Unveiling the antimalarial properties of Terminalia ivorensis (A. Chev) stem bark aqueous extract: In vivo efficacy testing and in silico predictions


Abstract views: 134 / PDF downloads: 63

Authors

  • Mariscal Brice Tchatat Tali University of Yaoundé 1, Faculty of Science, Laboratory for Phytobiochemistry and Medicinal Plants Studies, Antimicrobial and Biocontrol Agents Unit, P.O. Box 812, Yaoundé, Cameroon https://orcid.org/0000-0002-3003-5234
  • Eugenie Aimée Madiesse Kemgne Advanced Research & Health Innovation Hub, P.O. Box 20133, Yaounde, Cameroon https://orcid.org/0009-0009-4455-4738
  • Cedric Derick Jiatsa Mbouna University of Yaoundé 1, Faculty of Science, Laboratory for Phytobiochemistry and Medicinal Plants Studies, Antimicrobial and Biocontrol Agents Unit, P.O. Box 812, Yaoundé, Cameroon https://orcid.org/0000-0002-9501-6958
  • Marius Jaures Tsakem Nangap University of Yaoundé 1 Department of Animal Biology and Physiology, P.O. Box 812, Yaounde, Cameroon https://orcid.org/0009-0007-2327-6914
  • Aubin Youbi Kamche University of Yaoundé 1, Faculty of Science, Laboratory for Phytobiochemistry and Medicinal Plants Studies, Antimicrobial and Biocontrol Agents Unit, P.O. Box 812, Yaoundé, Cameroon https://orcid.org/0009-0001-4061-2912
  • Souleyman Hassan University of Yaoundé 1, Faculty of Science, Laboratory for Phytobiochemistry and Medicinal Plants Studies, Antimicrobial and Biocontrol Agents Unit, P.O. Box 812, Yaoundé, Cameroon https://orcid.org/0000-0002-2928-8613
  • Jean Claude Tchouankeu University of Yaoundé 1, Faculty of Science, Laboratory of Natural Products and Organic Synthesis, P.O. Box 812, Yaoundé, Cameroon https://orcid.org/0000-0002-5202-0316
  • Fabrice Fekam Boyom Advanced Research & Health Innovation Hub, P.O. Box 20133, Yaounde, Cameroon https://orcid.org/0000-0002-3147-364X

DOI:

https://doi.org/10.62313/ijpbp.2024.194

Keywords:

Malaria, Terminalia ivorensis, Drug efficacy, Plasmodium berghei, Biochemical markers, ADMET prediction

Abstract

Due to the spreading resistance to antimalarial drugs, new therapeutics are urgently needed, preferably with novel modes of action. Extracts from Terminalia ivorensis have previously been shown to possess activity in vitro against multidrug-resistant and drug-sensitive strains of Plasmodium falciparum. However, to the best of our knowledge, no scientific study has been published describing the antimalarial potential of these extracts through in vivo efficacy testing. This study aimed to determine the safety and antimalarial efficacy of the T. ivorensis stem bark aqueous extract (TiH2O) in a mouse model using the OECD 423 protocol and the suppressive and curative murine malaria models, and to predict in silico the pharmacokinetic properties and drug-likeness of two major phytochemical constituents. The in vivo antimalarial efficacy was assessed using the P. berghei NK65-infected mice. The TiH2O treatment impact on biochemical parameters was measured using established standard procedures. The pharmacokinetics prediction was achieved through the pkCSM predictor and Swiss ADME. The TiH2O extract was nontoxic in BALB/c mice at a lethal dose of 50 (LD50) > 2000 mg/kg. The TiH2O extract displayed strong antimalarial efficacy with 100% parasitemia suppression at 200 mg/kg b.w. after 4 days of treatment while its oral administration at 400 mg/kg b.w. in the curative model significantly decreased P. berghei parasitemia by 94.07% with a median efficacy dose (ED50) of 96.80 mg/kg. The administration of TiH2O extract restored the histological parameters disrupted by P. berghei, and the transaminase (ALT and AST) activity, creatinine, and bilirubin levels significantly decreased compared to the negative control mice. In silico explorations showed that the main constituents leucodelphidin (leucodelphinidin) and ellagic acid of the TiH2O extract have drug-like properties, thus indicating that T. ivorensis might constitute a promising source of antimalarial chemical entities with good pharmacokinetics and drug-like properties. The results obtained further corroborated the preliminary in vitro antiplasmodial studies of T. ivorensis stem bark aqueous extract. The metabolome of TiH2O extract should be further profiled in the prospects of characterizing novel natural product scaffolds to support antimalarial drug discovery.

