Etanercept attenuates traumatic brain injury in rats by reducing early microglial expression of tumor necrosis factor-α

Background: Tumor necrosis factor-alpha (TNF-alpha) is elevated early in injured brain after traumatic brain injury (TBI), in humans and in animals. Etanercept (a TNF-alpha antagonist with anti-inflammatory effects) attenuates TBI in rats by reducing both microglial and astrocytic activation and increased serum levels of TNF-alpha. However, it is not known whether etanercept improves outcomes of TBI by attenuating microglia-associated, astrocytes-associated, and/or neurons-associated TNF-alpha expression in ischemic brain. A well clinically relevant rat model, where a lateral fluid percussion is combined with systemic administration of etanercept immediately after TBI, was used. The neurological severity score and motor function was measured on all rats preinjury and on day 3 after etanercept administration. At the same time, the neuronal and glial production of TNF-alpha was measured by Immunofluorescence staining. In addition, TNF alpha contents of ischemic cerebral homogenates was measured using commercial enzyme-linked immunosorbent assay kits. Results: In addition to inducing brain ischemia as well as neurological and motor deficits, TBI caused significantly higher numbers of microglia-TNF-alpha double positive cells, but not neurons-TNF-alpha or astrocytes-TNF-alpha double positive cells in the injured brain areas than did the sham operated controls, when evaluated 3 days after TBI. The TBI-induced cerebral ischemia, neurological motor deficits, and increased numbers of microglia-TNF-alpha double positive cells and increased TNF-alpha levels in the injured brain were all significantly attenuated by etanercept therapy. Conclusion: This finding indicates that early microglia overproduction of TNF-alpha in the injured brain region after TBI contributes to cerebral ischemia and neurological motor deficits, which can be attenuated by etanercept therapy. Studies in this model could provide insight into the mechanisms underlying neurological motor disturbance in brain-injured patients.