration and improved the animals’ motor skills.
Prof. Alan Mackay-Sim commented “It is not out of the range of possibilities that epothilone B might be effective in people with HSP if it were able to rescue the death of corticospinal axons and assist their regeneration.”
Epothilone D, an almost identical compound to epothilone B, is a leading drug candidate emerging from the HSP research at Griffith University that is supported by this Foundation. In that research, epothilone D was found to reverse the impairment and restore function in HSP stem cells. Principal Investigator, Prof Alan Mackay-Sim made the following comments on this new study:
This recent paper in the eminent journal Science follows on from a body of work suggesting that drugs that stabilise the microtubules, part of the cell “skeleton”, can assist in repair of the nerve cells after spinal cord injury. Spinal cord injury cuts the axons of neurons. Axons are the long processes that connect neurons together. Spinal cord injury cuts these axons and causes them to retract, leading eventually to neuron death. Tubulin stablising drugs are used at high doses in cancer to stop cancer cells proliferating but at very low doses they can be beneficial by promoting axon recover and regrowth after spinal cord injury.
This study shows that epothilone B leads to regrowth of damaged axons and leads to recovery of motor functions after spinal cord injury in the rat. This work is exciting because epothilone B is already used clinically in humans, it can be injected and it can reach inside the brain and spinal cord, and it is used at very low doses. It is therefore a potentially injectable drug to assist recovery after spinal cord injury in humans. It is not out of the range of possibilities that epothilone B might be effective in people with HSP if it were able to rescue the death of corticospinal axons and assist their regeneration.
After central nervous system (CNS) injury, inhibitory factors in the lesion scar and poor axon growth potential prevent axon regeneration. Microtubule stabilization reduces scarring and promotes axon growth. However, the cellular mechanisms of this dual effect remain unclear. Here, delayed systemic administration of a blood-brain barrier-permeable microtubule-stabilizing drug, epothilone B (epoB), decreased scarring after rodent spinal cord injury (SCI) by abrogating polarization and directed migration of scar-forming fibroblasts.
Conversely, epothilone B reactivated neuronal polarization by inducing concerted microtubule polymerization into the axon tip, which propelled axon growth through an inhibitory environment. Together, these drug-elicited effects promoted axon regeneration and improved motor function after SCI. With recent clinical approval, epothilones hold promise for clinical use after CNS injury.
SOURCE: Science. 2015 Apr 17;348(6232):347-52. doi: 10.1126/science.aaa2958. Epub 2015 Mar 12. Copyright © 2015, American Association for the Advancement of Science. PMID: 25765066 [PubMed – indexed for MEDLINE] PMCID: PMC4445125 [Available on 2016-04-17]
Axonal regeneration. Systemic administration of epothilone B promotes axon regeneration after spinal cord injury.
Ruschel J1, Hellal F1, Flynn KC1, Dupraz S1, Elliott DA1, Tedeschi A1, Bates M2, Sliwinski C3, Brook G4, Dobrindt K5, Peitz M5, Brüstle O5, Norenberg MD6,Blesch A3, Weidner N3, Bunge MB2, Bixby JL2, Bradke F7.
- 1Axonal Growth and Regeneration, German Center for Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
- 2The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 Northwest 14th Terrace, Miami, FL33136, USA.
- 3Spinal Cord Injury Center, Heidelberg University Hospital, Schlierbacher Landstr. 200A, 69118 Heidelberg, Germany.
- 4Institute for Neuropathology, RWTH Aachen University, Steinbergweg 20, 52074, Aachen, Germany. Jülich-Aachen Research Alliance-Translational Brain Medicine.
- 5Institute of Reconstructive Neurobiology, Life&Brain Center, University of Bonn and Hertie Foundation, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.
- 6Departments of Pathology, Biochemistry and Molecular Biology, University of Miami School of Medicine, Miami, FL 33101, USA.
- 7Axonal Growth and Regeneration, German Center for Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany. [email protected].