title: 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.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129.
authors.forename: Chen
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129.
authors.forename: Michelle C
authors.initials: MC
authors.lastname: Klaw
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129; Department of Bioengineering, Temple University, Philadelphia, PA 19122.
authors.forename: Michel A
authors.initials: MA
authors.lastname: Lemay
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Baas
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129. Electronic address: vtom@drexelmed.edu.
authors.forename: Veronica J
authors.initials: VJ
authors.lastname: Tom
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects*; D019765:Chondroitin ABC Lyase / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D016547:Kinesins / Q000037:antagonists & inhibitors*; D009416:Nerve Regeneration / Q000187:drug effects*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000473:pathology*; D013871:Thiones / Q000494:pharmacology*
chemical_list: D011743:Pyrimidines; D013871:Thiones; C400223:monastrol; D016547:Kinesins; D019765:Chondroitin ABC Lyase
keywords: Axonal regeneration; Chondroitinase ABC; Kinesin-5; Monastrol; Peripheral nerve grafting; Spinal cord injury