Zhao Jianqi, Liu Guangyao, Shi Xiao, Huang Chunhong
School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 30006, Jiangxi, China.
The First Clinical Medical College, Nanchang University, Nanchang 330047, China.
Toxins (Basel). 2025 Jun 4;17(6):280. doi: 10.3390/toxins17060280.
Snakebite is a significant global public health challenge, and the limited application of antivenom has driven the exploration of novel therapies. Combination therapy using small-molecule drugs targeting phospholipases A (PLA2) and metalloproteinases (SVMP) in venom shows great potential. Although Rhamnetin and RXP03 exhibit notable anti-phospholipase and anti-metalloproteinase activities, respectively, their antiophidic potential remains poorly explored. This study aims to evaluate the inhibitory effects of Rhamnetin and RXP03 on snake venom toxicity. Methodologically, we conducted in vitro enzymatic assays to quantify PLA/SVMP inhibition, murine models of envenomation (subcutaneous/intramuscular venom injection) to assess local tissue damage and systemic toxicity, and histopathological/biochemical analyses. In vitro experiments demonstrated that Rhamnetin effectively inhibited PLA activity while RXP03 showed potent suppression of SVMP activity, with their combination significantly reducing venom-induced hemorrhagic activity. In murine models, the combined therapy markedly alleviated venom-triggered muscle toxicity and ameliorated oxidative stress. Furthermore, the combination enhanced motor performance and survival rate in mice, improved serum biochemical parameters, corrected coagulation disorders, and attenuated pathological damage in liver, kidney, heart, and lung tissues. This research demonstrates that dual-targeted therapy against metalloproteinases and phospholipases in snake venom can effectively prevent a series of injuries caused by snake venom. Collectively, the combined application of Rhamnetin and RXP03 exhibits significant inhibitory effects on a variety of venom-induced toxicities, providing pharmacological evidence for the development of antivenom therapies. However, the efficacy validation in this study was limited to murine models, and there is a discrepancy with clinical needs for delayed treatment in real-world envenomation scenarios. Despite these limitations, the findings provide robust preclinical evidence supporting the Rhamnetin-RXP03 combination therapy as a cost-effective, broad-spectrum antivenom strategy. Future studies are required to optimize dosing regimens and evaluate clinical translatability.
蛇咬伤是一项重大的全球公共卫生挑战，抗蛇毒血清的有限应用推动了新型疗法的探索。使用针对毒液中磷脂酶A（PLA2）和金属蛋白酶（SVMP）的小分子药物进行联合治疗显示出巨大潜力。尽管鼠李素和RXP03分别表现出显著的抗磷脂酶和抗金属蛋白酶活性，但其抗蛇毒潜力仍未得到充分探索。本研究旨在评估鼠李素和RXP03对蛇毒毒性的抑制作用。在方法上，我们进行了体外酶活性测定以量化PLA/SVMP抑制作用，采用蛇毒中毒的小鼠模型（皮下/肌肉注射毒液）来评估局部组织损伤和全身毒性，并进行了组织病理学/生化分析。体外实验表明，鼠李素有效抑制PLA活性，而RXP03对SVMP活性有强力抑制作用，二者联合可显著降低毒液诱导的出血活性。在小鼠模型中，联合治疗显著减轻了毒液引发的肌肉毒性并改善了氧化应激。此外，联合治疗提高了小鼠的运动能力和存活率，改善了血清生化参数，纠正了凝血障碍，并减轻了肝脏、肾脏、心脏和肺组织的病理损伤。本研究表明，针对蛇毒中的金属蛋白酶和磷脂酶的双靶点治疗可有效预防一系列由蛇毒引起的损伤。总体而言，鼠李素和RXP03的联合应用对多种毒液诱导的毒性具有显著抑制作用，为抗蛇毒疗法的开发提供了药理学证据。然而，本研究中的疗效验证仅限于小鼠模型，与现实世界中蛇咬伤中毒延迟治疗的临床需求存在差异。尽管存在这些局限性，但研究结果提供了有力的临床前证据，支持鼠李素 - RXP03联合治疗作为一种经济高效的广谱抗蛇毒策略。未来需要进一步研究优化给药方案并评估临床可转化性。
