Synergistic anti-malarial action of cryptolepine and artemisinins.

Arnold D Forkuo,Kwesi M Boadu,Michael F Ofori,Ben A Gyan,Elvis O Ameyaw,Charles Ansah,Andrea T Arku,Johnson N Boampong

doi:10.1186/s12936-016-1137-5

Abstract

BackgroundCryptolepine (CPE) is the major indoloquinoline isolated from the popular West African anti-malarial plant, Cryptolepis sanguinolenta. CPE possesses various pharmacological activities with potent anti-malarial activity against both chloroquine (CQ)-resistant and -sensitive strains. The search for safe and novel anti-malarial agents and combinations to delay resistance development to Plasmodium falciparum directed this work aimed at evaluating the anti-malarial interaction and safety of CPE in combination with some artemisinin derivatives.MethodsThe in vitro SYBR Green I, fluorescent-based, drug sensitivity assay using a fixed ratio method was carried out on the CQ-sensitive plasmodial strain 3D7 to develop isobolograms from three CPE-based combinations with some artemisinin derivatives. CPE and artesunate (ART) combinations were also evaluated using the Rane’s test in ICR mice infected with Plasmodium berghei NK-65 strains in a fixed ratio combination (1:1) and fractions of their ED50s in order to determine the experimental ED50 (Zexp) of the co-administered compounds. Isobolograms were constructed to compare the Zexp to the Zadd.ResultsCPE exhibited promising synergistic interactions in vitro with ART, artemether and dihydroartemisinin. In vivo, CPE combination with ART again showed synergy as the Zexp was 1.02 ± 0.02, which was significantly less than the Zadd of 8.3 ± 0.31. The haematological, biochemical, organ/body weight ratio and histopathology indices in the rats treated with CPE at all doses (25, 50, 100 mg kg−1po) and in combination with ART (4 mg kg−1) showed no significant difference compared to the control group.ConclusionThe combination of CPE with the artemisinin derivatives were safe in the rodent model and showed a synergistic anti-malarial activity in vivo and in vitro. This study supports the basis for the selection of CPE as a prospective lead compound as the search for new anti-malarial combinations continues.

Highlights

Cryptolepine (CPE) is the major indoloquinoline isolated from the popular West African anti-malarial plant, Cryptolepis sanguinolenta
Forkuo et al Malar J (2016) 15:89 availability coupled with the high cost of pharmaceuticals in many African countries has resulted in the majority of the populace depending on herbal medicines for treatment of several ailments, including malaria [5]
The degree of synergism was stronger in ARM (ΣFIC50 = 0.362), followed by DHA (ΣFIC50 = 0.403) and ART (ΣFIC50 = 0.693) (Fig. 2)

Summary

Introduction

Cryptolepine (CPE) is the major indoloquinoline isolated from the popular West African anti-malarial plant, Cryptolepis sanguinolenta. CPE possesses various pharmacological activities with potent anti-malarial activity against both chloroquine (CQ)-resistant and -sensitive strains. The search for safe and novel anti-malarial agents and combinations to delay resistance development to Plasmodium falciparum directed this work aimed at evaluating the anti-malarial interaction and safety of CPE in combination with some artemisinin derivatives. The aqueous root extract of Cryptolepis sanguinolenta is a well-known anti-malarial agent in West African ethnomedicine. It has gained popularity among indigenes for decades and is packaged for use in hospitals and other herbal centres. Bioactive compounds from medicinal plants used traditionally is an important approach for identifying novel and potent anti-malarial drug candidates. CPE is reported to possess several biological activities, including antihyperglycaemic [6], antifungal [7], antihypertensive [8], antibacterial [9], anti-inflammatory [10], antiplasmodial activities [11,12,13]

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