Ischemic and excitotoxic brain injury is enhanced in mice lacking the p55 tumor necrosis factor receptor

Ischemic and excitotoxic insults to the brain induce rapid production of tu mor necrosis factor-alpha (TNF), but the role of TNF in neuronal responses to brain injury are unclear. Two different TNF receptors (p55 and p75) are expressed in neurons and glia. To understand the role of TNF in brain injur y, we generated mice that lack p55, p75, or both receptors. We report that neuronal damage after focal cerebral ischemia-reperfusion is significantly increased in mice lacking p55 receptors (85 +/- 7 mm(3) infarct volume; mea n +/- SD) compared with wild-type mice (70 +/- 8 mm(3)) and mice lacking p7 5 receptors (72 +/- 6 mm(3)). Moreover, mice lacking p55 receptors exhibite d increased degeneration of CA3 hippocampal neurons after administration of the excitotoxin kainic acid compared with wild-type mice and mice lacking p75 receptors. When taken together with recent data showing that TNF can pr event apoptosis of cultured neurons exposed to oxidative and metabolic insu lts, our findings suggest that TNF plays a neuroprotective role after acute brain insults.