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T. Harada, K. Nakamura, K. Namekata, T. Saeki, M. Aihara, H. Yoshida, C. Harada; The Potential Role of Glutamate Transporters in the Pathogenesis of Normal Tension Glaucoma. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5493.
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© ARVO (1962-2015); The Authors (2016-present)
Glutamate neurotoxicity is assumed to be involved in the pathophysiology of glaucoma, and glutamate transporter is the only mechanism for the removal of glutamate from the extracellular fluid. In the retina, GLAST is expressed in Müller cells and EAAC1 is expressed in retinal ganglion cells (RGCs). In this study, we utilized knockout (KO) mice of these two glutamate transporters and examined their long-term effect on RGC survival. In addition, we tested whether loss of apoptosis signal-regulating kinase 1 (ASK1) could prevent RGC degeneration.
Retinal sections of EAAC1 and GLAST KO mice were examined at 0, 1, 2, 3, 5, 8, 16 and 32 weeks after birth. Intraocular pressure (IOP) was measured by a microneedle technique and visual function was tested by multifocal electroretinograms. The concentrations of vitreal glutamate, lipid peroxides and glutathione were examined by high-performance liquid chromatogray (HPLC) or enzyme-linked immunosorbent assay (ELISA). Effect of H2O2 on mixed culture of RGCs and Müller cells was determined by lactate dehydrogenase assay.
GLAST and EAAC1 KO mice showed spontaneously occurring RGC death and typical glaucomatous damage of the optic nerve without elevated IOP. Multifocal electroretinograms revealed impaired visual function in these mice. In GLAST KO mice, vitreal glutamate concentration was normal, but glutamate receptor blocker partially prevented RGC loss. On the other hand, the concentrations of lipid peroxides was increased and glutathione expression level was decreased, especially in Müller cells. In EAAC1 KO mice, RGCs were more vulnerable to oxidative stress. In addition, wild-type (WT) RGCs cocultured with Müller cells from GLAST KO mice were susceptible to free radical stimulation compared with those cocultured with WT Müller cells. Loss of ASK1 partially rescued RGC degeneartion and recovered visual function of glutamate transporter KO mice.
These findings suggest that glutamate transporters are necessary both to prevent excitotoxic retinal damage and to synthesize glutathione, a major cellular antioxidant and tri-peptide of glutamate, cysteine, and glycine. These mice are available as animal models of normal tension glaucoma (NTG) that offer a powerful system for investigating IOP-independent mechanisms of RGC loss and evaluating new treatments of NTG.
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