title: Two-tiered inhibition of axon regeneration at the dorsal root entry zone.
abstract: Glial-derived inhibitory molecules and a weak cell-body response prevent sensory axon regeneration into the spinal cord after dorsal root injury. Neurotrophic factors, particularly neurotrophin-3 (NT-3), may increase the regenerative capacity of sensory neurons after dorsal rhizotomy, allowing regeneration across the dorsal root entry zone (DREZ). Intrathecal NT-3, delivered at the time of injury, promoted an upregulation of the growth-associated protein GAP-43 primarily in large-diameter sensory profiles (which did not occur after rhizotomy alone), as well as regeneration of cholera toxin B-labeled sensory axons across the DREZ and deep into the dorsal horn. However, delaying treatment for 1 week compromised regeneration: although axons still penetrated the DREZ, growth within white matter was qualitatively and quantitatively restricted. This was not associated with an impaired cell-body response (GAP-43 upregulation was equivalent for both immediate and delayed treatments), or with astrogliosis at the DREZ, which begins almost immediately after rhizotomy, but with the delayed appearance of mature ED1-expressing phagocytes in the dorsal white matter between 1 and 2 weeks after lesion, marking the beginning of myelin breakdown. After rhizotomy with immediate NT-3 treatment, regeneration continues beyond 2 weeks, but in the dorsal gray matter rather than in the degenerating dorsal columns. The ability of NT-3 to promote regeneration across the DREZ, but not after the beginning of degeneration after delayed treatment reveals a hierarchy of inhibitory influences: the astrogliotic, but not the degenerative barrier is surmountable by NT-3 treatment.
authors: Sensory Function Group, Center for Neuroscience Research, Guy's King's and St. Thomas' School of Biomedical Science, London SE1 1UL, United Kingdom. matt.ramer@kcl.ac.uk
authors: M S
authors: MS
authors: Ramer
authors: I
authors: I
authors: Duraisingam
authors: J V
authors: JV
authors: Priestley
authors: S B
authors: SB
authors: McMahon
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001369:Axons / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D002772:Cholera Toxin; D004195:Disease Models, Animal; D019922:GAP-43 Protein / Q000378:metabolism; D005727:Ganglia, Spinal / Q000166:cytology / Q000502:physiology*; D005911:Gliosis / Q000473:pathology; D007150:Immunohistochemistry; D007278:Injections, Spinal; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020933:Neurotrophin 3 / Q000008:administration & dosage; D010586:Phagocytes / Q000378:metabolism / Q000473:pathology; D051381:Rats; D019051:Rhizotomy; D015854:Up-Regulation / Q000187:drug effects; D014855:Wallerian Degeneration / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
chemical_list: D000943:Antigens, Differentiation; D019922:GAP-43 Protein; D020933:Neurotrophin 3; D002772:Cholera Toxin