Takahashi Jennifer L, Giuliani Fabrizio, Power Christopher, Imai Yoshinori, Yong V Wee
Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.
Ann Neurol. 2003 May;53(5):588-95. doi: 10.1002/ana.10519.
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-1beta, could provide the mechanism for glutamate excitotoxicity. We found that whereas interleukin-1beta 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-1beta impairs the well-described glutamate-buffering capacity of astrocytes. In support, antagonists at AMPA/kainate glutamate receptors, NBQX and CNQX, blocked the interleukin-1beta toxicity to oligodendrocytes. Another microglia/macrophage cytokine, tumor necrosis factor-alpha, 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.
谷氨酸兴奋性毒性与多发性硬化症中少突胶质细胞的进行性丧失有关，但该病中谷氨酸代谢如何失调仍不清楚。由于在多发性硬化症的所有阶段都存在小胶质细胞活化，我们确定小胶质细胞产物白细胞介素-1β是否能为谷氨酸兴奋性毒性提供机制。我们发现，虽然白细胞介素-1β在纯培养中不会杀死少突胶质细胞，但在与星形胶质细胞和小胶质细胞共培养时会导致少突胶质细胞凋亡。对混合胶质细胞环境的这种需求表明，白细胞介素-1β损害了星形胶质细胞中众所周知的谷氨酸缓冲能力。作为支持，AMPA/海人酸谷氨酸受体拮抗剂NBQX和CNQX可阻断白细胞介素-1β对少突胶质细胞的毒性。另一种小胶质细胞/巨噬细胞细胞因子肿瘤坏死因子-α，也以NBQX可阻断的方式在混合胶质细胞环境中引发少突胶质细胞凋亡。这些结果在多发性硬化症所有阶段明显存在的持续性和隐匿性小胶质细胞活化与最近认识到的谷氨酸兴奋性毒性导致该病中少突胶质细胞破坏之间提供了一种机制联系。
