Neurotoxic responses by microglia elicited by excitotoxic injury in the mouse hippocampus.
BACKGROUND
Injury to the brain induces dramatic local changes in gene expression, cellular morphology and behavior. Activation of microglial cells occurs as an early event after central nervous system (CNS) injury, but it has not been determined whether such activation plays a causal role in neuronal death. We have investigated this question using an excitotoxin-mediated brain injury model system, in conjunction with an endogenous peptide factor (macrophage/microglial inhibiting factor, MIF) that ablates microglial contribution to the cascade.


RESULTS
Using MIF, we inhibited the microglial activation that normally follows excitotoxic injury. In cell culture studies, we found that such inhibition blocked the rapid release of microglia-derived tissue plasminogen activator (tPA), an extracellular serine protease made by both neurons and microglia, which we had previously identified as mediating a critical step in excitotoxin-induced neuronal death. Finally, infusion of MIF into the mouse brain prior to excitotoxic insult resulted in the protection of neurons from cell death.


CONCLUSIONS
Our results demonstrate that microglia undertake a neurotoxic role when excitotoxic injury occurs in the CNS. They also suggest that the tPA released from microglia has a critical role in triggering neurodegeneration.
Rogove
A D
AD
MSTP Program, University Medical Center at Stony Brook, Stony Brook, New York 11794-8651, USA.
Tsirka
S E
SE
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D005260:Female; D018698:Glutamic Acid / Q000633:toxicity; D006624:Hippocampus / Q000187:drug effects / Q000293:injuries* / Q000473:pathology; D007608:Kainic Acid / Q000633:toxicity*; D008263:Macrophage Migration-Inhibitory Factors / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D009410:Nerve Degeneration / Q000139:chemically induced; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D011247:Pregnancy; D010959:Tissue Plasminogen Activator / Q000502:physiology
D018690:Excitatory Amino Acid Agonists; D008263:Macrophage Migration-Inhibitory Factors; D018698:Glutamic Acid; D010959:Tissue Plasminogen Activator; D007608:Kainic Acid