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Arundic acid attenuates retinal ganglion cell death by increasing glutamate/aspartate transporter expression in a model of normal tension glaucoma.

Yanagisawa M, Aida T, Takeda T, Namekata K, Harada T, Shinagawa R, Tanaka K - Cell Death Dis (2015)

Bottom Line: 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.Thus, discovering compounds that can enhance EAAT1 expression and activity may be a novel strategy for therapeutic treatment of glaucoma.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.

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.

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Arundic acid rescues RGC death in GLAST+/− mice by increasing GLAST expression. (a) Hematoxylin and eosin-stained retinal sections from wild-type, GLAST+/− and GLAST−/− mice at P35, with or without arundic acid (10 mg/kg) treatment. The scale bar represents 100 μm and 50 μm in the upper and lower panels, respectively. GCL, ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer. (b) Quantitative analyses of the number of neurons in the GCL following arundic acid treatment. The numbers of neurons in the GCL were counted in retinal sections from one ora serrata through the optic nerve to the other ora serrata (N=6). The data represent the mean±S.E.M.. **P<0.01 as determined by one-way ANOVA with Tukey–Kramer's post hoc analysis
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fig3: Arundic acid rescues RGC death in GLAST+/− mice by increasing GLAST expression. (a) Hematoxylin and eosin-stained retinal sections from wild-type, GLAST+/− and GLAST−/− mice at P35, with or without arundic acid (10 mg/kg) treatment. The scale bar represents 100 μm and 50 μm in the upper and lower panels, respectively. GCL, ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer. (b) Quantitative analyses of the number of neurons in the GCL following arundic acid treatment. The numbers of neurons in the GCL were counted in retinal sections from one ora serrata through the optic nerve to the other ora serrata (N=6). The data represent the mean±S.E.M.. **P<0.01 as determined by one-way ANOVA with Tukey–Kramer's post hoc analysis

Mentions: On the basis of the increased expression of GLAST described above, we hypothesized that arundic acid could be neuroprotective by protecting against RGC degeneration in GLAST-deficient mice. Chronic oral treatment of GLAST+/− mice with arundic acid, starting at 22 days of age, lead to a significant prevention of RGC loss compared with vehicle-treated control GLAST+/− mice (Figure 3). The number of cells in the ganglion cell layer (GCL) of GLAST+/− mice subjected to arundic acid treatment was significantly increased (438±8 cells; N=6) relative to GLAST+/− mice without arundic acid treatment (366±11 cells; N=6; Figures 3a and b). Neuroprotective effects of arundic acid cannot be seen with GLAST activation when studied in GLAST−/− mice. Taken together, these results suggested that arundic acid attenuates RGC loss in GLAST+/− mice by specifically facilitating GLAST expression.


Arundic acid attenuates retinal ganglion cell death by increasing glutamate/aspartate transporter expression in a model of normal tension glaucoma.

Yanagisawa M, Aida T, Takeda T, Namekata K, Harada T, Shinagawa R, Tanaka K - Cell Death Dis (2015)

Arundic acid rescues RGC death in GLAST+/− mice by increasing GLAST expression. (a) Hematoxylin and eosin-stained retinal sections from wild-type, GLAST+/− and GLAST−/− mice at P35, with or without arundic acid (10 mg/kg) treatment. The scale bar represents 100 μm and 50 μm in the upper and lower panels, respectively. GCL, ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer. (b) Quantitative analyses of the number of neurons in the GCL following arundic acid treatment. The numbers of neurons in the GCL were counted in retinal sections from one ora serrata through the optic nerve to the other ora serrata (N=6). The data represent the mean±S.E.M.. **P<0.01 as determined by one-way ANOVA with Tukey–Kramer's post hoc analysis
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385923&req=5

fig3: Arundic acid rescues RGC death in GLAST+/− mice by increasing GLAST expression. (a) Hematoxylin and eosin-stained retinal sections from wild-type, GLAST+/− and GLAST−/− mice at P35, with or without arundic acid (10 mg/kg) treatment. The scale bar represents 100 μm and 50 μm in the upper and lower panels, respectively. GCL, ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer. (b) Quantitative analyses of the number of neurons in the GCL following arundic acid treatment. The numbers of neurons in the GCL were counted in retinal sections from one ora serrata through the optic nerve to the other ora serrata (N=6). The data represent the mean±S.E.M.. **P<0.01 as determined by one-way ANOVA with Tukey–Kramer's post hoc analysis
Mentions: On the basis of the increased expression of GLAST described above, we hypothesized that arundic acid could be neuroprotective by protecting against RGC degeneration in GLAST-deficient mice. Chronic oral treatment of GLAST+/− mice with arundic acid, starting at 22 days of age, lead to a significant prevention of RGC loss compared with vehicle-treated control GLAST+/− mice (Figure 3). The number of cells in the ganglion cell layer (GCL) of GLAST+/− mice subjected to arundic acid treatment was significantly increased (438±8 cells; N=6) relative to GLAST+/− mice without arundic acid treatment (366±11 cells; N=6; Figures 3a and b). Neuroprotective effects of arundic acid cannot be seen with GLAST activation when studied in GLAST−/− mice. Taken together, these results suggested that arundic acid attenuates RGC loss in GLAST+/− mice by specifically facilitating GLAST expression.

Bottom Line: 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.Thus, discovering compounds that can enhance EAAT1 expression and activity may be a novel strategy for therapeutic treatment of glaucoma.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.

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.

Show MeSH
Related in: MedlinePlus