title: Transgenic inhibition of astroglial NF-kappa B leads to increased axonal sparing and sprouting following spinal cord injury.
abstract: We previously showed that Nuclear Factor kappaB (NF-kappaB) inactivation in astrocytes leads to improved functional recovery following spinal cord injury (SCI). This correlated with reduced expression of pro-inflammatory mediators and chondroitin sulfate proteoglycans, and increased white matter preservation. Hence we hypothesized that inactivation of astrocytic NF-kappaB would create a more permissive environment for axonal sprouting and regeneration. We induced both contusive and complete transection SCI in GFAP-Inhibitor of kappaB-dominant negative (GFAP-IkappaBalpha-dn) and wild-type (WT) mice and performed retrograde [fluorogold (FG)] and anterograde [biotinylated dextran amine (BDA)] tracing 8 weeks after injury. Following contusive SCI, more FG-labeled cells were found in motor cortex, reticular formation, and raphe nuclei of transgenic mice. Spared and sprouting BDA-positive corticospinal axons were found caudal to the lesion in GFAP-IkappaBalpha-dn mice. Higher numbers of FG-labeled neurons were detected immediately rostral to the lesion in GFAP-IkappaBalpha-dn mice, accompanied by increased expression of synaptic and axonal growth-associated molecules. After transection, however, no FG-labeled neurons or BDA-filled axons were found rostral and caudal to the lesion, respectively, in either genotype. These data demonstrated that inhibiting astroglial NF-kappaB resulted in a growth-supporting terrain promoting sparing and sprouting, rather than regeneration, of supraspinal and propriospinal circuitries essential for locomotion, hence contributing to the improved functional recovery observed after SCI in GFAP-IkappaBalpha-dn mice.
authors.affiliation: Department of Neurological Surgery, University of Miami, Florida 33136, USA. r.brambilla@miami.edu
authors.forename: Roberta
authors.initials: R
authors.lastname: Brambilla
authors.forename: Andres
authors.initials: A
authors.lastname: Hurtado
authors.forename: Trikaldarshi
authors.initials: T
authors.lastname: Persaud
authors.forename: Kim
authors.initials: K
authors.lastname: Esham
authors.forename: Damien D
authors.initials: DD
authors.lastname: Pearse
authors.forename: Martin
authors.initials: M
authors.lastname: Oudega
authors.forename: John R
authors.initials: JR
authors.lastname: Bethea
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism / Q000473:pathology* / Q000502:physiology*; D001369:Axons / Q000473:pathology* / Q000502:physiology*; D005260:Female; D015316:Genetic Therapy; D020672:I-kappa B Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics*; D009416:Nerve Regeneration / Q000235:genetics / Q000502:physiology; D013119:Spinal Cord Injuries / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha