Swertiamarin-mediated immune modulation/adaptation confers protection against Plasmodium berghei
Abstract
Aims: Development of resistance by the malaria parasite, a systemic inflammatory and infectious pathogen, has raised the need for novel efficacious antimalarials. Plant-derived natural compounds are known to modulate the immune response and eradicate the infectious pathogens. Therefore we carried out experiments with swertiamarin to dissect its anti-inflammatory and immunomodulatory potential. Materials & methods: We carried out studies in Swiss albino mice that received infectious challenge with Plasmodium berghei and swertiamarin treatment in a prophylactic manner. Results & conclusion: Oral administration of swertiamarin prior to infectious challenge with P. berghei in experimental mice showed delayed parasite development as compared with untreated control. IFN-γ and IL-10 appeared to be adapted/modulated by regular swertiamarin treatment. Further, withdrawal of swertiamarin pressure did not affect parasite replication. However, the short half-life of swertiamarin limited its long-lasting therapeutic effect, requiring higher and frequent dosing schedules.
References
- 1. World Health Organization. World Malaria Report (2020). www.who.int/publications/i/item/9789240015791
- 2. Institute of Medicine (US) Committee on the Economics of Antimalarial Drugs. Saving lives, buying time: economics of malaria drugs in an age of resistance. National Academies Press (US) (2004). www.ncbi.nlm.nih.gov/books/NBK215631/
- 3. . Artemisinin and its derivatives: an important new class of antimalarial agents. Pharmacol. Ther. 90(2), 261–265 (2001).
- 4. . Antimalarial drug resistance, artemisinin-based combination therapy, and the contribution of modeling to elucidating policy choices. Am. J. Trop. Med. Hyg. 71(Suppl. 2), 179–186 (2004).
- 5. High-level artemisinin-resistance with quinine co-resistance emerges in P. falciparum malaria under in vivo artesunate pressure. BMC Med. 16(1), 181 (2018).
- 6. Spread of artemisinin resistance in Plasmodium falciparum malaria. N. Engl. J. Med. 371(5), 411–423 (2014).
- 7. World Health Organization. Global plan for artemisinin resistance containment (GPARC) (2011). https://apps.who.int/iris/bitstream/handle/10665/44482/9789241500838_eng.pdf
- 8. . Molecular surveillance of drug resistance: Plasmodium falciparum artemisinin resistance single nucleotide polymorphisms in Kelch protein propeller (K13) domain from Southern Pakistan. Malar. J. 20(1), 1–6 (2021).
- 9. Artemisinin resistance in Plasmodium falciparum malaria. N. Engl. J. Med. 361(5), 455–467 (2009).
- 10. Increased tolerance to artemisinin in Plasmodium falciparum is mediated by a quiescence mechanism. Antimicrob. Agents Chemother. 54(5), 1872–1877 (2010).
- 11. . Traditional antimalarials and the development of novel antimalarial drugs. J. Ethnopharmacol. 100(1), 67–71 (2005).
- 12. . Alkaloids from plants with antimalarial activity: a review of recent studies. Evid. Based Complement. Altern. Med. 2020, 8749083 (2020).
- 13. . In vitro anti plasmodial activity of Enicostemma littorale. Am. J. Infect. Dis. 5(3), 259–262 (2009).
- 14. . Anti-diabetic activity of swertiamarin is due to an active metabolite, gentianine, that upregulates PPAR-γ gene expression in 3T3-L1 cells. Phytother. Res. 27(4), 624–627 (2013).
- 15. . Chemical constituents of Gentianaceae XIX: CNS-depressant effects of swertiamarin. J. Pharm. Sci. 65(10), 1547–1549 (1976).
- 16. . The molecular targets of swertiamarin and its derivatives confer anti-diabetic and anti-hyperlipidemic effects. Curr. Drug Targets 19(16), 1958–1967 (2018).
- 17. . Anticholinergic action of Swertia japonica and an active constituent. J. Ethnopharmacol. 33(1-2), 31–35 (1991).
- 18. . Swertiamarin: an active lead from Enicostemma littorale regulates hepatic and adipose tissue gene expression by targeting PPAR-γ and improves insulin sensitivity in experimental NIDDM rat model. Evid. Based Complement. Altern. Med. 2013, 358673 (2013).
- 19. . Antioxidant and hepatoprotective effect of swertiamarin on carbon tetrachloride-induced hepatotoxicity via the Nrf2/HO-1 pathway. Cell Physiol. Biochem. 41(6), 2242–2254 (2017).
- 20. The anti-inflammatory secoiridoid glycosides from Gentianae scabrae radix: the root and rhizome of Gentiana scabra. J. Nat. Med. 69(3), 303–312 (2015).
- 21. . Ameliorative antimalarial effects of the combination of rutin and swertiamarin on malarial parasites. Asian Pac. J. Trop. Med. 6(6), 453–459 (2016).
- 22. Swertiamarin ameliorates inflammation and osteoclastogenesis intermediates in IL-1β induced rat fibroblast-like synoviocytes. Inflamm. Res. 63(6), 451–462 (2014).
- 23. . Immunomodulatory potential of Enicostema axillare (Lam.) A. Raynal, a traditional medicinal plant. J. Ethnopharmacol. 140(2), 239–246 (2012).
- 24. Swertiamarin attenuates inflammation mediators via modulating NF-κB/I κB and JAK2/STAT3 transcription factors in adjuvant induced arthritis. Eur. J. Pharm. Sci. 56, 70–86 (2014).
- 25. In vivo and in vitro immunomodulatory potential of swertiamarin isolated from Enicostema axillare (Lam.) A. Raynal that acts as an anti-inflammatory agent. Inflammation 37(5), 1374–1388 (2014).
- 26. Cerebral malaria: gamma-interferon redux. Front Cell Infect. Microbiol. 4, 113 (2014).
- 27. A role for natural regulatory T cells in the pathogenesis of experimental cerebral malaria. Am. J. Pathol. 171(2), 548–559 (2007).
- 28. Asymptomatic malaria infection is maintained by a balanced pro- and anti-inflammatory response. Front. Microbiol. 11, 559255–559255 (2020).
- 29. Evidence that interferon-γ plays a protective role during cerebral malaria. J. Infect. Dis. 192(5), 854–860 (2005).
- 30. . Tumor necrosis factor α in the pathogenesis of cerebral malaria. Cell. Mol. Life Sci. 60(8), 1623–1635 (2003).
- 31. Cytokines and malaria parasitemia. J. Clin. Immunol. 100(2), 208–218 (2001).
- 32. . The role of IL-10 in malaria: a double edged sword. Front. immunol. 10, 229 (2019).
- 33. . A systematic review of the protective role of swertiamarin in cardiac and metabolic diseases. Biomed. Pharmacother. 84, 1051–1060 (2016).
- 34. Role of IL-10-producing regulatory B cells in control of cerebral malaria in Plasmodium berghei infected mice. Eur. J. Immunol. 43(11), 2907–2918 (2013).