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Piperine Enhances Antimalarial Activity of Methyl Gallate and Palmatine Combination

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Abstract

Purpose

Artemisinin combination therapies, the first-line antimalarials in Nigeria, have reportedly suffered multiple failures in malaria treatment, hence the search for novel combination of other compounds. Methyl gallate and palmatine have been reported to exhibit antiplasmodial activities but the antimalarial activity of their combination has not been evaluated. Therefore, the evaluation of the combination of methyl gallate and palmatine for antimalarial activity in vitro and in vivo in the presence of piperine was carried out.

Materials and Methods

The inhibitory potential of methyl gallate and palmatine combination on β-hematin (hemozoin) formation was studied in vitro. Also, the antimalarial activity of methyl gallate and palmatine combination with/without a bioenhancer (piperine) was evaluated in Plasmodium berghei NK65-infected mice.

Results

Methyl gallate and palmatine in the ratio 3:2 acted synergistically in vitro and had the highest inhibitory effect (IC50 = 0.73 µg/mL) on β-hematin (hemozoin) formation. The 3:2 combination of methyl gallate and palmatine exhibited no antimalarial activity in vivo in the absence of piperine but caused reduction in parasitemia that exceeded 40% in the presence of piperine at the dose of 25 mg/kg body weight on days 6 and 8 post-inoculation in mice.

Conclusion

The 3:2 combination of methyl gallate and palmatine in the presence of piperine exhibited antimalarial activity in vivo, possibly by synergistic inhibition of hemozoin formation which may cause accumulation of haem within the food vacuole of Plasmodium spp. and its death.

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Data Availability

All essential data generated or analysed during this study are available from the corresponding author on reasonable request.

References

  1. WHO (2020) World malaria report 2020: 20 years of global progress and challenges. World Health Organization

  2. WHO (2018) World Malaria Report 2018. Geneva

  3. Schlitzer M (2008) Antimalarial drugs—what is in use and what is in the pipeline. Arch Pharm (Weinheim) 341:149–163. https://doi.org/10.1002/ardp.200700184

    Article  CAS  PubMed  Google Scholar 

  4. Beshir K, Sutherland CJ, Merinopoulos I, Durrani N, Leslie T, Rowland M, Hallett RL (2010) Amodiaquine resistance in Plasmodium falciparum malaria in Afghanistan is associated with the pfcrt SVMNT allele at codons 72 to 76. Antimicrob Agents Chemother 54:3714–3716. https://doi.org/10.1128/aac.00358-10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Witkowski B, Duru V, Khim N, Ross LS, Saintpierre B, Beghain J, Eam R (2017) A surrogate marker of piperaquine-resistant Plasmodium falciparum malaria: a phenotype–genotype association study. Lancet Infect Dis 17:174–183. https://doi.org/10.1016/S1473-3099(16)30415-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Dondorp AM, Fairhurst RM, Slutsker L, MacArthur JR, Guerin PJ, Wellems TE, Ringwald P, Newman RD, Plowe CV (2011) The threat of artemisinin-resistant malaria. N Engl J Med 365:1073–1075. https://doi.org/10.1056/NEJMp1108322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Foley M, Tilley L (1998) Quinoline antimalarials: Mechanisms of action and resistance and prospects for new agents. Pharmacol Ther 79:55–87. https://doi.org/10.1016/S0163-7258(98)00012-6

    Article  CAS  PubMed  Google Scholar 

  8. Vennerstrom JL, Nuzum EO, Miller RE, Dorn A, Gerena L, Dande PA, Ellis WY, Ridley RG, Milhous WK (1999) 8-aminoquinolines active against blood stage Plasmodium falciparum in vitro inhibit haematin polymerization. Antimicrob Agents Chemother 43:598–602. https://doi.org/10.1128/aac.43.3.598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Rosenthal PJ (2003) Antimalarial drug discovery: old and new approaches. J Exp Biol 206:3735–3744. https://doi.org/10.1242/jeb.00589

    Article  CAS  PubMed  Google Scholar 

  10. Plowe CV (2007) Combination therapy for malaria: mission accomplished? Clin Infect Dis 44:1075–1077. https://doi.org/10.1086/512743

