Acute and Chronic Toxicity of Indole Alkaloids from Leaves of Alstonia scholaris (L.) R. Br. in Mice and Rats

doi:10.1007/s13659-020-00237-1

应用天然产物 ›› 2020, Vol. 10 ›› Issue (2): 77-88.DOI: 10.1007/s13659-020-00237-1

Acute and Chronic Toxicity of Indole Alkaloids from Leaves of Alstonia scholaris (L.) R. Br. in Mice and Rats

Yun-Li Zhao^1,3, Min Su², Jian-Hua Shang^2,3, Xia Wang², Guy Sedar Singor Njateng⁴, Guang-Lei Bao², Jia Ma², Qing-Di Sun⁵, Fang Yuan², Jing-Kun Wang², Xiao-Dong Luo^1,3

1 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People's Republic of China;
2 Yunnan Institute of Medical Material, Kunming 650111, People's Republic of China;
3 Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, People's Republic of China;
4 Laboratory of Microbiology and Antimicrobial Substances, Faculty of Science, University of Dschang, P. O. Box 67, Dschang, Cameroon;
5 Jiangsu Nhwa Pharmaceutical Co., Ltd, Xuzhou 221009, People's Republic of China

收稿日期:2020-02-03 修回日期:2020-03-19 出版日期:2020-04-24 发布日期:2020-05-06
通讯作者: Jing-Kun Wang, Xiao-Dong Luo
基金资助:
The authors are grateful to the Yunnan Major Science and Technology Project (2019ZF003) and National Key Research and Development Program of China (2017YFC1704007) for partial financial support.

Acute and Chronic Toxicity of Indole Alkaloids from Leaves of Alstonia scholaris (L.) R. Br. in Mice and Rats

Yun-Li Zhao^1,3, Min Su², Jian-Hua Shang^2,3, Xia Wang², Guy Sedar Singor Njateng⁴, Guang-Lei Bao², Jia Ma², Qing-Di Sun⁵, Fang Yuan², Jing-Kun Wang², Xiao-Dong Luo^1,3

1 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People's Republic of China;
2 Yunnan Institute of Medical Material, Kunming 650111, People's Republic of China;
3 Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, People's Republic of China;
4 Laboratory of Microbiology and Antimicrobial Substances, Faculty of Science, University of Dschang, P. O. Box 67, Dschang, Cameroon;
5 Jiangsu Nhwa Pharmaceutical Co., Ltd, Xuzhou 221009, People's Republic of China

Received:2020-02-03 Revised:2020-03-19 Online:2020-04-24 Published:2020-05-06
Contact: Jing-Kun Wang, Xiao-Dong Luo
Supported by:
The authors are grateful to the Yunnan Major Science and Technology Project (2019ZF003) and National Key Research and Development Program of China (2017YFC1704007) for partial financial support.

摘要/Abstract

摘要： Alstonia scholaris (L.) R. Br. (Apocynaceae) is an evergreen tree that has been used to treat lung diseases. In this study, the toxicity profile of indole alkaloids from leaves of A. scholaris was investigated. In acute toxicity tests, mice were administered total alkaloids (TA) and five indole alkaloids. In a chronic toxicity test, rats were continuously administered TA (50, 100, and 300 mg/kg bw) for 13 weeks, followed by a 4-week recovery. A single administration of TA affected the behavior of mice, and at 12.8 g/kg bw, prone position, shortness of breath, wheezing, and convulsion were observed. The half-lethal dose (LD₅₀) in mice was 5.48 g/kg bw, almost 2740 times the clinical dose in humans. Among the five indole alkaloids, the maximum tolerance dose in mice ranged from 0.75 to 4 g/kg bw. The TA-treated rats did not die and showed no adverse effects or dose-dependent changes in weight or food and water consumption, despite fluctuations in hematological and biochemical parameters compared with historical data. Furthermore, both gross and histopathological observations revealed no abnormalities in any organ. With daily oral administration to rats, the non-observed-adverse-effect-level of TA was 100 mg/kg bw. The results indicate that TA is safe for clinical use.

关键词: Alstonia scholaris, Indole alkaloids, Acute toxicity, Chronic toxicity, Non-observed-adverse-effect-level

Abstract: Alstonia scholaris (L.) R. Br. (Apocynaceae) is an evergreen tree that has been used to treat lung diseases. In this study, the toxicity profile of indole alkaloids from leaves of A. scholaris was investigated. In acute toxicity tests, mice were administered total alkaloids (TA) and five indole alkaloids. In a chronic toxicity test, rats were continuously administered TA (50, 100, and 300 mg/kg bw) for 13 weeks, followed by a 4-week recovery. A single administration of TA affected the behavior of mice, and at 12.8 g/kg bw, prone position, shortness of breath, wheezing, and convulsion were observed. The half-lethal dose (LD₅₀) in mice was 5.48 g/kg bw, almost 2740 times the clinical dose in humans. Among the five indole alkaloids, the maximum tolerance dose in mice ranged from 0.75 to 4 g/kg bw. The TA-treated rats did not die and showed no adverse effects or dose-dependent changes in weight or food and water consumption, despite fluctuations in hematological and biochemical parameters compared with historical data. Furthermore, both gross and histopathological observations revealed no abnormalities in any organ. With daily oral administration to rats, the non-observed-adverse-effect-level of TA was 100 mg/kg bw. The results indicate that TA is safe for clinical use.

Key words: Alstonia scholaris, Indole alkaloids, Acute toxicity, Chronic toxicity, Non-observed-adverse-effect-level

Yun-Li Zhao, Min Su, Jian-Hua Shang, Xia Wang, Guy Sedar Singor Njateng, Guang-Lei Bao, Jia Ma, Qing-Di Sun, Fang Yuan, Jing-Kun Wang, Xiao-Dong Luo. Acute and Chronic Toxicity of Indole Alkaloids from Leaves of Alstonia scholaris (L.) R. Br. in Mice and Rats[J]. 应用天然产物, 2020, 10(2): 77-88.

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Acute and Chronic Toxicity of Indole Alkaloids from Leaves of Alstonia scholaris (L.) R. Br. in Mice and Rats

Acute and Chronic Toxicity of Indole Alkaloids from Leaves of Alstonia scholaris (L.) R. Br. in Mice and Rats

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