title: EphA4 blockers promote axonal regeneration and functional recovery following spinal cord injury in mice.
abstract: Upregulation and activation of developmental axon guidance molecules, such as semaphorins and members of the Eph receptor tyrosine kinase family and their ligands, the ephrins, play a role in the inhibition of axonal regeneration following injury to the central nervous system. Previously we have demonstrated in a knockout model that axonal regeneration following spinal cord injury is promoted in the absence of the axon guidance protein EphA4. Antagonism of EphA4 was therefore proposed as a potential therapy to promote recovery from spinal cord injury. To further assess this potential, two soluble recombinant blockers of EphA4, unclustered ephrin-A5-Fc and EphA4-Fc, were examined for their ability to promote axonal regeneration and to improve functional outcome following spinal cord hemisection in wildtype mice. A 2-week administration of either of these blockers following spinal cord injury was sufficient to promote substantial axonal regeneration and functional recovery by 5 weeks following injury. Both inhibitors produced a moderate reduction in astrocytic gliosis, indicating that much of the effect of the blockers may be due to promotion of axon growth. These studies provide definitive evidence that soluble inhibitors of EphA4 function offer considerable therapeutic potential for the treatment of spinal cord injury and may have broader potential for the treatment of other central nervous system injuries.
authors.affiliation: Centre for Neuroscience, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Yona
authors.initials: Y
authors.lastname: Goldshmit
authors.forename: Mark D
authors.initials: MD
authors.lastname: Spanevello
authors.forename: Sophie
authors.initials: S
authors.lastname: Tajouri
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Fiona
authors.initials: F
authors.lastname: Rogers
authors.forename: Martin
authors.initials: M
authors.lastname: Pearse
authors.forename: Mary
authors.initials: M
authors.lastname: Galea
authors.forename: Perry F
authors.initials: PF
authors.lastname: Bartlett
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Boyd
authors.forename: Ann M
authors.initials: AM
authors.lastname: Turnley
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009416:Nerve Regeneration / Q000187:drug effects*; D036122:Receptor, EphA4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D020127:Recovery of Function / Q000187:drug effects*; D013119:Spinal Cord Injuries / Q000188:drug therapy*
chemical_list: D007141:Immunoglobulin Fc Fragments; D011994:Recombinant Proteins; D036122:Receptor, EphA4