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The Journal of Neuroscience, November 15, 1999, 19(22):9813-9820

Neuronal Death and Blood-Brain Barrier Breakdown after Excitotoxic Injury Are Independent Processes

Zu-lin Chen^{1, 2}, Justin A. Indyk^{1, 2, 3}, Thomas H. Bugge⁴, Keith W. Kombrinck⁴, Jay L. Degen⁴, and Sidney Strickland^{1, 2}

¹ Department of Pharmacology, ² Program in Genetics, and ³ Medical Scientist Training Program, University at Stony Brook, Stony Brook, New York 11794-8651, and ⁴ Division of Developmental Biology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229

Neuronal damage in the CNS after excitotoxic injury is correlated with blood-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 dysfunction occurs too late to initiate neurodegeneration. In addition, plasma infused directly into the hippocampus is not toxic and does not affect excitotoxin-induced neuronal death. To test plasma protein recruitment in neuronal degeneration, we used plasminogen-deficient (plg^/) mice, which are resistant to excitotoxin-induced degeneration. Plasminogen is produced in the hippocampus and is also present at high levels in plasma, allowing us to determine the contribution of each source to cell death. Intrahippocampal delivery of plasminogen to plg^/ mice restored degeneration to wild-type levels, but intravenous delivery of plasminogen did not. Finally, although the neurons in plg^/ mice do not die after excitotoxin injection, BBB breakdown occurs to a similar extent as in wild-type mice, indicating that neuronal death is not necessary for BBB breakdown. These results indicate that excitotoxin-induced neuronal death and BBB breakdown are separable events in the hippocampus.

Key words: plasminogen; tPA; neurodegeneration; blood-brain barrier; kainate; hippocampus; mouse

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19229813-08$05.00/0

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