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 relevant rat model of non-penetrating head trauma. TNF alpha 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). TNF alpha was not elevated after mild injury. At 1 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 microvessels, also showed positive TNF alpha 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 TNF alpha. Intracerebroventricular administration of a selective TNF alpha antagonist--soluble TNF alpha receptor fusion protein (sTNFR:Fc) (37.5 microg)--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 TNF alpha after TBI contributes to subsequent neurological dysfunction.
Knoblach
S M
SM
Georgetown Institute for Cognitive and Computational Sciences, Georgetown University Medical Center, Washington, DC 20007-2197, USA. knoblachs@giccs.georgetown.edu
Fan
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L
Faden
A I
AI
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000276:immunology / Q000494:pharmacology; D001522:Behavior, Animal / Q000502:physiology; D001923:Brain Chemistry / Q000276:immunology*; D001930:Brain Injuries / Q000276:immunology*; D002540:Cerebral Cortex / Q000166:cytology / Q000276:immunology / Q000293:injuries; D004797:Enzyme-Linked Immunosorbent Assay; D000068800:Etanercept; D005455:Fluorescent Antibody Technique; D007074:Immunoglobulin G / Q000276:immunology; D007276:Injections, Intraventricular; D008297:Male; D009474:Neurons / Q000737:chemistry* / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis* / Q000276:immunology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept