Koriyama Yoshiki, Tanii Hideji, Ohno Mamoru, Kimura Takahito, Kato Satoru
Department of Molecular Neurobiology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan.
Brain Res. 2008 Nov 13;1240:196-203. doi: 10.1016/j.brainres.2008.09.021. Epub 2008 Sep 18.
N-beta-Alanyl-5-S-glutathionyl-3,4-dihydroxyphenylalanine (5-S-GAD), an antibacterial substance isolated from flesh fly, has been described as having multipotential biological activities toward various tissues. However, there has been no report testing its action on neural cells. In the present study, we investigate whether 5-S-GAD is neurotoxic or neuroprotective to the rat retina. 5-S-GAD at high doses (more than 200 pmol) induced apoptosis of retinal neurons 7 days after intraocular injection. 5-S-GAD at low doses (2-20 pmol) significantly attenuated the loss of retinal ganglion cells (RGCs) and the thinning of inner retina induced by NMDA in a dose-dependent manner. To understand the protective mechanism of 5-S-GAD, we investigated the influence of 5-S-GAD on the cell survival molecules, phospho-Akt and Bcl-2. 5-S-GAD (2-20 pmol) rapidly increased phospho-Akt expression 1-7 days and Bcl-2 expression 3-7 days after injection. The cellular localization of this increase was both in bipolar cells and RGCs. This neurosurvival effect of 5-S-GAD was further tested using another model of optic nerve injury. 5-S-GAD significantly blocked the apoptosis of RGCs 7 days after optic nerve crush. These results show that 5-S-GAD (2-20 pmol) protects against the NMDA- and optic nerve crush-induced apoptosis of RGCs. The neuroprotective action of 5-S-GAD in the retina might be mediated by the cell survival phospho-Akt/Bcl-2 system and offers a therapeutic option to rescue RGCs from various types of excitotoxic disease, such as glaucoma.
N-β-丙氨酰基-5-S-谷胱甘肽基-3,4-二羟基苯丙氨酸（5-S-GAD）是一种从麻蝇中分离出的抗菌物质，已被描述为对各种组织具有多种潜在生物活性。然而，尚无关于其对神经细胞作用的报道。在本研究中，我们调查了5-S-GAD对大鼠视网膜是具有神经毒性还是神经保护作用。眼内注射后7天，高剂量（超过200 pmol）的5-S-GAD诱导视网膜神经元凋亡。低剂量（2-20 pmol）的5-S-GAD以剂量依赖的方式显著减轻了NMDA诱导的视网膜神经节细胞（RGCs）损失和视网膜内层变薄。为了解释5-S-GAD的保护机制，我们研究了5-S-GAD对细胞存活分子磷酸化Akt和Bcl-2的影响。注射后1-7天，5-S-GAD（2-20 pmol）迅速增加磷酸化Akt表达，3-7天增加Bcl-2表达。这种增加在双极细胞和RGCs中均有细胞定位。使用另一种视神经损伤模型进一步测试了5-S-GAD的这种神经存活作用。视神经挤压7天后，5-S-GAD显著阻断了RGCs的凋亡。这些结果表明，5-S-GAD（2-20 pmol）可防止NMDA和视神经挤压诱导的RGCs凋亡。5-S-GAD在视网膜中的神经保护作用可能由细胞存活磷酸化Akt/Bcl-2系统介导，并为从各种类型的兴奋性毒性疾病（如青光眼）中挽救RGCs提供了一种治疗选择。
