Andrographolide is a labdane diterpene reported to have potent anti- inflammatory, anticancer and anti-viral activity [9
]. As such, the use of antibacterials and antivirals in malaria prophylaxis is also well documented [20
]. Identification of anti-plasmodial activity of this compound in view of its efficacious in vitro
and in vivo
performance opens up several opportunities for further exploration of this compound as a new anti-malarial.
During the erythrocytic life cycle, the period of activity of andrographolide was found evidently on the ring stage of the parasite. The point of action of this compound in the parasite life cycle corresponds with the protein and nucleic acid synthesis. Hence, they could be the “transcription blockers”; more studies focusing on this particular aspect are in progress.
The pharmacological targets of this compound and its mechanism of action on P. falciparum
are not known. However, the clue centers on the phenomenon of regulation of a transcription factor. As per Hidalgo et al. [9
], the anti-inflammatory action of andrographolide includes inhibition of the nuclear transcription factor-(kappa) B, making it a therapeutic target for the treatment of cancer and autoimmune diseases. The role of NF-kappaB (NF-κ
B) is also important in malaria as mentioned in a recent study [21
]; P. falciparum
infected erythrocytes have shown to induce NF-(kappa) B-regulated inflammatory pathways in human cerebral endothelium. The deciphering of anti-malarial activity in andrographolide against the blood stage of the plasmodial life cycle lays foundation to reevaluate its possible role in the regulation of this important transcription factor for the effective control of malaria.
There are several reports on various drug combinations showing their in vitro
and in vivo
interactions on malaria parasites [16
]. The synergy between andrographolide and curcumin is interesting in the fight against the emergence of drug resistance among parasites. Both curcumin and andrographolides being from the plant sources are already documented for their antioxidant [24
] and anti-inflammatory properties [25
], respectively. This information also generates scope to explore the possibility of modifying the molecular structures of both the plant-derived compounds such as andrographolide and curcumin with the objective of increasing their specific activity against plasmodial species. The semisynthetic modification of artemisinin to artesunate, artemether, and DHA has already yielded compounds with significantly higher activity. The other finding that deciphers the additiveness of andrographolide with artesunate, the most potent artemisinin derivative makes it important in the context that it offers opportunities to further standardize new ACT- (artemisinin-based combination therapies-) based formulae as possible antimalarial combination.
Andrographolide exhibited high level of activity in murine model when administered either with curcumin or artesunate by the intraperitoneal route, without any toxicity. The substantial decrease in level of parasitemia in response to test drug combinations compared to the control and extended periods of life, observed with the mice is the main finding of the present study. This may be attributed to the observed in vitro synergism or addictiveness between the putative drug compounds in different combination ratios. However, studies are in progress for effective dose determination for complete clearance of parasitemia from infected mice using AND+CUR and AND+AS combinations.