Preliminary safety assessment of oridonin in zebrafish

• Published in: Pharmaceutical biology Vol. 57; no. 1; pp. 632 - 640
• Main Authors: Tian, Lili, Sheng, Donglai, Li, Qiushuang, Guo, Chenxu, Zhu, Guofu
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 01.01.2019; Taylor & Francis Ltd; Taylor & Francis Group
• Subjects: Angiogenesis; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - toxicity; Antitumor activity; Biology; Body length; Chinese medicine; Danio rerio; Developmental stages; Diabetic retinopathy; Diterpenes, Kaurane - administration & dosage; Diterpenes, Kaurane - toxicity; Drug dosages; embryonic development effects; Embryos; Fertilization; Gene expression; Gene Expression Regulation, Developmental - drug effects; Growth and Development - drug effects; Hatching; Heart Rate; Isodon rubescens; Laboratories; Larva - drug effects; medicinal plant; Metastasis; Pharmacy; Safety; Swimming; swimming speed; Vascular endothelial growth factor; Vascular endothelial growth factor receptors; Vascular Endothelial Growth Factors - drug effects; VEGFR3; Zebrafish; swimming speed; VEGFR3; medicinal plant; embryonic development effects; body length
• ISSN: 1388-0209; 1744-5116
• DOI: 10.1080/13880209.2019.1662457

Context: Oridonin, isolated from the leaves of Isodon rubescens (Hemsl.) H.Hara (Lamiaceae), has good antitumor activity. However, its safety in vivo is still unclear. Objective: To investigate the preliminary safety of oridonin in zebrafish. Materials and methods: Embryo, larvae and adult zebrafish (n = 40) were used. Low, medium and high oridonin concentrations (100, 200 and 400 mg/L for embryo; 150, 300 and 600 mg/L for larvae; 200, 400 and 800 mg/L for adult zebrafish) and blank samples were administered. At specific stages of zebrafish development, spontaneous movement, heartbeat, hatching rate, etc., were recorded to assess the developmental effects of oridonin. VEGFA, VEGFR2 and VEGFR3 gene expression were also examined. Results: Low-dose oridonin increased spontaneous movement and hatching rate with median effective doses (ED 50 ) of 115.17 mg/L at 24 h post-fertilization (hpf) and 188.59 mg/L at 54 hpf, but these values decreased at high doses with half maximal inhibitory concentrations (IC 50 ) of 209.11 and 607.84 mg/L. Oridonin decreased heartbeat with IC 50 of 285.76 mg/L at 48 hpf, and induced malformation at 120 hpf with half maximal effective concentration (EC 50 ) of 411.94 mg/L. Oridonin also decreased body length with IC 50 of 324.78 mg/L at 144 hpf, and increased swimming speed with ED 50 of 190.98 mg/L at 120 hpf. The effects of oridonin on zebrafish embryo development may be attributed to the downregulation of VEGFR3 gene expression. Discussions and conclusions: Oridonin showed adverse effects at early stages of zebrafish development. We will perform additional studies on mechanism of oridonin based on VEGFR3.