References

Abiodun, O. O., Rodríguez-Nogales, A., Algieri, F., Gomez-Caravaca, A. M., Segura-Carretero, A., Utrilla, M. P., Rodriguez-Cabezas, M. E., & Galvez, J. (2016). Antiinflammatory and immunomodulatory activity of an ethanolic extract from the stem bark of Terminalia catappa L. (Combretaceae): In vitro and in vivo evidences. Journal of Ethnopharmacology, 192, 309-319. https://doi.org/10.1016/j.jep.2016.07.056

Anh Thu Pham, A. T. P., Dvergsnes, C., Togola, A., Wangensteen, H., Diallo, D., Paulsen, B., & Malterud, K. (2011). Terminalia macroptera, its current medicinal use and future perspectives. Journal of Ethnopharmacology, 137(3), 1486–1491. https://doi.org/10.1016/j.jep.2011.08.029

Annan, K., Sarpong, K., Asare, C., Dickson, R., Amponsah, K., Gyan, B., Ofori, M., & Gbedema, S. (2012). In vitro anti-plasmodial activity of three herbal remedies for malaria in Ghana: Adenia cissampeloides (Planch.) Harms., Termina liaivorensis A. Chev, and Elaeis guineensis Jacq. Pharmacognosy Research, 4(4), 225-229. https://doi.org/10.4103/0974-8490.102270

Appiah-Opong, R., Agyemang, K., Dotse, E., Atchoglo, P., Owusu, K. B. A., Aning, A., Sakyiamah, M., Adegle, R., Ayertey, F., & Appiah, A. A. (2022). Anti-plasmodial, cytotoxic and antioxidant activities of selected Ghanaian medicinal plants. Journal of Evidence-Based Integrative Medicine, 27. https://doi.org/10.1177/2515690X211073709

Asua, V., Conrad, M. D., Aydemir, O., Duvalsaint, M., Legac, J., Duarte, E., Tumwebaze, P., Chin, D. M., Cooper, R. A., & Yeka, A. (2021). Changing prevalence of potential mediators of aminoquinoline, antifolate, and artemisinin resistance across Uganda. The Journal of Infectious Diseases, 223(6), 985-994. https://doi.org/10.1093/infdis/jiaa687

BenSaad, L. A., Kim, K. H., Quah, C. C., Kim, W. R., & Shahimi, M. (2017). Anti-inflammatory potential of ellagic acid, gallic acid and punicalagin A&B isolated from Punica granatum. BMC Complementary and Alternative Medicine, 17, 47. https://doi.org/10.1186/s12906-017-1555-0

Biruk, H., Sentayehu, B., Alebachew, Y., Tamiru, W., Ejigu, A., & Assefa, S. (2020). In vivo antimalarial activity of 80% methanol and aqueous bark extracts of Terminalia brownii fresen.(Combretaceae) against Plasmodium berghei in mice. Biochemistry Research International, 2020, 9749410. https://doi.org/10.1155/2020/9749410

Camara, A., Haddad, M., Reybier, K., Traoré, M. S., Baldé, M. A., Royo, J., Baldé, A. O., Batigne, P., Haidara, M., & Baldé, E. S. (2019). Terminalia albida treatment improves survival in experimental cerebral malaria through reactive oxygen species scavenging and anti-inflammatory properties. Malaria Journal, 18, 431. https://doi.org/10.1186/s12936-019-3071-9

da Silva Junior, G. B., Pinto, J. R., Barros, E. J. G., Farias, G. M. N., & Daher, E. D. F. (2017). Kidney involvement in malaria: An update. Revista do Instituto de Medicina Tropical de São Paulo, 59, e53. https://doi.org/10.1590/S1678-9946201759053

