Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, 1638 NW 10Th Ave, Miami, FL, 33136, USA.
Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
Sci Rep. 2023 Oct 27;13(1):18471. doi: 10.1038/s41598-023-45855-0.
NMDA excitotoxicity, as a part of glutamate excitotoxicity, has been proposed to contribute significantly to many retinal diseases. Therefore, understanding mechanisms of NMDA excitotoxicity will provide further insight into the mechanisms of many retinal diseases. To study mechanisms of NMDA excitotoxicity in vivo, we used an animal model in which NMDA (20 mM, 2 µL) was injected into the vitreous of mice. We also used high-throughput expression profiling, various animals with reduced expression of target genes, and animals treated with the oral iron chelator deferiprone. We found that the expression of many genes involved in inflammation, programmed cell death, free radical production, oxidative stress, and iron and calcium signaling was significantly increased 24 h after NMDA treatment. Meanwhile, decreased activity of the pro-inflammatory TNF signaling cascade and decreased levels of ferrous iron (Fe, required for free radical production) led to significant neuroprotection in NMDA-treated retinas. Since increased TNF signaling activity and high Fe levels trigger regulated necrosis, which, in turn, lead to inflammation, we proposed an important role in NMDA excitotoxicity of a positive feedback loop in which regulated necrosis promotes inflammation, which subsequently triggers regulated necrosis.
NMDA 兴奋性毒性作为谷氨酸兴奋性毒性的一部分，被认为对许多视网膜疾病有重要贡献。因此，了解 NMDA 兴奋性毒性的机制将为许多视网膜疾病的机制提供进一步的认识。为了在体内研究 NMDA 兴奋性毒性的机制，我们使用了一种动物模型，其中将 NMDA（20mM，2µL）注入小鼠的玻璃体。我们还使用了高通量表达谱分析、各种靶基因表达减少的动物和口服铁螯合剂地拉罗司处理的动物。我们发现，NMDA 处理后 24 小时，许多参与炎症、程序性细胞死亡、自由基生成、氧化应激和铁钙信号的基因的表达显著增加。同时，促炎 TNF 信号级联反应的活性降低和亚铁（Fe，自由基生成所需）水平降低导致 NMDA 处理的视网膜中显著的神经保护作用。由于增加的 TNF 信号活性和高 Fe 水平引发调节性细胞坏死，而调节性细胞坏死又导致炎症，因此我们提出了一个重要的假设，即在 NMDA 兴奋性毒性中，一个正反馈环起着重要作用，其中调节性细胞坏死促进炎症，进而引发调节性细胞坏死。