    Article  CAS  PubMed  Google Scholar 

  11. Fidock DA, Rosenthal PJ, Croft SL, Brun R, Nwaka S (2004) Antimalarial drug discovery: efficacy models for compound screening. Nat Rev Drug Discov 3:509–520. https://doi.org/10.1038/nrd1416

    Article  CAS  PubMed  Google Scholar 

  12. Kaou AM, Mahiou-Leddet V, Mabrouki F, Hutter S, Laget M, Azas N, Yahaya I, Ollivier E (2010) Phytochemical study of plants used in traditional medicine in the treatment of malaria in the Comoros islands. Planta Med 76:P418. https://doi.org/10.1055/s-0030-1264716

    Article  Google Scholar 

  13. Malebo HM, Wenzler T, Cal M, Swaleh SM, Omolo MO, Hassanali A, Séquin U, Häussinger D, Dalsgaard P, Hamburger M, Brun R, Ndiege IO (2013) Anti-protozoal activity of aporphine and protoberberine alkaloids from Annickia kummeriae (Engl. & Diels) Setten & Maas (Annonaceae). BMC Complement Altern Med 13:48–58. https://doi.org/10.1186/1472-6882-13-48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zofou D, Tematio EL, Ntie-Kang F, Tene M, Ngemenya MN, Tane P, Titanji VPK (2013) New antimalarial hits from Dacryodes edulis (Burseraceae)-part I: Isolation, In vitro activity, in silico “drug-likeness” and pharmacokinetic profiles. PLoS ONE 8:e79544–e79553. https://doi.org/10.1371/journal.pone.0079544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Pustovidko AV, Rokitskaya TI, Severina II, Simonyan RA, Trendeleva TA, Lyamzaev KG, Antonenko YN, Rogov AG, Zvyagilskaya RA, Skulachev VP, Chernyak BV (2013) Derivatives of the cationic plant alkaloids berberine and palmatine amplify protonophorous activity of fatty acids in model membranes and mitochondria. Mitochondrion 13:520–525. https://doi.org/10.1016/j.mito.2012.09.006

    Article  CAS  PubMed  Google Scholar 

  16. Dhingra D, Bhankher A (2014) Behavioral and biochemical evidences for antidepressant-like activity of palmatine in mice subjected to chronic unpredictable mild stress. Pharmacol Reports 66:1–9. https://doi.org/10.1016/j.pharep.2013.06.001

    Article  CAS  Google Scholar 

  17. Fan W, Yuan G, Li Q, Lin W (2014) Antibacterial mechanisms of methyl gallate against ralstonia solanacearum. Australas Plant Pathol 43:1–7. https://doi.org/10.1007/s13313-013-0234-y

    Article  CAS  Google Scholar 

  18. Ryu BI, Kim KT (2022) Antioxidant activity and protective effect of methyl gallate against t-BHP induced oxidative stress through inhibiting ROS production. Food Sci Biotechnol 31:1063–1072. https://doi.org/10.1007/s10068-022-01120-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Dhingra D, Kumar V (2012) Memory-enhancing activity of palmatine in mice using elevated plus maze and morris water maze. Adv Pharmacol Sci 2012:357–368. https://doi.org/10.1155/2012/357368

    Article  CAS  Google Scholar 

  20. Choi JG, Mun SH, Chahar HS, Bharaj P, Kang OH, Kim SG, Shin DW, Kwon DY (2014) Methyl gallate from galla rhois successfully controls clinical isolates of Salmonella infection in both in vitro and in vivo systems. PLoS ONE 9:e102697. https://doi.org/10.1371/journal.pone.0102697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Asnaashari M, Farhoosh R, Sharif A (2014) Antioxidant activity of gallic acid and methyl gallate in triacylglycerols of kilka fish oil and its oil-in-water emulsion. Food Chem 159:439–444. https://doi.org/10.1016/j.foodchem.2014.03.038

