In Vivo Screening of Xanthones from Garcinia oligantha Identified Oliganthin H as a Novel Natural Inhibitor of Convulsions

Gong, Guiyi1,2,3; Chen, Hanbin1,2; Kam, Hiotong1,2; Chan, Ging1,2; Tang, Yue-Xun4; Wu, Man4; Tan, Hongsheng5; Tse, Yu-Chung6; Xu, Hong-Xi4,7; Lee, Simon Ming-Yuen1,2

2020-12-24

10.1021/acs.jnatprod.0c00963

JOURNAL OF NATURAL PRODUCTS   影响因子和分区

0163-3864

1520-6025

Epilepsy is a chronic neurological disorder, characterized by recurrent, spontaneous, and transient seizures, and affects more than 70 million people worldwide. Although two dozen antiepileptic drugs (AEDs) are approved and available in the market, seizures remain poorly controlled in one-third of epileptic patients who are suffering from drug resistance or various adverse effects. Recently, the xanthone skeleton has been regarded as an attractive scaffold for the discovery and development of emerging anticonvulsants. We had isolated several dihydroxanthone derivatives previously, including oliganthin H, oliganthin I, and oliganthin N, whose structures were similar and delicately elucidated by spectrum analysis or X-ray crystallographic data, from extracts of leaves of Garcinia oligantha. These xanthone analogues were evaluated for anticonvulsant activity, and a novel xanthone, oliganthin H, has been identified as a sound and effective natural inhibitor of convulsions in zebrafish in vivo. A preliminary structure-activity relationship analysis on the relationship between structures of the xanthone analogues and their activities was also conducted. Oliganthin H significantly suppressed convulsant behavior and reduced to about 25% and 50% of PTZ-induced activity, in 12.5 and 25 mu M treatment groups (P < 0.01 and 0.001), respectively. Meanwhile, it reduced seizure activity, velocity, seizure duration, and number of bursts in zebrafish larvae (P < 0.05). Pretreatment of oliganthin H significantly restored aberrant induction of gene expressions including npas4a, c-fos, pyya, and bdnf, as well as gabra1, gad1, glsa, and glula, upon PTZ treatment. In addition, in silico analysis revealed the stability of the oliganthin H-GABAA receptor complex and their detailed binding pattern. Therefore, direct interactions with the GABAA receptor and involvement of downstream GABA-glutamate pathways were possible mechanisms of the anticonvulsant action of oliganthin H. Our findings present the anticonvulsant activity of oliganthin H, provide a novel scaffold for further modifications, and highlight the xanthone skeleton as an attractive and reliable resource for the development of emerging AEDs.

SCI

英语

其他

Science and Technology Development Fund, Macau SAR["014/2017/A1","0058/2019/A1","0016/2019/AKP"] ; University of Macau[MYRG2019-00105-ICMS]

Plant Sciences ; Pharmacology & Pharmacy

Plant Sciences ; Chemistry, Medicinal ; Pharmacology & Pharmacy

WOS:000603402900025

AMER CHEMICAL SOC

PHARMACOLOGY & TOXICOLOGY

Web of Science

1.Univ Macau, State Key Lab Qual Res Chinese Med, Macau, Peoples R China
2.Univ Macau, Inst Chinese Med Sci, Macau, Peoples R China
3.Southern Univ Sci & Technol SUSTech, Affiliated Hosp 2, Shenzhen 518055, Peoples R China
4.Shanghai Univ Tradit Chinese Med, Sch Pharm, Shanghai 201203, Peoples R China
5.Shanghai Jiao Tong Univ, Clin Res Ctr, Sch Med, Shanghai 200240, Peoples R China
6.Southern Univ Sci & Technol SUSTech, Dept Biol, Guangdong Prov Key Lab Cell Microenvironm & Dis R, Shenzhen 518055, Peoples R China
7.Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Shanghai 201203, Peoples R China

Gong, Guiyi,Chen, Hanbin,Kam, Hiotong,et al. In Vivo Screening of Xanthones from Garcinia oligantha Identified Oliganthin H as a Novel Natural Inhibitor of Convulsions[J]. JOURNAL OF NATURAL PRODUCTS,2020,83(12).

Gong, Guiyi.,Chen, Hanbin.,Kam, Hiotong.,Chan, Ging.,Tang, Yue-Xun.,...&Lee, Simon Ming-Yuen.(2020).In Vivo Screening of Xanthones from Garcinia oligantha Identified Oliganthin H as a Novel Natural Inhibitor of Convulsions.JOURNAL OF NATURAL PRODUCTS,83(12).

Gong, Guiyi,et al."In Vivo Screening of Xanthones from Garcinia oligantha Identified Oliganthin H as a Novel Natural Inhibitor of Convulsions".JOURNAL OF NATURAL PRODUCTS 83.12(2020).