Pharmacologically inhibiting kinesin-5 activity with monastrol promotes axonal regeneration following spinal cord injury.

Abstract

While it is well established that the axons of adult neurons have a lower capacity for regrowth, some regeneration of certain CNS populations after spinal cord injury (SCI) is possible if their axons are provided with a permissive substrate, such as an injured peripheral nerve. While some axons readily regenerate into a peripheral nerve graft (PNG), these axons almost always stall at the distal interface and fail to reinnervate spinal cord tissue. Treatment of the glial scar at the distal graft interface with chondroitinase ABC (ChABC) can improve regeneration, but most regenerated axons need further stimulation to extend beyond the interface. Previous studies demonstrate that pharmacologically inhibiting kinesin-5, a motor protein best known for its essential role in mitosis but also expressed in neurons, with the pharmacological agent monastrol increases axon growth on inhibitory substrates in vitro. We sought to determine if monastrol treatment after an SCI improves functional axon regeneration. Animals received complete thoracic level 7 (T7) transections and PNGs and were treated intrathecally with ChABC and either monastrol or DMSO vehicle. We found that combining ChABC with monastrol significantly enhanced axon regeneration. However, there were no further improvements in function or enhanced c-Fos induction upon stimulation of spinal cord rostral to the transection. This indicates that monastrol improves ChABC-mediated axon regeneration but that further treatments are needed to enhance the integration of these regrown axons.

• Authors: Chen Xu, Michelle C Klaw, Michel A Lemay, Peter W Baas, Veronica J Tom
• Journal: Experimental neurology (Exp Neurol) Vol. 263 Pg. 172-6 (Jan 2015) ISSN: 1090-2430 [Electronic] United States
• PMID: 25447935 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014. Published by Elsevier Inc.

Chemical References

• Pyrimidines
• Thiones
• monastrol
• Kinesins
• Chondroitin ABC Lyase

Topics

• Animals
• Axons (drug effects)
• Chondroitin ABC Lyase (pharmacology)
• Disease Models, Animal
• Female
• Kinesins (antagonists & inhibitors)
• Nerve Regeneration (drug effects)
• Pyrimidines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Spinal Cord Injuries (pathology)
• Thiones (pharmacology)