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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 enhances glutamate uptake activity in Müller cells by an increase in the expression of GLAST mRNA. (a) Chemical structure of arundic acid. (b) In primary cultured Müller cells, glutamate transport is significantly increased after 14 days of treatment with 100 μM arundic acid. *P<0.05 as determined by one-way ANOVA with Tukey–Kramer's post hoc analysis. (c) Representative transport kinetics saturation curves for l-[3,4-3H]-glutamate uptake activity in primary cultured Müller cells treated with 100 μM arundic acid (closed square) or vehicle alone (open rhombus). Each data point corresponds to the mean±S.E.M. of three individual determinations. (d) Effects of arundic acid on GLAST mRNA expression in primary cultured Müller cells. GLAST mRNA expression is significantly increased following 100 μM arundic acid treatment. *P<0.05 as determined by one-way ANOVA with Dunnett's post hoc analysis. (e) Transport kinetics analysis of glutamate uptake activity by EAAT1-expressing HEK293T cells following treatment with 100 μM arundic acid (closed square) or vehicle alone (open rhombus). Data from three independent experiments generated mean values of 44.28±9.22 μM for Km and 2.04±0.51 nmol/mg/min for Vmax, in the absence of arundic acid, versus 54.96±18.57 μM for Km and 2.13±0.53 nmol/mg/min for Vmax, in the presence of arundic acid treatment. Thus, arundic acid had no effect on the kinetic properties of glutamate uptake by EAAT1-expressing HEK293T cells
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fig1: Arundic acid enhances glutamate uptake activity in Müller cells by an increase in the expression of GLAST mRNA. (a) Chemical structure of arundic acid. (b) In primary cultured Müller cells, glutamate transport is significantly increased after 14 days of treatment with 100 μM arundic acid. *P<0.05 as determined by one-way ANOVA with Tukey–Kramer's post hoc analysis. (c) Representative transport kinetics saturation curves for l-[3,4-3H]-glutamate uptake activity in primary cultured Müller cells treated with 100 μM arundic acid (closed square) or vehicle alone (open rhombus). Each data point corresponds to the mean±S.E.M. of three individual determinations. (d) Effects of arundic acid on GLAST mRNA expression in primary cultured Müller cells. GLAST mRNA expression is significantly increased following 100 μM arundic acid treatment. *P<0.05 as determined by one-way ANOVA with Dunnett's post hoc analysis. (e) Transport kinetics analysis of glutamate uptake activity by EAAT1-expressing HEK293T cells following treatment with 100 μM arundic acid (closed square) or vehicle alone (open rhombus). Data from three independent experiments generated mean values of 44.28±9.22 μM for Km and 2.04±0.51 nmol/mg/min for Vmax, in the absence of arundic acid, versus 54.96±18.57 μM for Km and 2.13±0.53 nmol/mg/min for Vmax, in the presence of arundic acid treatment. Thus, arundic acid had no effect on the kinetic properties of glutamate uptake by EAAT1-expressing HEK293T cells

Mentions: Arundic acid ((2R)-2-propyloctanoic acid, ONO-2506; Figure 1a) was originally discovered through screening for an agent to inhibit synthesis of S100β in astrocytes.17 A previous study showed that arundic acid administration markedly ameliorates brain damage in a transient middle cerebral artery occlusion rat model.18 These beneficial effects of arundic acid are associated with marked suppression of delayed extracellular glutamate accumulation in the peri-infarct areas.19 In searching for a possible mechanism of action, we hypothesized that arundic acid neuroprotection involves upregulation of EAAT1/GLAST.


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 enhances glutamate uptake activity in Müller cells by an increase in the expression of GLAST mRNA. (a) Chemical structure of arundic acid. (b) In primary cultured Müller cells, glutamate transport is significantly increased after 14 days of treatment with 100 μM arundic acid. *P<0.05 as determined by one-way ANOVA with Tukey–Kramer's post hoc analysis. (c) Representative transport kinetics saturation curves for l-[3,4-3H]-glutamate uptake activity in primary cultured Müller cells treated with 100 μM arundic acid (closed square) or vehicle alone (open rhombus). Each data point corresponds to the mean±S.E.M. of three individual determinations. (d) Effects of arundic acid on GLAST mRNA expression in primary cultured Müller cells. GLAST mRNA expression is significantly increased following 100 μM arundic acid treatment. *P<0.05 as determined by one-way ANOVA with Dunnett's post hoc analysis. (e) Transport kinetics analysis of glutamate uptake activity by EAAT1-expressing HEK293T cells following treatment with 100 μM arundic acid (closed square) or vehicle alone (open rhombus). Data from three independent experiments generated mean values of 44.28±9.22 μM for Km and 2.04±0.51 nmol/mg/min for Vmax, in the absence of arundic acid, versus 54.96±18.57 μM for Km and 2.13±0.53 nmol/mg/min for Vmax, in the presence of arundic acid treatment. Thus, arundic acid had no effect on the kinetic properties of glutamate uptake by EAAT1-expressing HEK293T cells
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: Arundic acid enhances glutamate uptake activity in Müller cells by an increase in the expression of GLAST mRNA. (a) Chemical structure of arundic acid. (b) In primary cultured Müller cells, glutamate transport is significantly increased after 14 days of treatment with 100 μM arundic acid. *P<0.05 as determined by one-way ANOVA with Tukey–Kramer's post hoc analysis. (c) Representative transport kinetics saturation curves for l-[3,4-3H]-glutamate uptake activity in primary cultured Müller cells treated with 100 μM arundic acid (closed square) or vehicle alone (open rhombus). Each data point corresponds to the mean±S.E.M. of three individual determinations. (d) Effects of arundic acid on GLAST mRNA expression in primary cultured Müller cells. GLAST mRNA expression is significantly increased following 100 μM arundic acid treatment. *P<0.05 as determined by one-way ANOVA with Dunnett's post hoc analysis. (e) Transport kinetics analysis of glutamate uptake activity by EAAT1-expressing HEK293T cells following treatment with 100 μM arundic acid (closed square) or vehicle alone (open rhombus). Data from three independent experiments generated mean values of 44.28±9.22 μM for Km and 2.04±0.51 nmol/mg/min for Vmax, in the absence of arundic acid, versus 54.96±18.57 μM for Km and 2.13±0.53 nmol/mg/min for Vmax, in the presence of arundic acid treatment. Thus, arundic acid had no effect on the kinetic properties of glutamate uptake by EAAT1-expressing HEK293T cells
Mentions: Arundic acid ((2R)-2-propyloctanoic acid, ONO-2506; Figure 1a) was originally discovered through screening for an agent to inhibit synthesis of S100β in astrocytes.17 A previous study showed that arundic acid administration markedly ameliorates brain damage in a transient middle cerebral artery occlusion rat model.18 These beneficial effects of arundic acid are associated with marked suppression of delayed extracellular glutamate accumulation in the peri-infarct areas.19 In searching for a possible mechanism of action, we hypothesized that arundic acid neuroprotection involves upregulation of EAAT1/GLAST.

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