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Antimalarial properties and preventive effects on mitochondrial dysfunction by extract and fractions of Phyllanthus amarus (Schum. and Thonn) in Plasmodium berghei-infected mice

  • John Oludele Olanlokun EMAIL logo , Cecilia Opeyemi Babarinde and Olufunso Olabode Olorunsogo
Published/Copyright: November 9, 2020

Abstract

Objectives

Broad spectrum antimalarial drugs without deleterious effects on mitochondria are scarce. It is in this regard that we investigated the potency of methanol extract and solvent fractions of Phyllanthus amarus on chloroquine-susceptible and resistant strains of Plasmodium berghei, toxicity and its consequential effects on mitochondrial permeability transition (mPT) pore opening.

Methods

Malaria was induced in male Swiss mice with susceptible (NK 65) strain, divided into groups (n=5) and treated with 100, 200 and 400 mg/kg of methanol extract, n-hexane, dichloromethane, ethylacetate and methanol fractions daily for seven days. Percentage parasitemia and parasite clearance were determined microscopically. The two most potent fractions were tested on resistant (ANKA) strains. Heme and hemozoin contents were determined spectrophotometrically. The mPT, mitochondrial ATPase (mATPase) and lipid peroxidation (mLPO) were determined spectrophotometrically. Similar groups of animals were used for toxicity studies.

Results

Dichloromethane fraction (400 mg/kg) had the highest antimalarial curative effect via least parasitemia (0.49) and high clearance (96.63) compared with the negative control (10.08, 0.00, respectively), had the highest heme and least hemozoin contents (16.23; 0.03) compared with the negative control (8.2, 0.126, respectively). Malaria infection opened the mPT, caused significant increase in mLPO and enhanced mATPase; while dichloromethane fraction reversed these conditions. Serum ALT, AST, ALP, GGT, urea and creatinine of dichloromethane fraction-treated mice decreased relative to control. No significant lesion was noticed in liver and kidney tissue sections.

Conclusions

Dichloromethane fraction of Phyllanthus amarus had the highest antimalarial activity with the highest mito-protective effect and it was well tolerated without toxic effects.


Corresponding author: John Oludele Olanlokun, Laboratories for Biomembrane Research and Biotechnology, Department of Biochemistry, University of Ibadan, Ibadan, Nigeria, E-mail:

Acknowledgments

The authors acknowledge Professor O.G. Ademowo of Institute of Advanced Medical Research and Training (IAMRAT), College of Medicine, University of Ibadan, for supplying both chloroquine susceptible and resistant strains of Plasmodium berghei. We also appreciate Mr. Eric Sabo who operated the ultra centrifuge.

  1. Research funding: None declared.

  2. Author contributions: JOO conceived this idea and designed this experiment, wrote the manuscript, COB treated the animals and ran the assays, OOO supplied equipment for the study. All authors read and approved the manuscript.

  3. Competing interests: Authors declared that there is no conflict of interest.

  4. Ethical approval: This research involves the use of and the handling of experimental animals was conform with the World Medical Association Declaration of Helsinki regarding ethical conduct of research involving experimental animals.

References

1. World Health Organisation. Guidelines for the Treatment of Malaria. Geneva, Switzerland: World Health Organization; 2015.Search in Google Scholar

2. Olanlokun, JO, Balogun, AA, Olorunsogo, OO. Regulated rutin co-administration reverses mitochondrial-mediated apoptosis in Plasmodium berghei-infected mice. BiochemBiophys Res Comm 2020;522:328–34. https://doi.org/10.1016/j.bbrc.2019.11.067. 31767147.Search in Google Scholar

3. Newman, DJ, Cragg, GM. Natural products as sources of new drugs over the last 25 years. J Nat Prod 2007;70:461–77. https://doi.org/10.1021/np068054v.Search in Google Scholar

4. Schmidt, TJ, Khalid, SA, Romanha, AJ, Alves, TMA, Biavatti, MW, Brun, R, et al.. The potential of secondary metabolites from plants as drugs or leads against protozoan neglected diseases—Part I. Curr Med Chem 2012;19:2128–75. https://doi.org/10.2174/092986712800229023.Search in Google Scholar

5. Pohlit, AM, Lima, RBS, Frausin, G, Rocha E Silva, LF, Lopes, S, Moraes, CB, et al.. Amazonian plant natural products: perspectives for discovery new antimalarial drug leads. Molecules 2013;18:9219–40. https://doi.org/.10.3390/molecules18089219.10.3390/molecules18089219Search in Google Scholar

