Evaluation of the neuroprotective efficacy of the gramine derivative ITH12657 against NMDA-induced excitotoxicity in the rat retina

IF 2.1 4区医学 Q1 ANATOMY & MORPHOLOGY

Frontiers in Neuroanatomy Pub Date : 2024-02-13 DOI:10.3389/fnana.2024.1335176

Johnny Di Pierdomenico, Alejandro Gallego-Ortega, María Norte-Muñoz, Beatriz Vidal-Villegas, Isaac Bravo, María Boluda-Ruiz, Jose Manuel Bernal-Garro, Iván Fernandez-Bueno, Jose Carlos Pastor-Jimeno, María Paz Villegas-Pérez, Marcelino Avilés-Trigueros, Cristobal de los Ríos, Manuel Vidal-Sanz

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Abstract

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.

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评估禾本科衍生物 ITH12657 对大鼠视网膜 NMDA 诱导的兴奋毒性的神经保护功效

目的本研究旨在探讨一种名为 ITH12657 的新型禾本科衍生物在 NMDA 玻璃体内注射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 大鼠左眼接受 100 mM NMDA 玻璃体内注射，每天皮下注射 ITH12657 或药物治疗。研究了 ITH12657 的最佳剂量反应、治疗窗口研究和最佳治疗时间。根据上述研究得出的 Brn3a + RGCs 的最佳存活率，研究了 ITH12657 在体内（视网膜厚度和全视场视网膜电图）和体外（通过量化 Brn3a + RGCs、αRGCs 及其亚型 α-ONsRGCs、α-ONtRGCs 和 α-OFFRGCs）的保护作用。结果在注射 NMDA 前 12 小时开始给药 10 mg/kg ITH12657 并连续给药 3 天后，Brn3a + RGCs 对 NMDA 诱导的兴奋毒性的保护效果最为显著。在体内，经 ITH12657 处理的大鼠在 NMDA 诱导的视网膜兴奋毒性面前表现出明显的视网膜厚度保护和功能保护。体内外结果显示，ITH12657 能显著保护 Brn3a + RGC、αRGC 和 αONs-RGC 群体免受 NMDA 诱导的兴奋毒性，但不能保护 αOFF-RGC 群体免受 NMDA 诱导的兴奋毒性，而 α-ONtRGC 群体则能完全抵抗 NMDA 诱导的兴奋毒性。结论在NMDA诱导的视网膜损伤前12小时开始皮下注射10毫克/千克的ITH12657，并持续3天，能最好地保护Brn3a + RGC、αRGC和αONs-RGC免受兴奋毒性诱导的RGC死亡。αOFF-RGCs群体对NMDA诱导的兴奋毒性极为敏感，而α-ONtRGCs则完全耐受NMDA诱导的兴奋毒性。

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来源期刊

Frontiers in Neuroanatomy ANATOMY & MORPHOLOGY-NEUROSCIENCES

CiteScore

4.70

自引率

3.40%

发文量

122

审稿时长

>12 weeks

期刊介绍： Frontiers in Neuroanatomy publishes rigorously peer-reviewed research revealing important aspects of the anatomical organization of all nervous systems across all species. Specialty Chief Editor Javier DeFelipe at the Cajal Institute (CSIC) is supported by an outstanding Editorial Board of international experts. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide.