title: Rapid mitochondrial dysfunction mediates TNF-alpha-induced neurotoxicity.
abstract: Tumor necrosis factor alpha (TNF-α) is known to exacerbate ischemic brain injury; however, the mechanism is unknown. Previous studies have evaluated the effects of TNF-α on neurons with long exposures to high doses of TNF-α, which is not pathophysiologically relevant. We characterized the rapid effects of TNF-α on basal respiration, ATP production, and maximal respiration using pathophysiologically relevant, post-stroke concentrations of TNF-α. We observed a reduction in mitochondrial function as early as 1.5 h after exposure to low doses of TNF-α, followed by a decrease in cell viability in HT-22 cells and primary neurons. Subsequently, we used the HT-22 cell line to determine the mechanism by which TNF-α causes a rapid and profound reduction in mitochondrial function. Pre-treating with TNF-R1 antibody, but not TNF-R2 antibody, ameliorated the neurotoxic effects of TNF-α, indicating that TNF-α exerts its neurotoxic effects through TNF-R1. We observed an increase in caspase 8 activity and a decrease in mitochondrial membrane potential after exposure to TNF-α which resulted in a release of cytochrome c from the mitochondria into the cytosol. These novel findings indicate for the first time that an acute exposure to pathophysiologically relevant concentrations of TNF-α has neurotoxic effects mediated by a rapid impairment of mitochondrial function. This study focuses on the neurotoxic mechanism of a pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-α). We demonstrate a prompt mitochondrial dysfunction followed by nerve cell loss after exposure to TNF-α. These studies may provide evidence that the immune system can rapidly and adversely affect brain function and that TNF-α signaling may be a target for neuroprotection.
authors.affiliation: Neurobiology and Anatomy, West Virginia University, Morgantown, West Virginia, USA; Center for Neuroscience, Morgantown, WV, USA; Center for Basic and Translational Stroke Research, Morgantown, WV, USA.
authors.forename: Danielle N
authors.initials: DN
authors.lastname: Doll
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Rellick
authors.forename: Taura L
authors.initials: TL
authors.lastname: Barr
authors.forename: Xuefang
authors.initials: X
authors.lastname: Ren
authors.forename: James W
authors.initials: JW
authors.lastname: Simpkins
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
chemical_list: D014409:Tumor Necrosis Factor-alpha
keywords: TNF-alpha; cytokines; inflammation; mitochondria; neuro-toxicity; stroke