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禾本科碱衍生物ITH12657对大鼠视网膜中N-甲基-D-天冬氨酸（NMDA）诱导的兴奋性毒性的神经保护作用评估。

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

作者信息

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

机构信息

Departamento de Oftalmología, Universidad de Murcia e IMIB-Arrixaca, Murcia, Spain.

Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Madrid, Spain.

出版信息

Front Neuroanat. 2024 Feb 13;18:1335176. doi: 10.3389/fnana.2024.1335176. eCollection 2024.

DOI:10.3389/fnana.2024.1335176
PMID:38415017
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10898249/
Abstract

PURPOSE

The 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.

METHODS

Adult 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 (retinal thickness and full-field Electroretinography), and by quantifying the surviving population of Brn3a + RGCs, αRGCs and their subtypes α-ONsRGCs, α-ONtRGCs, and α-OFFRGCs.

RESULTS

Administration 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. , ITH12657-treated rats showed significant preservation of retinal thickness and functional protection against NMDA-induced retinal excitotoxicity. 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.

CONCLUSION

Subcutaneous 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.

摘要

目的

本研究旨在探讨一种名为ITH12657的新型禾本科碱衍生物在玻璃体内注射N-甲基-D-天冬氨酸（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，并每天皮下注射ITH12657或赋形剂进行治疗。研究了ITH12657的最佳剂量反应、治疗窗口以及最佳治疗持续时间。基于上述研究中获得的Brn3a +视网膜神经节细胞（RGCs）的最佳存活率，通过检测视网膜厚度和全视野视网膜电图，并对Brn3a + RGCs、αRGCs及其亚型α-ONsRGCs、α-ONtRGCs和α-OFFRGCs的存活细胞数量进行定量，研究ITH12657的保护作用。

结果

在NMDA注射前12小时开始给予10 mg/kg ITH12657，并持续给药3天，可对Brn3a + RGCs提供最佳的显著保护，使其免受NMDA诱导的兴奋性毒性。ITH12657治疗的大鼠视网膜厚度得到显著保留，对NMDA诱导的视网膜兴奋性毒性具有功能保护作用。结果表明，ITH12657对Brn3a + RGC、αRGC和αONs-RGC群体免受NMDA诱导的兴奋性毒性具有显著保护作用，但对αOFF-RGC群体无保护作用，而α-ONtRGC群体对NMDA诱导的兴奋性毒性完全耐受。

结论

在NMDA诱导的视网膜损伤前12小时开始皮下给予10 mg/kg ITH12657，并持续3天，可对Brn3a + RGCs、αRGC和αONs-RGC提供最佳保护，使其免受兴奋性毒性诱导的RGC死亡。αOFF-RGC群体极其敏感，而α-ONtRGCs对NMDA诱导的兴奋性毒性完全耐受。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db8d/10898249/c46c4f135660/fnana-18-1335176-g012.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db8d/10898249/6cfe5341333a/fnana-18-1335176-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db8d/10898249/b62f220cd756/fnana-18-1335176-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db8d/10898249/5468c527df4d/fnana-18-1335176-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db8d/10898249/b998722c833a/fnana-18-1335176-g010.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db8d/10898249/c46c4f135660/fnana-18-1335176-g012.jpg

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