Pundkar Chetan, Thanapaul Rex Jeya Rajkumar Samdavid, Govindarajulu Manoj, Phuyal Gaurav, Long Joseph B, Arun Peethambaran
Blast-Induced Neurotrauma Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
National Research Council (NRC) Research Associateship Programs, National Academies of Sciences, Engineering, and Medicine, Washington, DC 20001, USA.
Neurol Int. 2025 Mar 17;17(3):42. doi: 10.3390/neurolint17030042.
BACKGROUND/OBJECTIVES: Blast-induced traumatic ocular injuries (bTOI) pose a significant risk to military and civilian populations, often leading to visual impairment or blindness. Retina, the innermost layer of ocular tissue consisting of photoreceptor and glial cells, is highly susceptible to blast injuries. Despite its prevalence, the molecular mechanisms underlying retinal damage following bTOI remain poorly understood, hindering the development of targeted therapies. Melatonin, a neuroprotective indoleamine with antioxidant, anti-inflammatory, and circadian regulatory properties, is synthesized in the retina and plays a crucial role in retinal health. Similarly, retina-specific genes, such as , , and RPE65, are essential for photoreceptor function, visual signaling, and the visual cycle. However, their responses to blast exposure have not been thoroughly investigated.
In this study, we utilized a ferret model of bTOI to evaluate the temporal expression of melatonin-synthesizing enzymes, such as tryptophan hydroxylase 1 and 2 (1 and 2), Aralkylamine N-acetyltransferase (), and Acetylserotonin-O-methyltransferase (), and retina-specific genes (, ) and retinal pigment epithelium-specific 65 kDa protein () at 4 h, 24 h, 7 days, and 28 days post-blast. Ferrets were exposed to tightly coupled blast overpressure waves using an advanced blast simulator, and retinal tissues were collected for quantitative polymerase chain reaction (qPCR) analysis.
The results revealed dynamic and multiphasic transcriptional responses. 1 and 2 exhibited significant upregulation at 24 h, followed by downregulation at 28 days, indicating blast-induced dysregulation of tryptophan metabolism, including melatonin synthesis. Similarly, and showed acute downregulation post-blast, with late-phase disruptions. expression increased at 24 h but declined at 28 days, while and demonstrated early upregulation followed by downregulation, reflecting potential disruptions in circadian regulation and the visual cycle.
These findings highlight the complex regulatory mechanisms underlying retinal responses to bTOI, involving neuroinflammation, oxidative stress, and disruptions in melatonin synthesis and photoreceptor cell functions. The results emphasize the therapeutic potential of melatonin in mitigating retinal damage and preserving visual function.
背景/目的：爆炸所致创伤性眼损伤（bTOI）对军事人员和平民构成重大风险，常导致视力损害或失明。视网膜是眼组织的最内层，由光感受器和神经胶质细胞组成，极易受到爆炸损伤。尽管其很常见，但bTOI后视网膜损伤的分子机制仍知之甚少，这阻碍了靶向治疗的发展。褪黑素是一种具有抗氧化、抗炎和昼夜节律调节特性的神经保护性吲哚胺，在视网膜中合成，对视网膜健康起着关键作用。同样，视网膜特异性基因，如[此处原文缺失具体基因名称]、[此处原文缺失具体基因名称]和视网膜色素上皮特异性65 kDa蛋白（RPE65），对光感受器功能、视觉信号传导和视觉循环至关重要。然而，它们对爆炸暴露的反应尚未得到充分研究。
在本研究中，我们利用bTOI雪貂模型评估爆炸后4小时、24小时、7天和28天褪黑素合成酶（如色氨酸羟化酶1和2（TPH1和TPH2）、芳烷基胺N-乙酰转移酶（AANAT）和乙酰血清素-O-甲基转移酶（ASMT））、视网膜特异性基因（[此处原文缺失具体基因名称]、[此处原文缺失具体基因名称]）和视网膜色素上皮特异性65 kDa蛋白（RPE65）的时间表达。使用先进的爆炸模拟器使雪貂暴露于紧密耦合的爆炸超压波中，并收集视网膜组织进行定量聚合酶链反应（qPCR）分析。
结果显示出动态和多相的转录反应。TPH1和TPH2在24小时时显著上调，随后在28天时下调，表明爆炸诱导色氨酸代谢失调，包括褪黑素合成。同样，[此处原文缺失具体基因名称]和[此处原文缺失具体基因名称]在爆炸后急性下调，后期出现紊乱。AANAT表达在24小时时增加，但在28天时下降，而[此处原文缺失具体基因名称]和RPE65显示早期上调随后下调，反映出昼夜节律调节和视觉循环可能受到破坏。
这些发现突出了视网膜对bTOI反应的复杂调节机制，涉及神经炎症、氧化应激以及褪黑素合成和光感受器细胞功能的破坏。结果强调了褪黑素在减轻视网膜损伤和保护视觉功能方面的治疗潜力。
