Systemic Administration of an Apelin Receptor Agonist Prevents NMDA-Induced Loss of Retinal Neuronal Cells in Mice
Systemic Administration of an Apelin Receptor Agonist Prevents NMDA-Induced Loss of Retinal Neuronal Cells in Mice
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DOI：
10.1007/s11064-019-02948-5
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发表时间：
2020-01
影响因子：
4.4
通讯作者：
Fumiya Shibagaki;Yuki Ishimaru;A. Sumino;A. Yamamuro;Y. Yoshioka;S. Maeda
中科院分区：
文献类型：
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作者：
Fumiya Shibagaki;Yuki Ishimaru;A. Sumino;A. Yamamuro;Y. Yoshioka;S. Maeda
通过N-甲基-d-天冬氨酸（NMDA）受体的谷氨酸兴奋性毒性被认为是涉及视网膜疾病如糖尿病视网膜病变和急性闭角型青光眼中视网膜神经元细胞（包括视网膜神经节细胞）损失的因素。在本文中，我们报告了全身施用ML 233（一种apelin受体激动剂）对由玻璃体内注射NMDA诱导的视网膜神经元细胞死亡的保护作用。腹腔注射ML 233可防止NMDA诱导的暗视阈值反应（STR）幅度的降低，这主要反映了视网膜神经节细胞的活性。免疫组织化学染色显示，ML 233抑制NMDA诱导的视网膜神经节细胞和无长突细胞的丢失。此外，ML 233抑制玻璃体内注射NMDA后视网膜中血影蛋白αII（一种通过钙蛋白酶激活裂解的神经元细胞骨架蛋白）的分解。ML 233的腹膜内给药增加了视网膜中Akt的磷酸化，Akt是神经元中的一种有效的抗凋亡蛋白。此外，口服ML 233可防止NMDA引起的STR振幅降低和视网膜神经节细胞丢失。这些结果表明，ML 233的全身给药保护视网膜神经元免受NMDA受体介导的兴奋性毒性，并且激活apelin受体的药物可能是预防这些视网膜疾病进展的新候选药物。
Glutamate excitotoxicity via N-methyl-d-aspartate (NMDA) receptors is thought to be a factor involved in the loss of retinal neuronal cells, including retinal ganglion cells, in retinal diseases such as diabetic retinopathy and acute angle closure glaucoma. Herein we report the protective effect of systemic administration of ML233, an apelin receptor agonist, against retinal neuronal cell death induced by the intravitreal injection of NMDA into mice. Intraperitoneal administration of ML233 prevented the NMDA-induced reduction in the amplitude of scotopic threshold responses (STR), which mainly reflect the activity of the retinal ganglion cells. Immunohistochemical staining showed that ML233 inhibited the NMDA-induced loss of retinal ganglion cells and amacrine cells. In addition, ML233 suppressed the breakdown of spectrin αII, a neuronal cytoskeleton protein cleaved by calpain activation, in the retina after intravitreal injection of NMDA. Intraperitoneal administration of ML233 increased the phosphorylation of Akt, a potent anti-apoptotic protein in neurons, in the retina. Furthermore, oral administration of ML233 protected against the decrease in the STR amplitudes and the loss of retinal ganglion cells caused by NMDA. These results suggest that systemic administration of ML233 protected retinal neurons from NMDA receptor-mediated excitotoxicity and that drugs activating the apelin receptor may be a new candidate for preventing the progression of these retinal diseases.