2025年4月28日出版的《中国药理学报》杂志发表了科学家的一项最新研究成果。来自中国医学科学院的李祎亮课题组的最新研究提出了熊果酸衍生物UA312通过靶向chrna3和grik5改善电离辐射诱导的斑马鱼心脏毒性和神经发育毒性。

在本研究中，课题组研究了UA的优化衍生物UA312对斑马鱼胚胎和幼虫辐射诱导的发育毒性的影响。分别在4、24、48和72 hpf条件下观察胚胎和幼虫的存活率。UA312以3hpf照射，胚胎以6hpf照射。在4 hpf下辐照0.88 Gy/min，然后将胚胎移至新鲜缓冲液。该团队确定了40UA312的μM浓度对斑马鱼胚胎和幼虫是安全的。

该研究团队发现，UA312 （40 μM）处理可以恢复IR诱导的斑马鱼胚胎和幼虫的早期发育不良。转录组学分析显示，暴露于IR抑制了斑马鱼神经发育和心肌细胞功能相关的多种途径，通过评估心脏形态异常、神经递质水平变化和运动行为改变证实了这一点；UA312治疗可以改善这些改变。该研究团队证明了UA312通过靶向chrna3和grik5显著逆转了相关的信号通路。

综上所述，本研究发现了一种很有前景的辐射保护药物UA312，它可以通过靶向chrna3和grik5减轻IR诱导的斑马鱼心脏毒性和神经发育毒性。UA312可作为一种新型的抗人体急性IR损伤的辐射防护剂。

据介绍，电离辐射引起的生物损伤不仅与暴露于组织组分的时间和剂量有关，还与细胞的发育状态有关。目前，氨磷汀是唯一一种用于放射治疗临床适应症的辐射防护剂，但该化合物存在毒性大、半衰期短、对神经系统无保护作用等诸多缺点。熊果酸（UA）是一种天然的五环三萜，具有多种保护作用，包括抗炎、抗癌和抗氧化作用。由于其溶解度和生物利用度差，UA主要与脂质体一起给药。

附：英文原文

Title: Ursolic acid derivative UA312 ameliorates ionizing radiation-induced cardiotoxicity and neurodevelopmental toxicity in zebrafish via targeting chrna3 and grik5

Author: Xu, Fei-fei, Shang, Yue, Wei, Hui-qiang, Zhang, Wei-ying, Wang, Li-xing, Hu, Tong, Zhang, Shu-qin, Li, Yan-li, Shang, Hai-hua, Hou, Wen-bin, Gou, Wen-feng, Fan, Sai-jun, Li, Yi-liang

Issue&Volume: 2025-04-28

Abstract: The biological damage caused by ionizing radiation (IR) depends not only on the time and doses of exposure to tissue components but also on the developmental state of the cells. Currently, amifostine is the only radiation-protective agent used for clinical indications related to radiation therapy, but this compound has multiple drawbacks including high toxicity, short half-life and no protective effect on the nervous system. Ursolic acid (UA), a natural pentacyclic triterpenoid that exhibits multiple protective effects including anti-inflammatory, anticarcinogenic, and antioxidant effects. Due to its poor solubility and bioavailability, UA is mostly administered with liposomes. In this study we investigated the impact of UA312, an optimized derivative of UA, on radiation-induced developmental toxicity in zebrafish embryos and larvae. Embryo and larvae survival were observed at 4, 24, 48, and 72 hpf. UA312 was administered at 3 hpf, while embryos were irradiated with 6Gy of γ-irradiation (dose rate: 0.88Gy/min) at 4 hpf, then the embryos were moved to a fresh buffer. We determined that 40μM of UA312 was a safe concentration for zebrafish embryos and larvae. We found that treatment with UA312 (40μM) restored IR-induced early developmental dysplasia of the zebrafish embryos and larvae. Transcriptomic analysis revealed that exposure to IR inhibited multiple pathways related to neurodevelopment and cardiomyocyte function in zebrafish, which were validated by assessing abnormal cardiac morphology, variations in neurotransmitter levels and alterations in locomotor behavior; and that UA312 treatment ameliorated these alterations. We demonstrated that UA312 treatment significantly reversed the related signaling pathways by targeting chrna3 and grik5. In conclusion, this study identified a promising radioprotective drug, UA312, which alleviates IR-induced cardiotoxicity and neurodevelopmental toxicity in zebrafish by targeting chrna3 and grik5. UA312 may be developed as a novel radioprotective agent against acute IR damage in humans.

DOI: 10.1038/s41401-025-01564-0

Source: https://www.nature.com/articles/s41401-025-01564-0