Yanagisawa M, Aida T, Takeda T, Namekata K, Harada T, Shinagawa R, Tanaka K
Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Visual Research Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
Cell Death Dis. 2015 Mar 19;6(3):e1693. doi: 10.1038/cddis.2015.45.
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.
青光眼是全球第二大致盲原因，其特征是由于视网膜神经节细胞（RGCs）及其轴突的逐渐丧失而导致视力逐渐受损。谷氨酸兴奋性毒性被认为是青光眼RGC死亡的一种机制。与这一观点一致，我们之前报道谷氨酸/天冬氨酸转运体（GLAST）缺陷小鼠表现出与青光眼相似的视神经变性。因此，上调GLAST的药物可能对青光眼的神经保护有用。虽然已知许多化合物可增加另一种胶质谷氨酸转运体EAAT2/GLT1的表达，但很少有化合物能增加GLAST的表达。阿仑酸是一种胶质调节剂，可通过减轻细胞外谷氨酸的增加来改善迟发性缺血性脑损伤。我们假设阿仑酸的神经保护作用涉及GLAST的上调。为了验证这一假设，我们研究了阿仑酸对GLAST表达和谷氨酸摄取的影响。我们发现阿仑酸在体外和体内均可诱导GLAST表达。此外，阿仑酸治疗通过上调杂合子（GLAST(+/-)）小鼠的GLAST来预防RGC死亡。此外，阿仑酸可刺激人神经胶质母细胞瘤细胞中人类GLAST同源物EAAT1的表达。因此，发现能够增强EAAT1表达和活性的化合物可能是治疗青光眼的一种新策略。
