EAAC1 gene deletion alters zinc homeostasis and enhances cortical neuronal injury after transient cerebral ischemia in mice

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• 作者：Bong Geom Jang^a ; Seok Joon Won^b ; Jin Hee Kim^a ; Bo Young Choi^a ; Min Woo Lee^a ; Min Sohn^c ; Hong Ki Song^d ; Sang Won Suh^a ; ^{swsuh@hallym.ac.kr}
• 关键词：EAAC1 ; Cysteine ; Zinc ; Ischemia ; Reactive oxygen species
• 刊名：Journal of Trace Elements in Medicine and Biology
• 出版年：2012
• 期刊代码：6_0946672X
• 类别：ch
• 出版时间：June, 2012
• 卷：26
• 期：2-3
• 页码：85-88
• 文件大小：501 K

摘要

The excitatory amino acids glutamate and cysteine are actively transported into neurons from the extracellular space by the high affinity glutamate transporter EAAC1. The astrocyte glutamate transporters, GLT1 and GLAST, are the primary mediators of glutamate clearance. EAAC1 has a limited role in this function. However, uptake of cysteine into neurons via EAAC1 contributes to neuronal antioxidant function by providing cysteine substrate for glutathione synthesis. Mice in which the EAAC1 gene has been deleted were seen to have enhanced susceptibility to neuronal oxidative stress and developed brain atrophy and cognitive function decline with aging. The aim of the current study was to evaluate if EAAC1 confers protection against ischemic events. Young adult CD-1 wild-type or EAAC1^{鈭?/em>/鈭?/sup> mice were subjected to 30 min of bilateral common carotid artery occlusion and evaluated for neuronal death and zinc translocation. The intensity of TSQ fluorescence in the cytoplasm of cortical neurons in the EAAC1鈭?/em>/鈭?/sup> mice was significantly higher than wild-type mice, indicating that the cortical neurons of EAAC1鈭?/em>/鈭?/sup> mice contain higher cytoplasmic concentrations of labile (or free) zinc. Zinc translocation into cortical neurons was also enhanced in EAAC1鈭?/em>/鈭?/sup> mice. Three days after ischemia, Fluoro-Jade B staining revealed that EAAC1鈭?/em>/鈭?/sup> mice had more than twice as many degenerating neurons as wild-type mice. N-acetylcysteine, a membrane-permeant cysteine pro-drug, normalized basal zinc levels, reduced TSQ (+) neurons and reduced ischemic neuronal death in the EAAC1鈭?/em>/鈭?/sup> mice when delivered in a pre-treatment fashion. Taken together, this study implicates EAAC1-dependent cysteine uptake as an endogenous source of enhancing antioxidant function and zinc homeostasis in neurons in the ischemic brain.}