Neuronal death and blood-brain barrier breakdown after excitotoxic injury are independent processes

Neuronal damage in the CNS after excitotoxic injury is correlated with bloo d-brain barrier (BBB) breakdown. We have used a glutamate analog injection model and genetically altered mice to investigate the relationship between these two processes in the hippocampus. Our results show that BBB dysfuncti on occurs too late to initiate neurodegeneration. In addition, plasma infus ed directly into the hippocampus is not toxic and does not affect excitotox in-induced neuronal death. To test plasma protein recruitment in neuronal d egeneration, we used plasminogen-deficient (plg(-/-)) mice, which are resis tant to excitotoxin-induced degeneration. Plasminogen is produced in the hi ppocampus and is also present at high levels in plasma, allowing us to dete rmine the contribution of each source to cell death. Intrahippocampal deliv ery of plasminogen to plg(-/-) mice restored degeneration to wild-type leve ls, but intravenous delivery of plasminogen did not. Finally, although the neurons in plg(-/-) mice do not die after excitotoxin injection, BBB breakd own occurs to a similar extent as in wild-type mice, indicating that neuron al death is not necessary for BBB breakdown. These results indicate that ex citotoxin-induced neuronal death and BBB breakdown are separable events in the hippocampus.