title: Arundic acid attenuates retinal ganglion cell death by increasing glutamate/aspartate transporter expression in a model of normal tension glaucoma.
abstract: Glaucoma is the second leading cause of blindness worldwide and is characterized by gradual visual impairment owing to progressive loss of retinal ganglion cells (RGCs) and their axons. Glutamate excitotoxicity has been implicated as a mechanism of RGC death in glaucoma. Consistent with this claim, we previously reported that glutamate/aspartate transporter (GLAST)-deficient mice show optic nerve degeneration that is similar to that observed in glaucoma. Therefore, drugs that upregulate GLAST may be useful for neuroprotection in glaucoma. Although many compounds are known to increase the expression of another glial glutamate transporter, EAAT2/GLT1, few compounds are shown to increase GLAST expression. Arundic acid is a glial modulating agent that ameliorates delayed ischemic brain damage by attenuating increases in extracellular glutamate. We hypothesized that arundic acid neuroprotection involves upregulation of GLAST. To test this hypothesis, we examined the effect of arundic acid on GLAST expression and glutamate uptake. We found that arundic acid induces GLAST expression in vitro and in vivo. In addition, arundic acid treatment prevented RGC death by upregulating GLAST in heterozygous (GLAST(+/-)) mice. Furthermore, arundic acid stimulates the human GLAST ortholog, EAAT1, expression in human neuroglioblastoma cells. Thus, discovering compounds that can enhance EAAT1 expression and activity may be a novel strategy for therapeutic treatment of glaucoma.
authors: Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors: M
authors: M
authors: Yanagisawa
authors: Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors: T
authors: T
authors: Aida
authors: Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors: T
authors: T
authors: Takeda
authors: Visual Research Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
authors: K
authors: K
authors: Namekata
authors: Visual Research Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
authors: T
authors: 0000000161670997
authors: T
authors: Harada
authors: Discovery Research Laboratories I, Minase Research Institute, Ono Pharmaceutical Co. Ltd., 1-1, Sakurai 3-chome, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors: R
authors: R
authors: Shinagawa
authors: 1] Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan [2] The Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan [3] JST, CREST, 7, Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan.
authors: K
authors: K
authors: Tanaka
mesh_terms: D000818:Animals; D002210:Caprylates / Q000008:administration & dosage*; D016923:Cell Death / Q000187:drug effects; D027341:Excitatory Amino Acid Transporter 1 / Q000096:biosynthesis* / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D005901:Glaucoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D051379:Mice; D009410:Nerve Degeneration / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009900:Optic Nerve / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000473:pathology
chemical_list: D002210:Caprylates; D027341:Excitatory Amino Acid Transporter 1; C459360:ONO2506; C493394:SLC1A3 protein, human; C493393:Slc1a3 protein, mouse; D018698:Glutamic Acid