Abstract
Traditional medicines have been used to treat malaria for thousands of years and are the source of artemisinin and quinine derivatives. With the increasing levels of drug resistance, the high cost of artemisisnin-based combination therapies, and fake antimalarials drugs, traditional medicine have become an important and sustainable source of malaria treatment. For the benefit of those who use traditional medicine to treat malaria, there is an urgent need to study the efficacy and toxicity of herbal remedies. Hintonia latiflora stem bark infusions are use in Mexican traditional medicine to treat malaria, diabetes, and gastrointestinal diseases. Its efficacy in the treatment of complicated malaria and its ability to generate DNA damage to the host is not fully evaluated. In our search for antimalarial natural products, in the present study, we tested the efficacy of H. latiflora stem bark methanolic extract (HlMeOHe) in CD1 male mice infected with lethal Plasmodium yoelii yoelii and its in vivo cytotoxicity and genotoxicity. To assess the antimalarial activity, the extract was evaluated in a 4-day test scheme in oral doses of 1,200, 600, and 300 mg/kg prior acute toxicity test; oral chloroquine (15 mg/kg) was used as positive control. The ability of 1,200 mg/kg of HlMeOHe to induce cytotoxicity and DNA damage in the peripheral blood of mice was assessed using a fluorochrome-mediated viability test and the micronucleus (MN) assay; N-ethyl-N-nitrosourea (ENU) was used as a positive control. HlMeOHe median acute toxicity (LD50) was 2,783.71 mg/kg and LD10 was 1,293.76 mg/kg (taken as the highest work dose). Plasmodium yoelii yoelii-infected mice in the untreated control group died between 6 and 7 days post-infection (PI) with parasitemia over 70 %. Even though mice treated with 600 and 300 mg/kg showed a chemosuppression percentage of total parasitemia of 99.23 and 23.66, respectively, animals in both groups died 6 to 7 days PI with parasitemia over 45 %. A 4-day dosage of 1,200 mg/kg of the extract showed, in the P. yoelii yoelii-infected mice, a 100 % chemosuppression of total parasitemia on 5 days PI and a 23 days survival time with a mean parasitemia of 23.6 % at the date of death. Only mice treated with chloroquine survived until the end of the experiment. Cell viability was not affected. The average number of micronuclei in the treated mice increased significantly (P < 0.05) to 4.8 MN when compared with the untreated control group (0.9 MN). The results obtained in this study showed that the infection outcome of P. yoelii yoelii-infected mice is affected by HlMeOHe. Although a concentration of 1,200 mg/kg of HlMeOHe is suitable to use in the treatment of malaria fever, slowed down the parasite replication, retarded the patency time, and increased the infected P. yoelii yoelii mice survival time, its chemical composition should be studied in detail in order to reduce its genotoxic potential.
Similar content being viewed by others
References
Aguilar CA, Camacho PJR (1998) Plantas medicinales del herbario IMSS: su distribución por enfermedades. IMSS, México, pp 112–113
Argotte RR, Ramírez AG, Rodríguez GM, Ovilla MM, LAnz MH, Rodríguez MH, González CM, Alvarez L (2006) Antimalarial 4-phenylcoumarins from the stem bark of Hintonia latiflora. J Nat Prod 69(10):1442–1444
Bagavan A, Rahuman AA, Kaushik NK, Sahal D (2011) In vitro antimalarial activity of medicinal plant extracts against Plasmodium falciparum. Parasitol Res 108:15–22
Baumann J, Von Brucchau Sen F, Wurm G (1980) Flavonoids and related compounds as inhibition of arachidonic acid peroxidation. Prostaglandins 20:627–639
Bero J, Frédérich M, Joëlle QL (2009) Antimalarials compounds isolated from plants used in traditional medicine. Pharm Pharmacol 61:1401–1433
