Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors

Brain injury, as occurs in stroke or head trauma, induces a dramatic increase in levels of tumor necrosis factor− (TNF), but its role in brain injury response is unknown. We generated mice genetically deficient in TNF receptors (TNFR−KO) to determine the role of TNF in brain cell injury responses. Damage to neurons caused by focal cerebral ischemia and epileptic seizures was exacerbated in TNFR−KO mice, indicating that TNF serves a neuroprotective function. Oxidative stress was Increased and levels of an antioxidant enzyme reduced in brain cells of TNFR−KO mice, indicating that TNF protects neurons by stimulating antioxidant pathways. Injury−induced microglial activation was suppressed in TNFR−KO mice, demonstrating a key role for TNF in injury−induced immune response. Drugs that target TNF signaling pathways may prove beneficial in treating stroke and traumatic brain injury.

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