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Interleukin‐1β promotes oligodendrocyte death through glutamate excitotoxicity
Author(s) -
Takahashi Jennifer L.,
Giuliani Fabrizio,
Power Christopher,
Imai Yoshinori,
Yong V. Wee
Publication year - 2003
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.10519
Subject(s) - excitotoxicity , nbqx , glutamate receptor , microglia , ampa receptor , oligodendrocyte , kainate receptor , neuroglia , neuroscience , biology , immunology , chemistry , receptor , inflammation , biochemistry , central nervous system , myelin
Abstract Glutamate excitotoxicity is implicated in the progressive loss of oligodendrocytes in multiple sclerosis, but how glutamate metabolism is dysregulated in the disease remains unclear. Because there is microglia activation in all stages of multiple sclerosis, we determined whether a microglia product, interleukin‐1β, could provide the mechanism for glutamate excitotoxicity. We found that whereas interleukin‐1β did not kill oligodendrocytes in pure culture, it produced apoptosis of oligodendrocytes in coculture with astrocytes and microglia. This requirement for a mixed glia environment suggests that interleukin‐1β impairs the well‐described glutamate‐buffering capacity of astrocytes. In support, antagonists at AMPA/kainate glutamate receptors, NBQX and CNQX, blocked the interleukin‐1β toxicity to oligodendrocytes. Another microglia/macrophage cytokine, tumor necrosis factor‐α, also evoked apoptosis of oligodendrocytes in a mixed glia environment in an NBQX‐blockable manner. These results provide a mechanistic link between the persistent and insidious microglia activation that is evident in all stages of multiple sclerosis, with the recent appreciation that glutamate excitotoxicity leads to the destruction of oligodendrocytes in the disease. Ann Neurol 2003;53:588–595