期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2004
卷号：101
期号：20
页码：7751-7756
DOI：10.1073/pnas.0307850101
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Developing oligodendrocytes (OLs) are highly vulnerable to excitotoxicity and oxidative stress, both of which are important in the pathogenesis of many brain disorders. OL excitotoxicity is mediated by ionotropic glutamate receptors (iGluRs) of the {alpha}-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate type on these cells. Here we report that metabotropic GluRs (mGluRs) are highly expressed in OL precursors but are down-regulated in mature OLs. Activation of group 1 mGluRs attenuates OL excitotoxicity by controlling downstream oxidative stress after iGluR overactivation and also prevents nonexcitotoxic forms of oxidative stress by inhibiting reactive oxygen species accumulation and intracellular glutathione loss. The modulating effect of group 1 mGluRs on hypoxic-ischemic OL injury is not due to iGluR endocytosis that occurs in neurons in response to mGluR activation but requires activation of PKC{alpha} after G protein coupling to phospholipase C. Our results reveal a previously undescribed role for mGluRs in limiting OL injury and suggest that targeting group 1 mGluRs may be a useful therapeutic strategy for treating disorders that involve excitotoxic injury and/or oxidative stress to OLs.
