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-alpha (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.
Bruce
A J
AJ
Sanders-Brown Research Center on Aging, University of Kentucky, Lexington 40536-0230, USA.
Boling
W
W
Kindy
M S
MS
Peschon
J
J
Kraemer
P J
PJ
Carpenter
M K
MK
Holtsberg
F W
FW
Mattson
M P
MP
D000818:Animals; D001930:Brain Injuries / Q000378:metabolism / Q000473:pathology*; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D007150:Immunohistochemistry; D015227:Lipid Peroxidation; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000494:pharmacology*; D018384:Oxidative Stress; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D013482:Superoxide Dismutase / Q000378:metabolism
D009498:Neurotoxins; D018124:Receptors, Tumor Necrosis Factor; D013482:Superoxide Dismutase