Daina, A., Michielin, O., & Zoete, V. (2017). SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports, 7, 42717. https://doi.org/10.1038/srep42717

de Araujo, A. R., Ramos-Jesus, J., de Oliveira, T. M., de Carvalho, A. M. A., Nunes, P. H. M., Daboit, T. C., Carvalho, A. P., Barroso, M. F., de Almeida, M. P., & Plácido, A. (2019). Identification of Eschweilenol C in derivative of Terminalia fagifolia Mart. and green synthesis of bioactive and biocompatible silver nanoparticles. Industrial Crops and Products, 137, 52-65. https://doi.org/10.1016/j.indcrop.2019.05.012

Deepika, & Maurya, P. K. (2022). Ellagic acid: insight into its protective effects in age-associated disorders. 3 Biotech, 12, 340. https://doi.org/10.1007/s13205-022-03409-7

Eloff, J., Katerere, D., & McGaw, L. (2008). The biological activity and chemistry of the southern African Combretaceae. Journal of Ethnopharmacology, 119(3), 686-699. https://doi.org/10.1016/j.jep.2008.07.051

Knight, D. J., & Peters, W. (1980). The antimalarial activity of N-benzyloxydihydrotriazines: I. The activity of clociguanil (BRL 50216) against rodent malaria, and studies on its mode of action. Annals of Tropical Medicine & Parasitology, 74(4), 393-404. https://doi.org/10.1080/00034983.1980.11687360

Komlaga, G., Cojean, S., Dickson, R. A., Beniddir, M. A., Suyyagh-Albouz, S., Mensah, M. L., Agyare, C., Champy, P., & Loiseau, P. M. (2016). Antiplasmodial activity of selected medicinal plants used to treat malaria in Ghana. Parasitology Research, 115, 3185-3195. https://doi.org/10.1007/s00436-016-5080-8

Landau, I., Chabaud, A., Mora-Silvera, E., Coquelin, F., Boulard, Y., Renia, L., & Snounou, G. (1999). Survival of rodent malaria merozoites in the lymphatic network: potential role in chronicity of the infection. Parasite, 6(4), 311-322. https://doi.org/10.1051/parasite/1999064311

Luth, M. R., Gupta, P., Ottilie, S., & Winzeler, E. A. (2018). Using in vitro evolution and whole genome analysis to discover next generation targets for antimalarial drug discovery. ACS Infectious Diseases, 4(3), 301-314. https://doi.org/10.1021/acsinfecdis.7b00276

Mihreteab, S., Platon, L., Berhane, A., Stokes, B. H., Warsame, M., Campagne, P., Criscuolo, A., Ma, L., Petiot, N., & Doderer-Lang, C. (2023). Increasing prevalence of artemisinin-resistant HRP2-negative malaria in Eritrea. New England Journal of Medicine, 389(13), 1191-1202. https://doi.org/10.1056/NEJMoa2210956

Njomnang Soh, P., Witkowski, B., Gales, A., Huyghe, E., Berry, A., Pipy, B., & Benoit-Vical, F. (2012). Implication of glutathione in the in vitro antiplasmodial mechanism of action of ellagic acid. PLoS ONE, 7(9), e45906. https://doi.org/10.1371/journal.pone.0045906

OECD (2002). OECD Guidelines for the Testing of Chemicals, Section 4, Test No. 423: Acute Oral Toxicity - Acute Toxic Class Method. Oecd Guideline for Testing of Chemicals (Issue December).

Paquet, T., Le Manach, C., Cabrera, D. G., Younis, Y., Henrich, P. P., Abraham, T. S., Lee, M. C., Basak, R., Ghidelli-Disse, S., & Lafuente-Monasterio, M. J. (2017). Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase. Science Translational Medicine, 9(387), eaad9735. https://doi.org/10.1126/scitranslmed.aad9735

Pires, D. E., Blundell, T. L., & Ascher, D. B. (2015). pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. Journal of Medicinal Chemistry, 58(9), 4066-4072. https://doi.org/10.1021/acs.jmedchem.5b00104

Rocamora, F., & Winzeler, E. A. (2020). Genomic approaches to drug resistance in malaria. Annual Review of Microbiology, 74, 761-786. https://doi.org/10.1146/annurev-micro-012220-064343

Singh, A., & Rosenthal, P. J. (2001). Comparison of efficacies of cysteine protease inhibitors against five strains of Plasmodium falciparum. Antimicrobial Agents and Chemotherapy, 45(3), 949-951.

