title: Axonal thinning and extensive remyelination without chronic demyelination in spinal injured rats.
abstract: Remyelination following spinal cord injury (SCI) is thought to be incomplete; demyelination is reported to persist chronically and is proposed as a compelling therapeutic target. Yet most reports do not distinguish between the myelin status of intact axons and injury-severed axons whose proximal stumps persist but provide no meaningful function. We previously found full remyelination of spared, intact rubrospinal axons caudal to the lesion in chronic mouse SCI. However, the clinical concept of chronically demyelinated spared axons remains controversial. Since mouse models may have limitations in clinical translation, we asked whether the capacity for full remyelination is conserved in clinically relevant chronic rat SCI. We determined myelin status by examining paranodal protein distribution on anterogradely labeled, intact corticospinal and rubrospinal axons throughout the extent of the lesion. Demyelination was evident on proximal stumps of severed axons, but not on intact axons. For the first time, we demonstrate that a majority of intact axons exhibit remyelination (at least one abnormally short internode, <100 μm). Remarkably, shortened internodes were significantly concentrated at the lesion epicenter and individual axons were thinned by 23% compared with their rostral and caudal zones. Mathematical modeling predicted a 25% decrease in conduction velocity at the lesion epicenter due to short internodes and axonal thinning. In conclusion, we do not find a large chronically demyelinated population to target with remyelination therapies. Interventions may be better focused on correcting structural or molecular abnormalities of regenerated myelin.
authors.affiliation: Department of Neurological Surgery, University of Washington, Seattle, Washington 98109, USA.
authors.forename: Berit E
authors.initials: BE
authors.lastname: Powers
authors.forename: Jurate
authors.initials: J
authors.lastname: Lasiene
authors.forename: Jason R
authors.initials: JR
authors.lastname: Plemel
authors.forename: Larry
authors.initials: L
authors.lastname: Shupe
authors.forename: Steve I
authors.initials: SI
authors.lastname: Perlmutter
authors.forename: Wolfram
authors.initials: W
authors.lastname: Tetzlaff
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Horner
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology*; D002574:Cervical Vertebrae / Q000293:injuries; D003288:Contusions / Q000473:pathology; D003711:Demyelinating Diseases / Q000473:pathology; D005260:Female; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008124:Locomotion / Q000502:physiology; D009186:Myelin Sheath / Q000473:pathology*; D009431:Neural Conduction / Q000502:physiology; D011712:Pyramidal Tracts / Q000473:pathology; D011817:Rabbits; D051381:Rats; D012984:Software; D013119:Spinal Cord Injuries / Q000473:pathology*; D013904:Thoracic Vertebrae / Q000293:injuries