The potential role of glutamate transporters in the pathogenesis of normal tension glaucoma
The potential role of glutamate transporters in the pathogenesis of normal tension glaucoma
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DOI：
10.1172/jci30178
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发表时间：
2007-07-01
影响因子：
15.9
通讯作者：
Tanaka, Kohichi
中科院分区：
文献类型：
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作者：
Harada, Takayuki;Harada, Chikako;Tanaka, Kohichi
青光眼是一种由视网膜神经节细胞（RGC）变性引起的进行性视神经病变，是导致不可逆性失明的主要原因之一。虽然青光眼通常与眼内压（IOP）升高有关，但在一个重要的青光眼亚组中未检测到IOP升高，如正常眼压性青光眼（NTG）。此外，在一些青光眼患者中，显著的IOP降低并不能阻止疾病的进展。因此，了解与IOP无关的RGC丢失机制非常重要。在这里，我们表明，缺乏谷氨酸转运蛋白GLAST或EAAC 1的小鼠表现出自发性RGC和视神经变性，而没有IOP升高。在GLAST缺陷小鼠中，Muller神经胶质细胞中的谷胱甘肽水平降低;谷氨酸受体阻断剂的施用防止了RGC损失。在EAAC 1缺陷小鼠中，RGCs更容易受到氧化应激的影响。这些研究结果表明，谷氨酸转运蛋白是必要的，以防止兴奋毒性视网膜损伤和合成谷胱甘肽，一种主要的细胞抗氧化剂和三肽的谷氨酸，半胱氨酸和甘氨酸。我们相信这些小鼠是NTG的第一个动物模型，为研究NTG中神经变性的机制和开发针对IOP非依赖性RGC损失机制的治疗提供了强大的系统。
Glaucoma, a progressive optic neuropathy due to retinal ganglion cell (RGC) degeneration, is one of the leading causes of irreversible blindness. Although glaucoma is often associated with elevated intraocular pressure (IOP), IOP elevation is not detected in a significant subset of glaucomas, such as normal tension glaucoma (NTG). Moreover, in some glaucoma patients, significant IOP reduction does not prevent progression of the disease. Thus, understanding IOP-independent mechanisms of RGC loss is important. Here, we show that mice deficient in the glutamate transporters GLAST or EAAC1 demonstrate spontaneous RGC and optic nerve degeneration without elevated IOP. In GLAST-deficient mice, the glutathione level in Muller glia was decreased; administration of glutamate receptor blocker prevented RGC loss. In EAAC1-deficient mice, RGCs were more vulnerable to oxidative stress. These findings suggest that glutamate transporters are necessary both to prevent excitotoxic retinal damage and to synthesize glutathione, a major cellular antioxidant and tripeptide of glutamate, cysteine, and glycine. We believe these mice are the first animal models of NTG that offer a powerful system for investigating mechanisms of neurodegeneration in NTG and developing therapies directed at IOP-independent mechanisms of RGC loss.