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

被引：0

作者：

Xu, Fei-fei ^{[1
]}

Shang, Yue ^{[1
]}

Wei, Hui-qiang ^{[1
]}

Zhang, Wei-ying ^{[2
]}

Wang, Li-xing ^{[3
]}

Hu, Tong ^{[3
]}

Zhang, Shu-qin ^{[1
]}

Li, Yan-li ^{[1
]}

Shang, Hai-hua ^{[1
]}

Hou, Wen-bin ^{[1
]}

Gou, Wen-feng ^{[1
]}

Fan, Sai-jun ^{[1
]}

Li, Yi-liang ^{[1
]}

机构：

[1] Chinese Acad Med Sci & Peking Union Med Coll, Tianjin Key Lab Radiat Med & Mol Nucl Med, Inst Radiat Med, Tianjin 300192, Peoples R China

[2] Nankai Univ, Coll Life Sci, State Key Lab Med Chem Biol, Tianjin Key Lab Prot Sci,Dept Biochem & Mol Biol, Tianjin 300071, Peoples R China

[3] Shenyang Pharmaceut Univ, Dept Pharmacol, Shenyang 110016, Peoples R China

来源：

ACTA PHARMACOLOGICA SINICA | 2025年

基金：

中国国家自然科学基金;

关键词：

ionizing radiation; UA312; radioprotective agent; myocardial activity; neurotoxicity; zebrafish; AMIFOSTINE; DAMAGE; GLUTAMATE;

D O I：

10.1038/s41401-025-01564-0

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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 6 Gy of gamma-irradiation (dose rate: 0.88 Gy/min) at 4 hpf, then the embryos were moved to a fresh buffer. We determined that 40 mu M of UA312 was a safe concentration for zebrafish embryos and larvae. We found that treatment with UA312 (40 mu M) 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.

引用

页数：16