    Article  CAS  PubMed  Google Scholar 

  22. Khurana S, Hollingsworth A, Piche M, Venkataraman K, Kumar A, Ross GM, Tai TC (2014) Antiapoptotic actions of methyl gallate on neonatal rat cardiac myocytes exposed to H2O2. Oxid Med Cell Longev. https://doi.org/10.1155/2014/657512

    Article  PubMed  PubMed Central  Google Scholar 

  23. Zhang L, Li J, Ma F, Yao S, Li N, Wang J, Wang Y, Wang X, Yao Q (2012) Synthesis and cytotoxicity evaluation of 13-n berberine and palmatine analogues as anticancer agents. Molecules 17:11295–11302. https://doi.org/10.3390/molecules171011294

    Article  CAS  Google Scholar 

  24. Nonaka M, Murata Y, Takano R, Han Y, Kabir MHB, Kato K (2018) Screening of a library of traditional Chinese medicines to identify anti-malarial compounds and extracts. Malar J 17:1–10. https://doi.org/10.1186/s12936-018-2392-4

    Article  Google Scholar 

  25. Wu B, Kulkarni K, Basu S, Zhang S, Hu M (2011) First-pass metabolism via UDP-glucuronosyltransferase: a barrier to oral bioavailability of phenolics. J Pharm Sci 100:3655–3681. https://doi.org/10.1002/jps.22568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rasoanaivo P, Wright CW, Willcox ML, Gilbert B (2011) Whole plant extracts versus single compounds for the treatment of malaria: synergy and positive interactions. Malar J 10:1–12. https://doi.org/10.1186/1475-2875-10-S1-S4

    Article  Google Scholar 

  27. Lambert JD, Hong J, Kim DH, Mishin VM, Yang CS (2004) Piperine enhances the bioavailability of the tea polyphenol (−)-epigallocatechin-3-gallate in mice. J Nutr 134:1948–1952. https://doi.org/10.1093/jn/134.8.1948

    Article  CAS  PubMed  Google Scholar 

  28. Ncokazi KK, Egan TJ (2005) A colorimetric high-throughput β-haematin inhibition screening assay for use in the search for antimalarial compounds. Anal Biochem 338:306–319. https://doi.org/10.1016/j.ab.2004.11.022

    Article  CAS  PubMed  Google Scholar 

  29. Fivelman QL, Adagu IS, Warhurst DC (2004) Modified fixed-ratio isobologram method for studying in vitro interactions between atovaquone and proguanil or dihydroartemisinin against drug-resistant strains of Plasmodium falciparum. Antimicrob Agents Chemother 48:4097–4102. https://doi.org/10.1128/aac.48.11.4097-4102.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ohrt C, Willingmyre GD, Lee P, Knirsch C, Milhous W (2002) Assessment of azithromycin in combination with other antimalarial drugs against Plasmodium falciparum in vitro. Antimicrob Agents Chemother. https://doi.org/10.1128/aac.46.8.2518-2524.2002

    Article  PubMed  PubMed Central  Google Scholar 

  31. He Z, Chen L, You J, Qin L, Chen X (2010) In vitro interactions between antiretroviral protease inhibitors and artemisinin endoperoxides against Plasmodium falciparum. Int J Antimicrob Agents 35:191–193. https://doi.org/10.1016/j.ijantimicag.2009.09.016

    Article  CAS  PubMed  Google Scholar 

  32. Peters W (1965) Drug resistance in Plasmodium berghei I chloroquine resistance. Exp Parasitol 17:80–89. https://doi.org/10.1016/0014-4894(65)90012-3

    Article  CAS  PubMed  Google Scholar 

  33. Ryley JF, Peters W (1970) The antimalarial activity of some quinolone esters. Ann Trop Med Parasitol 64:209–222. https://doi.org/10.1080/00034983.1970.11686683

    Article  CAS  PubMed  Google Scholar 

  34. de Souza NB, de Andrade IM, Carneiro PF, Jardim GAM, de Melo IMM, da Silva Júnior EN, Krettli AU (2014) Blood shizonticidal activities of phenazines and naphthoquinoidal compounds against Plasmodium falciparum in vitro and in mice malaria studies. Mem Inst Oswaldo Cruz 109:546–552. https://doi.org/10.1590/0074-0276130603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Egan TJ (2008) Haemozoin formation. Mol Biochem Parasitol 157:127–136. https://doi.org/10.1016/j.molbiopara.2007.11.005