Biblioteca Digital de la Medicina Tradicional Mexicana© D.R. Hecho en México (2009). http://www.medicinatradicionalmexicana.unam.mx/index.php. Accessed 26 November 2013
Bruguera M, Herrera S, Lázaro E, Madurga M, Navarro M, de Abajo F (2007) Hepatitis aguda asociada al consumo de copalchi. A prpósito de 5 casos. Gastroenterol Hepatol 30(2):66–68
Cock IE (2011) Problems of reproducibility and efficacy of bioassays using crude extracts, with reference to Aloe vera. Pharmacogn Commun 1(1):52–62
Cristians S, Bye R, Navarrete A, Mata R (2013) Gastroprotective effect of Hintonia latiflora and Hintonia standleyana aqueous extracts and compounds. J Ethnopharmacol 145:530–535
Eloff NJ (1998) Which extractant should be used for the screening and isolation of antimicrobial components from plants. J Ethnopharmacol 60:1–8
European Medicines Agency London (2008) Guideline on the assessment of genotoxicity of herbal substances/preparations. www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003569.pdf. Accessed 26 Nov 2013
Fasinu PS, Bouic PJ, Rosenkranz B (2012) An overview of the evidence and mechanisms of herb-drug interactions. Front Pharmacol 3:1–19
Fernandes LM, Garcez WS, Mantovani MS, Figueiredo PO, Fernandes CA, Garcez SR, Guterres ZR (2013) Assesemment of the in vitro and in vivo genotoxicity of extracts and indole monoterpene alkaloid from the roots of Galianthe thalictroides (Rubiaceae). Food Chem Toxicol 59:405–411
Guerrero AJ, Medina CO, Brindis O, Bye R, Pedraza CHJ, Nacarrete A, Mata R (2007) Antidiabetic properties of selected Mexican copalchis of the Rubiaceae family. Phytochem 68:2087–2095
Hayashi M, Morita T, Kodama Y, Sofuni T, Ishidate M Jr (1990) The micronucleus assay with mouse peripheral blood reticulocytes using acridine orange-coated slides. Mutat Res 245:245–249
Jena GB, Kaul CL, Ramarao P (2002) Genotoxicity testing, a regulatory requirement for drug discovery and development: impact of ICH guidelines. Indian J Pharmacol 34:86–99
Kesara N, Phunuch M, Ronnatari R, Wanna C, Juntra K (2013) Identification of resistance of Plasmodium falciparum to artesunate-mefloquine combination in an area along the Thai-Myanmar border. Malar J 12:1–14
Kumar PA, Jeyakandan M, Kumar MA, Selvam G (2011) Exploring potential of quinoxaline moiety. Int J Pharm Tech Res 3:386–392
Leyte LM, Figueroa M, González MC, Gelnn AE, González AM, Mata R (2013) Metabolites from the entophytic fungus Sporomiella minimoides isolated from Hintonia latiflora. Phytochem 96:273–278
Martínez M (1969) Las Plantas Medicinales de México, 1st edn. Andrés Botas, México, pp 86–87
Mata R, Acevedo L, Méndez BD, Guerrero AJ, Rivero BE, Rodrígez JM (2008) Development and validation of liquid chromatography method for quantification of the active markers of Hintonia standleyana and Hintonia latiflora crude drugs. Pharm Biol 46:105–110
Mata R, Cristians S, Escandón RS, Juárez RK, Rivero CI (2013) Mexican antidiabetic herbs: valuable sources of inhibitors of α glucosidases. J Nat Prod 76(3):468–483
Monroy O, Castillo EP (2000) Plantas medicinales utilizadas en el Estado de Morelos. Centro de Investigaciones Biológicas. UAEM, México, pp 214–215
Muregi FW, Kirira PG, Ishih A (2011) Novel rational drug design strategies with potential to revolutionize malaria chemotherapy. Curr Med Chem 18(1):113–143
Noster S, Kraus I (1990) In vitro antimalarial activity of Coutarea latoflora and Exostema caribaeum extracts on Plasmodium falciparum. Planta Med 56:63–65
Oliveira PRN, Testa G, Medina RP, Oliveira MA, Kato L, da Silva CC, Carvalho JE, Santin MO (2013) Cytotoxicity activity of Guettarda pohlinana Müll. Arg. (Rubiaceae). Nat Prod Res 27(18):1677–1681