Sinxadi, P., Donini, C., Johnstone, H., Langdon, G., Wiesner, L., Allen, E., Duparc, S., Chalon, S., McCarthy, J. S., & Lorch, U. (2020). Safety, tolerability, pharmacokinetics, and antimalarial activity of the novel Plasmodium phosphatidylinositol 4-kinase inhibitor MMV390048 in healthy volunteers. Antimicrobial Agents and Chemotherapy, 64, aac.01896-01819. https://doi.org/10.1128/aac.01896-19

Sloan, R. C., Rosenbaum, M., O'Rourke, D., Oppelt, K., Frasier, C. R., Waston, C. A., Allan, A. G., & Brown, D. A. (2011). High doses of ketamine–xylazine anesthesia reduce cardiac ischemia–reperfusion injury in guinea pigs. Journal of the American Association for Laboratory Animal Science, 50(3), 349-354.

Solyakov, L., Halbert, J., Alam, M. M., Semblat, J. P., Dorin-Semblat, D., Reininger, L., Bottrill, A. R., Mistry, S., Abdi, A., & Fennell, C. (2011). Global kinomic and phospho-proteomic analyses of the human malaria parasite Plasmodium falciparum. Nature Communications, 2(1), 565. https://doi.org/10.1038/ncomms1558

Sumbe, R. R., & Barkade, G. D. (2023). A systematic review on malaria. Indian Journal of Pharmacy and Pharmacology, 10(2), 54-63. https://doi.org/10.18231/j.ijpp.2023.014

Tali, M. B. T., Dize, D., Wouamba, S. C. N., Fokou, P. V. T., Keumoe, R., Ngansop, C. N., Njionhou, M. S. N., Mbouna, C. D. J., Tchokouaha, L. R. Y., & Maharaj, V. (2022). In vitro antiplasmodial activity-directed investigation and UPLC–MS fingerprint of promising extracts and fractions from Terminalia ivorensis A. Chev. and Terminalia brownii Fresen. Journal of Ethnopharmacology, 296, 115512. https://doi.org/10.1016/j.jep.2022.115512

Tewari, R., Straschil, U., Bateman, A., Böhme, U., Cherevach, I., Gong, P., Pain, A., & Billker, O. (2010). The systematic functional analysis of Plasmodium protein kinases identifies essential regulators of mosquito transmission. Cell Host & Microbe, 8(4), 377-387. http://dx.doi.org/doi:10.1016/j.chom.2010.09.006

Uwimana, A., Legrand, E., Stokes, B. H., Ndikumana, J. L. M., Warsame, M., Umulisa, N., Ngamije, D., Munyaneza, T., Mazarati, J. B., & Munguti, K. (2020). Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda. Nature Medicine, 26(10), 1602-1608. https://doi.org/10.1038/s41591-020-1005-2

Uwimana, A., Umulisa, N., Venkatesan, M., Svigel, S. S., Zhou, Z., Munyaneza, T., Habimana, R. M., Rucogoza, A., Moriarty, L. F., & Sandford, R. (2021). Association of Plasmodium falciparum kelch13 R561H genotypes with delayed parasite clearance in Rwanda: an open-label, single-arm, multicentre, therapeutic efficacy study. The Lancet Infectious Diseases, 21(8), 1120-1128. https://doi.org/10.1016/S1473-3099(21)00142-0

World Malaria Report (2022). Geneva: World Health Organization; 2022. Licence: CC BY-NC-SA 3.0 IGO.

World Malaria Report (2023). World malaria report 2023. https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2023.

Downloads

Published

03.04.2024

How to Cite

Tchatat Tali, M. B., Madiesse Kemgne, E. A., Jiatsa Mbouna, C. D., Tsakem Nangap, M. J., Youbi Kamche, A., Hassan, S., Tchouankeu, J. C., & Boyom, F. F. (2024). Unveiling the antimalarial properties of Terminalia ivorensis (A. Chev) stem bark aqueous extract: In vivo efficacy testing and in silico predictions. International Journal of Plant Based Pharmaceuticals, 4(1), 30–39. https://doi.org/10.62313/ijpbp.2024.194

Issue

Section

Research Articles
Received 2024-02-07
Accepted 2024-04-03
Published 2024-04-03