    Article  CAS  PubMed  Google Scholar 

  36. eSilva LFR, Nogueira KL, da Silva Pinto AC, Katzin AM, Sussmann RA, Muniz MP, de Andrade Neto VF, Chaves FCM, Coutinho JP, Lima ES, Krettli AU (2015) In vivo antimalarial activity and mechanisms of action of 4-nerolidylcatechol derivatives. Antimicrob Agents Chemother 59:3271–3280. https://doi.org/10.1128/aac.05012-14

    Article  Google Scholar 

  37. Miller LH, Ackerman HC, Su XZ, Wellems TE (2013) Malaria biology and disease pathogenesis: insights for new treatments. Nat Med 19:156–167. https://doi.org/10.1038/nm.3073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Vennerstrom JL, Klayman DL (1988) Protoberberine alkaloids as antimalarials. J Med Chem 31:1084–1087. https://doi.org/10.1021/jm00401a006

    Article  CAS  PubMed  Google Scholar 

  39. Ma BL, Ma YM (2013) Pharmacokinetic properties, potential herb–drug interactions and acute toxicity of oral rhizoma coptidis alkaloids. Expert Opin Drug Metab Toxicol 9:51–61. https://doi.org/10.1517/17425255.2012.722995

    Article  CAS  PubMed  Google Scholar 

  40. Yang QC, Wu WH, Han FM, Chen Y (2009) Identification of in vivo and in vitro metabolites of palmatine by liquid chromatography–tandem mass spectrometry. J Pharm Pharmacol 61:647–652. https://doi.org/10.1211/jpp.61.05.0014

    Article  CAS  PubMed  Google Scholar 

  41. Gilbert B, Alves L (2003) Synergy in plant medicines. Curr Med Chem 10:13–20. https://doi.org/10.2174/0929867033368583

    Article  CAS  PubMed  Google Scholar 

  42. Williamson EM (2001) Synergy and other interactions in phytomedicines. Phytomedicine 8:401–409. https://doi.org/10.1078/0944-7113-00060

    Article  CAS  PubMed  Google Scholar 

  43. Martinelli A, Rodrigues LA, Cravo P (2008) Plasmodium chabaudi: efficacy of artemisinin+ curcumin combination treatment on a clone selected for artemisinin resistance in mice. Exp Parasitol 119:304–307. https://doi.org/10.1016/j.exppara.2008.02.011

    Article  CAS  PubMed  Google Scholar 

  44. Bhardwaj RK, Glaeser H, Becquemont L, Klotz U, Gupta SK, Fromm MF (2002) Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4. J Pharmacol Exp Ther 302:645–650. https://doi.org/10.1124/jpet.102.034728

    Article  CAS  PubMed  Google Scholar 

  45. Kumar S, Bhandari C, Sharma P, Agnihotri N (2018) Role of piperine in chemoresistance. Role of nutraceuticals in cancer chemosensitization. Elsevier, Amsterdam, pp 259–286. https://doi.org/10.1016/B978-0-12-812373-7.00013-9

    Chapter  Google Scholar 

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Authors and Affiliations

  1. Department of Biochemistry, Faculty of Life Sciences, University of Ilorin, Ilorin, Nigeria

    Adegbenro P. Adegunloye & Joseph O. Adebayo

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  1. Adegbenro P. Adegunloye
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  2. Joseph O. Adebayo
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JOA designed the study while APA carried out the bench work. JOA and APA both wrote and reviewed the manuscript.

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Correspondence to Joseph O. Adebayo.

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The handling of animals and research protocols were in adherence to guidelines approved by the University Ethical Review Committee (UERC), University of Ilorin, Nigeria with ethical approval number UERC/ASN/2016/596.

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Adegunloye, A.P., Adebayo, J.O. Piperine Enhances Antimalarial Activity of Methyl Gallate and Palmatine Combination. Acta Parasit. (2024). https://doi.org/10.1007/s11686-024-00850-x

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