Owolabi MS, Lawal OA, Dosoky NS, Satyal P, William N (2013) Chemical composition, antimicrobial, and cytotoxic assessment of Mitracarpus scaber Zucc. (Rubiaceae) essential oil from southwestern Nigeria. Am J Ess Oils Nat Prod 1(1):4–6
Peters W, Robinson BL (1992) The chemotherapy of rodent malaria. XLVII. Studies on pyronaridine and other Mannich base antimalarials. Ann Trop Med Parasitol 86(5):455–465
Ravikumar S, Inbaneson SJ, Suganthi P, Ramasmy G, Venkatesan M (2011a) In vitro antiplasmodial activity of ethanolic extracts of seaweed macroalgae against Plasmodium falciparum. Parasitol Res 108:1411–1416
Ravikumar S, Inbaneson SJ, Suganthi P, Gnanadesigan M (2011b) In vitro antiplasmodial activity of ethanolic extracts of mangrove plants from South East coast of India against chloroquine-sensitive Plasmodium falciparum. Parasitol Res 108:873–878
Rivera N, Marrero PY, Arán VJ, Martínez C, Malagón F (2013a) Biological assay of a novel quinoxalinone with antimalarial efficacy on Plasmodium yoelii yoelii. Parasitol Res 112(4):1523–1527
Rivera N, Rojas M, Zepeda A, Malagón F, Arán VJ, Marreo PG, Rivera E, Fortoul TI (2013b) In vivo genotoxicity and cytotoxicity assessment of a novel quinoxalinone with trichomonacide activity. J Appl Toxicol 33(12):1493–1499
Stevens LH, Stoopen GM, Elbers IJW, Molthoff JW, Bakker HAC, Lommen A, Bosch DW (2000) Effect of climate conditions and plant development stage on the stability of antibodies expressed in transgenic tobacco. Plant Physiol 124(1):173–182
Strauss GHS (1991) Non- random cell killing in cryopreservation: implications for performance of the battery of leukocytes tests (BLT), I. Toxic and immunotoxic effects. Mutat Res 252:1–15
Taamali A, Abaza L, Arráez RD, Segura CA, Fernández GA, Zarrouk M, Youssef NB (2013) Characterization of phenolic compounds by HPLC-TOF/IT/MS in buds and open flowers of chemali olive cultivar. Phytochem Anal. doi:10.1002/pca.2450
Taraknath C, Muhkopadhyay A, Khan KA, Giri AK (1998) Comparative mutagenic and genotoxic effects of three antimalarial drugs, chloroquine, primaquine and amodiaquine. Mutagenesis 13(6):619–624
Traore MS, Baldé MA, Diallo MST, Baldé ES, Diané S, Camara A, Diallo A, Balde A, Keita A, Keita SM, Oularé K, Magassouba FB, Diakité I, Pieters L, Baldé AM (2013) Ethnobotanical survey on medicinal plants used by Guinean traditional healers in the treatment of malaria. J Ethnopharmacol. doi:10.1016/j.jep.2013.10.048
Vickers A, Zollman C (1999) ABC of complementary medicine. Br Med J 319:1050–1053
WHO (2011) The world medicine situation. Traditional medicines: global situations, issues and challenges. WHO, Genebra, 12p
Willaman JJ (1961) Alkaloid-bearing plants and their contained alkaloids. Agricultural Research Service, Department of Agriculture, Washington DC, 1234
Acknowledgments
This research was partially supported by project CONACyT 182003 and by projects PAPIIT-DGAPA IN-229611 and IN-209612, UNAM. Marcela Rojas is a Postgraduate student in Biological Sciences, UNAM, and the recipient of a CONACyT scholarship (grant 216027). Diana Reynada is an undergraduate Biology student, UNAM. The authors thank Alfonso E. Campos Sepúlveda and Ma. Elena Martínez Enriquez for their technical assistance. We also appreciate the technical assistance of Enrique Pinzón Estrada and Ismael Torres Saldaña.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Rivera, N., López, P.Y., Rojas, M. et al. Antimalarial efficacy, cytotoxicity, and genotoxicity of methanolic stem bark extract from Hintonia latiflora in a Plasmodium yoelii yoelii lethal murine malaria model. Parasitol Res 113, 1529–1536 (2014). https://doi.org/10.1007/s00436-014-3797-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00436-014-3797-9