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Systemic Administration of an Apelin Receptor Agonist Prevents NMDA-Induced Loss of Retinal Neuronal Cells in Mice.
Neurochemical Research ( IF 4.4 ) Pub Date : 2020-01-01 , DOI: 10.1007/s11064-019-02948-5
Fumiya Shibagaki 1 , Yuki Ishimaru 1 , Akihide Sumino 1, 2 , Akiko Yamamuro 1 , Yasuhiro Yoshioka 1 , Sadaaki Maeda 1
Affiliation  

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.

中文翻译:

Apelin受体激动剂的全身给药可防止NMDA诱导的小鼠视网膜神经元细胞丢失。

通过N-甲基-D-天冬氨酸(NMDA)受体引起的谷氨酸兴奋性毒性被认为是视网膜疾病如糖尿病性视网膜病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)丧失的一个因素。本文中,我们报告全身性给予apelin受体激动剂ML233对由玻璃体内注射NMDA诱导的小鼠引起的视网膜神经元细胞死亡的保护作用。腹膜内给予ML233可防止NMDA诱导的暗疮阈值反应(STR)幅度降低,这主要反映了视网膜神经节细胞的活性。免疫组织化学染色表明,ML233抑制了NMDA诱导的视网膜神经节细胞和无长突细胞的丢失。此外,ML233抑制了血影蛋白αII的分解,玻璃体内注射NMDA后,视网膜中通过钙蛋白酶激活而裂解的神经元细胞骨架蛋白。腹膜内给予ML233可增加视网膜中神经元中一种有效的抗凋亡蛋白Akt的磷酸化。此外,口服ML233可以防止STR振幅的降低和由NMDA引起的视网膜神经节细胞的丢失。这些结果表明,ML233的全身给药可保护视网膜神经元免受NMDA受体介导的兴奋性毒性作用,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。视网膜神经元中一种有效的抗凋亡蛋白。此外,口服ML233可以防止STR振幅的降低和由NMDA引起的视网膜神经节细胞的丢失。这些结果表明,ML233的全身给药可保护视网膜神经元免受NMDA受体介导的兴奋性毒性作用,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。视网膜神经元中一种有效的抗凋亡蛋白。此外,口服ML233可以防止STR振幅的降低和由NMDA引起的视网膜神经节细胞的丢失。这些结果表明,ML233的全身给药可保护视网膜神经元免受NMDA受体介导的兴奋性毒性作用,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。
更新日期:2020-01-01
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