6. Olanlokun, JO, Balogun, FA, Olorunsogo, OO. Chemotherapeutic and prophylactic antimalarial drugs induce cell death through mitochondrial-mediated apoptosis in murine models. Drug Chem Toxicol 2018. https://doi.org/10.1080/01480545.2018.1536139.Search in Google Scholar

7. Gopalakrishnan, AM, Kumar, N. Antimalarial action of artesunate involves DNA damage mediated by reactive oxygen species. Antimicrob Agents Chemother 2015. https://doi.org/10.1128/AAC.03663-14.Search in Google Scholar

8. Alkadi, HO. Antimalarial drug toxicity: a review. Chemotherapy 2007;53:385–91. https://doi.org/10.1159/000109767.Search in Google Scholar

9. Ryley, JF, Peters, W. The antimalarial activity of some quinolone esters. Ann Trop Med Parasitol 1970;84:209–22. https://doi.org/10.1080/00034983.1970.11686683.Search in Google Scholar

10. Asakura, T, Minakata, K, Adachi, K, Russell, MO, Schwartz, E. Denatured hemoglobin in sickle erythrocytes. J Clin Invest 1977;59:633–40. https://doi.org/10.1172/jci108681.Search in Google Scholar

11. Orjih, AU, Fitch, CD. Hemozoin production by Plasmodium falciparum variation with strain and exposure to chloroquine. Biochim Biophys Acta 1993;1157:270–4. https://doi.org/10.1016/0304-4165(93)90109-l.Search in Google Scholar

12. Johnson, D, Lardy, H. Isolation of liver or kidney mitochondria. Methods Enzymol 1967;10:94–6. https://doi.org/10.1016/0076-6879(67)10018-9.Search in Google Scholar

13. Lapidus, RG, Sokolove, PM. Spermine inhibition of the permeability transition of isolated rat liver mitochondria: an investigation of mechanism. J Biochem Biophys Met 1993;64:246–53. https://doi.org/10.1006/abbi.1993.1507.Search in Google Scholar

14. Lardy, HA, Wellman, H. The catalyst effects of 2, 4-dinitrophenol on adenosine triphosphatase hydrolysis by cell particles and soluble enzymes. J Biol Chem 1953;201:357–70. 13044805.10.1016/S0021-9258(18)71378-1Search in Google Scholar

15. Varshney, R, Kale, RK. Effects of calmodulin antagonists on radiation-induced lipid peroxidation in microsomes. Int J Radiat Biol 1990;58:733–43. https://doi.org/10.1080/09553009014552121.Search in Google Scholar

16. Adam-Vizi, V, Seregi, A. Receptor independent stimulatory effect of nor-adrenaline on Na+/K+-ATPase in rat brain homogenate. Role of lipid peroxidation. Biochem Pharmacol 1982;34:2231–6. https://doi.org/10.1016/0006-2952(82)90106-x.Search in Google Scholar

17. Ajala, TO, Igwilo, CI, Oreagba, IA, Odeku, OA. The antiplasmodial effect of the extracts and formulated capsules of Phyllanthus amarus on Plasmodium yoelii infection in mice. AsianAsian Pac J Trop Med 2011;4:283–7. https://doi.org/10.1016/s1995-7645(11)60087-4.Search in Google Scholar

18. Haldar, K, Mohandas, N. Malaria, erythrocytic infection, and anemia. Hematology Am Soc Hematol Educ Program 2009;1:87–93. doi:https://doi.org/10.1182/asheducation.2009.1.87.Search in Google Scholar

19. Tekwani, BL, Walker, LA. Targeting the hemozoin synthesis pathway for new antimalarial drug discovery: technologies for in vitro beta-hematin formation assay. Comb Chem High Throughput Screen 2005;8:63–79. https://doi.org/10.2174/1386207053328101.Search in Google Scholar

20. Baines, CP. The mitochondrial permeability transition pore and ischemia reperfusion injury. Basic Res Cardiol 2009;104:181–8. https://doi.org/10.1007/s00395-009-0004-8.Search in Google Scholar

21. Marrelli, MT, Brotto, M. The effect of malaria and anti-malarial drugs on skeletal and cardiac muscles. Malar J 2016;15:524. https://doi.org/10.1186/s12936-016-1577-y.Search in Google Scholar

