Transgenic inhibition of astroglial NF-κB leads to increased axonal sparing and sprouting following spinal cord injury |
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Authors: | Roberta Brambilla res Hurtado† Trikaldarshi Persaud Kim Esham Damien D Pearse‡ Martin Oudega§ John R Bethea‡¶ |
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Institution: | The Miami Project to Cure Paralysis, Department of Neurological Surgery, Miller School of Medicine, University of Miami, Miami, Florida, USA; International Center for Spinal Cord Injury, Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland, USA; Neuroscience Program, Miller School of Medicine, University of Miami, Miami, Florida, USA; Departments of Physical Medicine and Rehabilitation and Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, Florida, USA |
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Abstract: | We previously showed that Nuclear Factor κB (NF-κB) 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-κB would create a more permissive environment for axonal sprouting and regeneration. We induced both contusive and complete transection SCI in GFAP-Inhibitor of κB-dominant negative (GFAP-IκBα-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-IκBα-dn mice. Higher numbers of FG-labeled neurons were detected immediately rostral to the lesion in GFAP-IκBα-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-κB 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-IκBα-dn mice. |
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Keywords: | anterograde tracing astrocytes GAP-43 neuroprotection retrograde tracing transgenic mice |
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