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

Abstract

Tumor necrosis factor-alpha (TNFα) is a pleiotropic cytokine involved in inflammatory cascades associated with CNS injury. To examine the role of TNFα in the acute pathophysiology of traumatic brain injury (TBI), we studied its expression, localization and modulation in a clinically relevant rat model of non-penetrating head trauma. TNFα levels increased significantly in the injured cortex at 1 and 4, but not at 12, 24 or 72 h after severe lateral fluid-percussion trauma (2.6–2.7 atm). TNFα was not elevated after mild injury. At 1 and 4 h after severe TBI, marked increases of TNFα were localized immunocytochemically to neurons of the injured cerebral cortex. A small population of astrocytes, ventricular cells and microvessels, also showed positive TNFα staining, but this expression was 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 TNFα. Intracerebroventricular administration of a selective TNFα antagonist—soluble TNFα receptor fusion protein (sTNFR:Fc) (37.5 μg)—at 15 min before and 1 h after TBI, improved performance 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 TNFα after TBI contributes to subsequent neurological dysfunction.