22. van Niekerk, DD, Penkler, GP, Toit, F, Snoep, JL. Targeting glycolysis in the malaria parasite Plasmodium falciparum. FEBS J 2016;283:634–46. https://doi.org/10.1111/febs.13615.Search in Google Scholar

23. Alam, A, Neyaz, K, Hasan, SI. Exploiting Unique Structural and Functional Properties of malarial glycolytic enzymes forantimalarial drug development. Mal Res Treat 2014. https://doi.org/10.1155/2014/451065.Search in Google Scholar

24. Zorova, LD, Popkov, VA, Plotnikov, EY, Silachev, DN, Pevzner, IB, Jankauskas, SS, et al.. Mitochondrial membrane potential. Anal Biochem 2018;552:50–9. doi:https://doi.org/10.1016/j.ab.2017.07.009.Search in Google Scholar

25. Long, Q, Yang, K, Yang, Q. Regulation of mitochondrial ATP synthasein cardiac pathophysiology. Am J Cardiocasc Dis 2015;5:19–32. 26064790.Search in Google Scholar

26. Barbato, S, Sgarbi, G, Gorini, G, Baracca, A, Solaini, G. The inhibitor protein (IF1) of the F1F0-ATPase modulates human osteosarcoma cell bioenergetics. J Bio Chem 2015;290:6338–48. https://doi.org/10.1074/jbc.m114.631788.Search in Google Scholar

27. Kain, HS, Glennon, KK, Vjayan, K, Arang, N, Douglass, AN, Fortin, CL, et al.. Liver stage malaria infection is controlled by host regulators of lipid peroxidation. Cell Death Differ 2019;27:44–54. https://doi.org/10.1038/s41418-019-0338-1.Search in Google Scholar

28. Scaccabarozzi, D, Deroost, K, Corbett, Y, Lays, N, Corsetto, P, Salè, FO, et al.. Differential induction of malaria liverpathology in mice infected with Plasmodiumchabaudi AS or Plasmodium berghei NK65. Malar J 2018;17:18. https://doi.org/10.1186/s12936-017-2159-3.Search in Google Scholar

29. Ozer, J, Ratner, M, Shaw, M, Bailey, W, Schomaker, S. The current state of serum biomarkers of hepatotoxicity. Toxicology 2008;245:194–205. https://doi.org/10.1016/j.tox.2007.11.021.Search in Google Scholar

30. Meyer, DJ, Harvey, JW. Hepatobiliary and skeletal muscle enzymes and liver function tests. In: Meyer, DJ, Harvey, JW, editors. Veterinary laboratory medicine: interpretation and diagnosis, 3rd ed. St. Louis (MO): Saunders; 2004. 169–92 pp.Search in Google Scholar

31. Boone, L, Meyer, D, Cusick, P, Ennulat, D, Provencher Bolliger, A, Everds, N, et al.. Selection and interpretation of clinical pathology indicators of hepatic injury in preclinical studies. Vet Clin Pathol 2005;34:182–8. https://doi.org/10.1111/j.1939-165x.2005.tb00041.x.Search in Google Scholar

32. Willebrords, J, Pereira, IV, Maes, M, Cogliati, B, Vinken, M. Strategies, models and biomarkers in experimental non-alcoholic fatty liver disease research. Prog Lipid Res 2015;59:106–25. https://doi.org/10.1016/j.plipres.2015.05.002.Search in Google Scholar

33. Chen, CA, Chen, M. Simultaneous occurrence of hepatic focal nodular hyperplasia and uterine endometrial stromal nodule in a patient having treated breast infiltrating ductal carcinoma. Acta Obstet Gynecol Scand 2003;82:585–6. https://doi.org/10.1034/j.1600-0412.2003.00142.x.Search in Google Scholar

34. Rowaiye, AB, Omobowale, T, Salami, SA, Asala, TM, Oni, SO, Aiyedoju, A, et al.. Investigating the ameliorative effects of the aqueous extract of Pleurotus ostreatus on cyclophosphamide-induced cytotoxicity in rabbits. Toxicol Environ Health Sci 2020. https://doi.org/10.1007/s13530-020-00014-0.Search in Google Scholar

Received: 2020-03-14
Accepted: 2020-07-25
Published Online: 2020-11-09

© 2020 Walter de Gruyter GmbH, Berlin/Boston

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