Dual neuronal response to tumor necrosis factor-alpha following spinal cord injury



L. Y. Chi; J. Yu; H. Zhu; X. G. Li; S. G. Zhu; Z. Z. Li; L. C. Pettigrew; D. Grass; J. J. Hickman;M. S. Kindy


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Abbreviated Journal Title

Neural Regen. Res.


spinal cord injury; tumor necrosis factor-alpha; rats; inflammation; motor function; astrocytes; microglia; nerve growth factor; brain-derived neurotrophic factors; NERVE GROWTH-FACTOR; BRAIN-INJURY; TRANSGENIC MICE; GENE-EXPRESSION; WORKING-MEMORY; CYTOKINES; RATS; APOPTOSIS; SYSTEM; INFLAMMATION; Cell Biology; Neurosciences


BACKGROUND: Numerous studies have shown that tumor necrosis factor a (TNF-alpha) is closely correlated with spinal cord injury (SCI), but the mechanisms of TNF-alpha and therapeutic treatments for SCI are still poorly understood. OBJECTIVE: To determine the role of TNF-alpha in the pathogenesis of SCI. DESIGN, TIME AND SETTING: An in vivo experiment based on genetically engineered animals was performed at the Medical University of South Carolina, Charleston, South Carolina, USA, between June 2007 and October 2008. MATERIALS: TNF-alpha transgenic rats (Xenogen Biosciences in Cranbury, New Jersey, USA) were utilized in this study. METHODS: TNF-alpha transgenic (tg) and wild-type (WT) rats underwent a complete single-level laminectomy at the 10(th) thoracic vertebra (T(10)). MAIN OUTCOME MEASURES: Motor function of rat hindlimb was assessed using the Basso, Beattie, and Bresnahan hindlimb locomotor rating scale. Histological evaluation of spinal cord tissue loss was conducted. Immunohistochemistry for astrocytes, microglia/macrophages, and TNF receptors (TNFRs) was performed on spinal cord tissue sections. TNF-alpha mRNA expression was detected by real-time polymerase chain reaction. The concentrations of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in the supernatant were determined using an enzyme-linked immunosorbent assay kit for rat NGF or BDNF, respectively. The rats were injected subcutaneously with etanercept to verify that TNF-alpha was the direct effect of the modulation of behavioral and neurodegenerative outcomes in the TNF-alpha tg rats. RESULTS: TNF-alpha tg rats showed higher expression of TNF-alpha mRNA in the spinal cord prior to SCI. TNF-alpha tg rats showed worse motor deficits than WT rats in the acute period ( < 3 days) after SCI (P < 0.01), while in the chronic period, TNF-alpha tg rats exhibited persistent elevated baseline levels of TNF-alpha mRNA and improved recovery in motor function and tissue healing compared to WT rats (P < 0.01). Following SCI, the number of microglia/macrophages in TNF-alpha tg rat was always greater than in WT rat (P < 0.01). There were no significant differences in NGF and BDNF levels in the supernatant of spinal cord homogenates. TNFR1 expression was significantly greater in the TNF-alpha tg rats compared to the WT rats (P < 0.01). However, TNFR2 expression did not reveal a significant increase in the TNF-alpha tg rats compared to the WT rats. Finally, treatment with etanercept reduced injury acutely, but exacerbated the injury chronically. CONCLUSION: Overexpression of TNF-alpha is deleterious in the acute phase, but beneficial in the chronic phase in the response to SCI. The role of TNF-alpha post-injury may depend on TNF-alpha expression in the spinal cord and its differential binding to TNFR1. Our observations may have clinical relevance that antagonists or inhibitors of TNF-alpha could be administered within the early time window post-injury, and appropriate amounts of TNF-alpha could be administered during the chronic stage, in order to improve the final neurological recovery in patients with SCI.

Journal Title

Neural Regeneration Research





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