Early neuronal expression of tumor necrosis factor-alpha after experimental brain injury contributes to neurological impairment

Tumor necrosis factor-alpha (TNF alpha) is a pleiotropic cytokine involved in inflammatory cascades associated with CNS injury. To examine the role of TNF alpha in the acute pathophysiology of traumatic brain injury (TBI), we studied its expression, localization and modulation in a clinically releva nt rat model of non-penetrating head trauma. TNF alpha levels increased sig nificantly in the injured cortex at I and 4, but not at 12, 14 or 72 h afte r severe lateral fluid-percussion trauma (2.6-2.7 atm). TNF alpha was not e levated after mild injury. At I and 4 h after severe TBI, marked increases of TNF alpha were localized immunocytochemically to neurons of the injured cerebral cortex. A small population of astrocytes, ventricular cells and mi crovessels, also showed positive TNF alpha staining, but this expression wa s not injury-dependent. Macrophages that were present in a hemorrhagic zone along the external capsule, corpus callosum and alveus hippocampus at 4 h after TBI did not express TNF alpha. Intracerebroventricular administration of a selective TNF alpha antagonist-soluble TNF alpha receptor fusion prot ein (sTNFR:Fc) (37.5 mu g)-at 15 min before and 1 h after TBI, improved per formance in a series of standardized motor tasks after injury. In contrast: intravenous administration of sTNFR:Fc (0.2, 1 or 5 mg/kg) at 15 min after trauma did not improve motor outcome. Collectively, this evidence suggests that enhanced early neuronal expression of TNF alpha after TBI contributes to subsequent neurological dysfunction. (C) 1999 Elsevier Science B.V. All rights reserved.