PurposeThe aim of this study was to investigate, the neuroprotective effects of a new Gramine derivative named: ITH12657, in a model of retinal excitotoxicity induced by intravitreal injection of NMDA.MethodsAdult Sprague Dawley rats received an intravitreal injection of 100 mM NMDA in their left eye and were treated daily with subcutaneous injections of ITH12657 or vehicle. The best dose–response, therapeutic window study, and optimal treatment duration of ITH12657 were studied. Based on the best survival of Brn3a + RGCs obtained from the above-mentioned studies, the protective effects of ITH12657 were studied in vivo (retinal thickness and full-field Electroretinography), and ex vivo by quantifying the surviving population of Brn3a + RGCs, αRGCs and their subtypes α-ONsRGCs, α-ONtRGCs, and α-OFFRGCs.ResultsAdministration of 10 mg/kg ITH12657, starting 12 h before NMDA injection and dispensed for 3 days, resulted in the best significant protection of Brn3a + RGCs against NMDA-induced excitotoxicity. In vivo, ITH12657-treated rats showed significant preservation of retinal thickness and functional protection against NMDA-induced retinal excitotoxicity. Ex vivo results showed that ITH12657 afforded a significant protection against NMDA-induced excitotoxicity for the populations of Brn3a + RGC, αRGC, and αONs-RGC, but not for the population of αOFF-RGC, while the population of α-ONtRGC was fully resistant to NMDA-induced excitotoxicity.ConclusionSubcutaneous administration of ITH12657 at 10 mg/kg, initiated 12 h before NMDA-induced retinal injury and continued for 3 days, resulted in the best protection of Brn3a + RGCs, αRGC, and αONs-RGC against excitotoxicity-induced RGC death. The population of αOFF-RGCs was extremely sensitive while α-ONtRGCs were fully resistant to NMDA-induced excitotoxicity.

中文翻译：

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禾谷胺衍生物 ITH12657 对 NMDA 诱导的大鼠视网膜兴奋性毒性的神经保护功效评估

目的本研究的目的是研究一种名为 ITH12657 的新型禾谷碱衍生物在玻璃体内注射 NMDA 诱导的视网膜兴奋性毒性模型中的神经保护作用。方法成年 Sprague Dawley 大鼠左眼玻璃体内注射 100 mM NMDA每天皮下注射 ITH12657 或媒介物进行治疗。研究了 ITH12657 的最佳剂量反应、治疗窗研究和最佳治疗持续时间。根据上述研究获得的Brn3a + RGCs的最佳存活率，研究ITH12657的保护作用体内（视网膜厚度和全视野视网膜电图），以及离体通过量化 Brn3a + RGC、αRGC 及其亚型 α-ONsRGC、α-ONtRGC 和 α-OFFRGC 的存活群体。 结果 在 NMDA 注射前 12 小时开始施用 10 mg/kg ITH12657，分配 3 天，结果Brn3a + RGC 对抗 NMDA 诱导的兴奋性毒性的最佳显着保护。体内，ITH12657 治疗的大鼠表现出显着的视网膜厚度保留和针对 NMDA 诱导的视网膜兴奋性毒性的功能保护。离体结果表明，ITH12657对Brn3a + RGC、αRGC和αONs-RGC群体提供了显着的针对NMDA诱导的兴奋性毒性的保护作用，但对αOFF-RGC群体没有作用，而α-ONtRGC群体对NMDA完全耐药结论 在 NMDA 诱导的视网膜损伤前 12 小时开始皮下注射 10 mg/kg ITH12657 并持续 3 天，对 Brn3a + RGC、αRGC 和 αONs-RGC 产生针对兴奋毒性诱导的 RGC 的最佳保护死亡。αOFF-RGCs 群体对 NMDA 诱导的兴奋性毒性极其敏感，而 α-ONtRGCs 完全抵抗。