Mohamad Mohamad Haiqal Nizar, Abu Izuddin Fahmy, Fazel Muhammad Fattah, Agarwal Renu, Iezhitsa Igor, Juliana Norsham, Mellor Ian R, Franzyk Henrik
Institute of Medical Science Technology, Universiti Kuala Lumpur, Kuala Lumpur, Malaysia.
School of Medicine, International Medical University, Kuala Lumpur, Malaysia.
Front Pharmacol. 2021 Dec 14;12:798794. doi: 10.3389/fphar.2021.798794. eCollection 2021.
N-methyl-D-aspartate receptor (NMDAR) overstimulation is known to mediate neurodegeneration, and hence represents a relevant therapeutic target for neurodegenerative disorders including glaucoma. This study examined the neuroprotective effects of philanthotoxin (PhTX)-343 against NMDA-induced retinal injury in rats. Male Sprague Dawley rats were divided into three groups; group 1 received phosphate buffer saline as the negative control, group 2 was injected with NMDA (160 nM) to induce retinal excitotoxic injury, and group 3 was pre-treated with PhTX-343 (160 nM) 24 h before NMDA exposure. All treatments were given intravitreally and bilaterally. Seven days post-treatment, rats were subjected to visual behaviour assessments using open field and colour recognition tests. Rats were then euthanized, and the retinas were harvested and subjected to haematoxylin and eosin (H&E) staining for morphometric analysis and 3-nitrotyrosine (3-NT) ELISA protocol as the nitrosative stress biomarker. PhTX-343 treatment prior to NMDA exposure improved the ability of rats to recognize visual cues and preserved visual functions (i.e., recognition of objects with different colours). Morphological examination of retinal tissues showed that the fractional ganglion cell layer thickness within the inner retina (IR) in the PhTX-343 treated group was greater by 1.28-fold as compared to NMDA-treated rats ( < 0.05) and was comparable to control rats ( > 0.05). Additionally, the number of retinal cell nuclei/100 μm in IR for the PhTX-343-treated group was greater by 1.82-fold compared to NMDA-treated rats ( < 0.05) and was comparable to control group ( > 0.05). PhTX-343 also reduced the retinal 3-NT levels by 1.74-fold compared to NMDA-treated rats ( < 0.05). In conclusion, PhTX-343 pretreatment protects against NMDA-induced retinal morphological changes and visual impairment by suppressing nitrosative stress as reflected by the reduced retinal 3-NT level.
已知N-甲基-D-天冬氨酸受体（NMDAR）过度刺激会介导神经退行性变，因此是包括青光眼在内的神经退行性疾病的一个相关治疗靶点。本研究检测了 philanthotoxin（PhTX）-343对NMDA诱导的大鼠视网膜损伤的神经保护作用。雄性Sprague Dawley大鼠分为三组；第1组接受磷酸盐缓冲盐水作为阴性对照，第2组注射NMDA（160 nM）以诱导视网膜兴奋性毒性损伤，第3组在暴露于NMDA前24小时用PhTX-343（160 nM）进行预处理。所有处理均通过玻璃体双侧注射给予。处理后7天，使用旷场和颜色识别测试对大鼠进行视觉行为评估。然后对大鼠实施安乐死，摘取视网膜，进行苏木精和伊红（H&E）染色以进行形态计量分析，并采用3-硝基酪氨酸（3-NT）ELISA法作为亚硝化应激生物标志物。在暴露于NMDA之前用PhTX-343处理可提高大鼠识别视觉线索的能力并保留视觉功能（即识别不同颜色的物体）。视网膜组织的形态学检查显示，与NMDA处理的大鼠相比，PhTX-343处理组的视网膜内层（IR）内神经节细胞层厚度分数增加了1.28倍（P<0.05），与对照组相当（P>0.05）。此外，与NMDA处理的大鼠相比，PhTX-343处理组IR中每100μm视网膜细胞核数量增加了1.82倍（P<0.05），与对照组相当（P>0.05）。与NMDA处理的大鼠相比，PhTX-343还使视网膜3-NT水平降低了1.74倍（P<0.05）。总之，PhTX-343预处理可通过抑制视网膜3-NT水平降低所反映的亚硝化应激，预防NMDA诱导的视网膜形态变化和视觉损伤。
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