Anti-malarial activity of traditional Kampo medicine Coptis rhizome extract and its major active compounds

Awet Alem Teklemichael,Farhana Mosaddeque,Osamu Kaneko,Katsuko Komatsu,Juntra Karbwang,Mohamed Gomaa Kamel,Kazufumi Toume,Nguyen Tien Huy,Kenji Hirayama,Shusaku Mizukami

doi:10.1186/s12936-020-03273-x

Awet Alem Teklemichael, Farhana Mosaddeque + Show 8 more

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https://doi.org/10.1186/s12936-020-03273-x

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Abstract

BackgroundHerbal medicine has been a rich source of new drugs exemplified by quinine and artemisinin. In this study, a variety of Japanese traditional herbal medicine (‘Kampo’) were examined for their potential anti-malarial activities.MethodsA comprehensive screening methods were designed to identify novel anti-malarial drugs from a library of Kampo herbal extracts (n = 120) and related compounds (n = 96). The anti-malarial activity was initially evaluated in vitro against chloroquine/mefloquine-sensitive (3D7) and-resistant (Dd2) strains of Plasmodium falciparum. The cytotoxicity was also evaluated using primary adult mouse brain cells. After being selected through the first in vitro assay, positive extracts and compounds were examined for possible in vivo anti-malarial activity.ResultsOut of 120 herbal extracts, Coptis rhizome showed the highest anti-malarial activity (IC50 1.9 µg/mL of 3D7 and 4.85 µg/mL of Dd2) with a high selectivity index (SI) > 263 (3D7) and > 103 (Dd2). Three major chlorinated compounds (coptisine, berberine, and palmatine) related to Coptis rhizome also showed anti-malarial activities with IC50 1.1, 2.6, and 6.0 µM (against 3D7) and 3.1, 6.3, and 11.8 µM (against Dd2), respectively. Among them, coptisine chloride exhibited the highest anti-malarial activity (IC50 1.1 µM against 3D7 and 3.1 µM against Dd2) with SI of 37.8 and 13.2, respectively. Finally, the herbal extract of Coptis rhizome and its major active compound coptisine chloride exhibited significant anti-malarial activity in mice infected with Plasmodium yoelii 17X strain with respect to its activity on parasite suppression consistently from day 3 to day 7 post-challenge. The effect ranged from 50.38 to 72.13% (P < 0.05) for Coptis rhizome and from 81 to 89% (P < 0.01) for coptisine chloride.ConclusionCoptis rhizome and its major active compound coptisine chloride showed promising anti-malarial activity against chloroquine-sensitive (3D7) and -resistant (Dd2) strains in vitro as well as in vivo mouse malaria model. Thus, Kampo herbal medicine is a potential natural resource for novel anti-malarial agents.

Highlights

Herbal medicine has been a rich source of new drugs exemplified by quinine and artemisinin
Due to the lowest 50% inhibitory concentration (IC50) and high selectivity index (SI), Coptis rhizome was further evaluated against P. falciparum Dd2 strain and IC50 and SI were determined to be 4.85 μg/mL and > 103, respectively (Table 1)
The Kampo formula Orengedokuto that contains a high amount of Coptis rhizome by percentage weight was selected and evaluated against CQ/MQ-sensitive (3D7) and resistant (Dd2) strain of P. falciparum

Summary

Introduction

Herbal medicine has been a rich source of new drugs exemplified by quinine and artemisinin. In 2018, 228 million cases of malaria resulted in 405,000 death, of which 93% of the cases and 94% of deaths were in the World Health Organization (WHO). Successful malaria control can be achieved through the treatment with efficient anti-malarial drugs, such as quinine and chloroquine (CQ) [6, 7]. The inappropriate use of CQ led to the emergence and spread of CQ-resistant Plasmodium falciparum parasites which resulted in reducing CQ’s usage for the prophylaxis and treatment for malaria in the late 1970s [8,9,10]. P. falciparum has been recently reported to be resistant to artemisinin in Greater Mekong Sub-region [11,12,13,14]

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