Inhibition of heme detoxification pathway in malaria parasite by 3-hydroxy-11-keto-β-boswellic acid isolated from Boswellia serrata - 13/11/21
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Abstract |
Malaria eradication is still a major global health problem in developing countries, which has been of more concern ever since the malaria parasite has developed resistance against frontline antimalarial drugs. Historical evidence proves that the plants possess a major resource for the development of novel anti-malarial drugs. In the present study, the bioactivity guided fractionation of the oleogum-resin of Boswellia serrata Roxb. yielded the optimum activity in the ethyl acetate fraction with an IC50 of 22 ± 3.9 μg/mL and 26.5 ± 4.5 μg/mL against chloroquine sensitive (NF54) and resistant (K1) strains of Plasmodium falciparum respectively. Further, upon fractionation, the ethyl acetate fraction yielded four major compounds, of which 3-Hydroxy-11-keto-β-boswellic acid (KBA) was found to be the most potent with IC50 values 4.5 ± 0.60 µg/mL and 6.25 ± 1.02 μg/mL against sensitive and resistant strains respectively. KBA was found to inhibit heme detoxification pathways, one of the most common therapeutic targets, which probably lead to an increase in reactive oxygen species (ROS) and nitric oxide (NO) detrimental to P. falciparum. Further, the induced intracellular oxidative stress affected the macromolecules in terms of DNA damage, increased lipid peroxidation, protein carbonylation as well as loss of mitochondrial membrane potential. However, it did not exhibit any cytotoxic effect in VERO cells. Under in vivo conditions, KBA exhibited a significant reduction in parasitemia, retarding the development of anaemia, resulting in an enhancement of the mean survival time in Plasmodium yoelii nigeriensis (chloroquine-resistant) infected mice. Further, KBA did not exhibit any abnormality in serum biochemistry of animals that underwent acute oral toxicity studies at 2000 mg/kg body weight.
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Highlights |
• | Activity-guided isolated molecule (KBA)from resins B. serrata was found to be the most potent activity against both strains. |
• | KBA was found to exert its activity by inhibiting heme detoxification pathway leading to imposition of oxidative stress. |
• | Induced oxidative stress affects macromolecule/organelles viz, DNA, Protein, Lipid and Mitochondria. |
• | Reduced parasitemia and increased hemoglobin level was observed in rodent malaria model upon the treatment of KBA. |
• | KBA was safe and well tolerated by the rodent animal model in acute oral toxicity. |
Keywords : Boswellia serrata Roxb, Hydroxy-11-keto-β-boswellic acid, Anti-plasmodial, Heme detoxification, Oxidative stress, Acute oral toxicity
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Vol 144
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