Abstract
In the search for new therapeutic agents for Chagas’ disease, we screened extracts obtained from the Brazilian plant Pterodon pubescens found commercially in the medicinal flora market. We investigated the potential trypanocidal effect of the oleaginous ethanolic extract of P. pubescens seeds and its fractions (PF1, PF1.1, PF1.2, and PF1.3) and of geranylgeraniol (GG-OH), the sole component of the hexane fraction (PF1.2). In experiments with bloodstream trypomastigotes of Trypanosoma cruzi, performed at 37°C in culture medium, PF1.2 and GG-OH showed similar potency, while the oleaginous extract from P. pubescens seeds and the other fractions were about three times less active. GG-OH inhibited the proliferation of intracellular amastigotes, at concentrations which do not affect the mammalian host cell. Transmission electron microscopy and flow cytometry analysis indicate the mitochondrion, an organelle that plays a central role in apoptosis, of both epimastigotes and of trypomastigotes as the major target of GG-OH. On the other hand, the ultrastructural images of the endoplasmic reticulum profiles, myelin-like figures, and concentric membranous arrangements inside damaged mitochondrion are suggestive of an autophagic pathway leading to parasite death. Because the different forms of cell death share some morphological features such as mitochondrial collapse, further studies are needed to disclose the trypanocidal action of GG-OH.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Arriaga AMC, Castro MAB, Silveira ER, Braz-Filho R (2000) Further diterpenoids isolated from Pterodon polygalaeflorus. J Braz Chem Soc 11:187–190
Braga MV, de Souza W (2006) Effects of protein kinase and phosphatidylinositol-3 kinase inhibitors on growth and ultrastructure of Trypanosoma cruzi. FEMS Microbiol Lett 256:209–216
Bras M, Queenan B, Susin SA (2005) Programmed cell death via mitochondria: different modes of dying. Biochemistry 70:231–239
Braz-Filho R, Gottlieb OR (1971) The isoflavones from Pterodon pubescens. Phytochemistry 10:2835–2836
Calixto NO, Costa-e-Silva MC, Gayer CR, Coelho MG, Paes MC, Todeschini AR (2007) Antiplatelet activity of geranylgeraniol isolated from Pterodon pubescens fruit oil is mediated by inhibition of cyclooxygenase-1. Planta Med 73:480–483
Coelho MGP, Marques PR, Gayer CR, Vaz LC, Neto JF, Sabino KC (2001) Subacute toxicity evaluation of a hydroalcoholic extract of Pterodon pubescens seeds in mice with collagen-induced arthritis. J Ethnopharmacol 77:159–164
Coelho MGP, Sabino KC, Dalmau SR (2004) Immunomodulatory effects of sucupira (Pterodon pubescens) seed infusion on collagen-induced arthritis. Clin Exp Rheumatol 22:213–218
Coelho LP, Reis PA, de Castro FL, Gayer CR, Lopes CS, Silva MC, Sabino KC, Todeschini AR, Coelho MGP (2005) Antinociceptive properties of ethanolic extract and fractions of Pterodon pubescens Benth seeds. J Ethnopharmacol 98:109–116
Coura JR, de Castro SL (2002) A critical review on Chagas disease chemotherapy. Mem Inst Oswaldo Cruz 97:3–24
De Castro SL, Pinto MCFR, Pinto AV (1994) Screening of natural and synthetic drugs Trypanosoma cruzi: I-Establishing a structure/activity relationship. Microbios 78:83–90
Fascio M, Mors WB, Gilbert B, Mahajan IR, Monteiro MB, Dos Santos Filho D, Vichnewiski W (1976) Diterpenoid furans from Pterodon species. Phytochemistry 15:201–203
Hacker G, Paschen SA (2007) Therapeutic targets in the mitochondrial apoptotic pathway. Expert Opin Ther Targets 11:515–526
Inoue Y, Hada T, Shiraishi A, Hirose K, Hamashima H, Kobayashi S (2005) Biphasic effects of geranylgeraniol, teprenone, and phytol on the growth of Staphylococcus aureus. Antimicrob Agents Chemother 49:1770–1774
Katz N, dos Santos Filho D, Sarti SJ, Mendes NM, Rocha Filho PA, Araujo N (1993) Chemoprophylactic activity on Schistosomiasis mansoni of soaps containing essential oil from the fruits of Pterodon pubescens. Rev Inst Med Trop São Paulo 35:183–191
Marques DD, Machado MIL, Carvalho MG, Meleira LAC, Braz-Filho R (1998) Isoflavonoids and triterpenoids isolated from Pterodon polygalaeflorus. J Braz Chem Soc 9:295–301
Masuda Y, Nakaya M, Nakajo S, Nakaya K (1997) Geranylgeraniol potently induces caspase-3-like activity during apoptosis in human leukemia U937 cells. Biochem Biophys Res Comm 234:641–645
Masuda Y, Nakaya M, Aiuchi T, Hashimoto S, Nakajo S, Nakaya K (2000) The mechanism of geranylgeraniol-induced apoptosis involves activation, by a caspase-3-like protease, of a c-jun N-terminal kinase signaling cascade and differs from mechanisms of apoptosis induced by conventional chemotherapeutic drugs. Leuk Res 24:937–950
Menna-Barreto RFS, Henriques-Pons A, Pinto AV, Morgado-Diaz JA, Soares MJ, de Castro SL (2005) Effect of a b-lapachone-derived naphthoimidazole on Trypanosoma cruzi: identification of target organelles. J Antimicrob Chemother 56:1035–1041
Moncayo A, Ortiz-Yanine MI (2006) An update on Chagas disease (human American trypanosomiasis). Ann Trop Med Parasitol 100:663–677
Ohizumi H, Masuda Y, Yoda M, Hashimoto S, Aiuchi T, Nakajo S, Sakai I, Ohsawa S, Nakaya K (1997) Induction of apoptosis in various tumor cell lines by geranylgeraniol. Anticancer Res 17:1051–1057
Sabino KC, Gayer CR, Vaz LC, Santos LR, Felzenszwalb I, Coelho MGP (1999) In vitro and in vivo toxicological study of the Pterodon pubescens seed oil. Toxicol Lett 108:27–35
Santa-Rita RM, Lira R, Barbosa HS, Urbina JA, De Castro SL (2005) Antiproliferative synergism of lysophospholipid analogues and ketoconazole against Trypanosoma cruzi (Kinetoplastida: Trypanosomatidae): cellular and ultrastructural analysis. J Antimicrob Chemother 55:780–784
Santos Filho D, Sarti SJ, Katz N, Araújo N, Rocha Filho PA, Abreu JE, Bortolin ME (1987) Chemoprophylactic activity of soaps containing essential oil from the fruit of Pterodon pubescens in schistosomiasis mansoni. Mem Inst Oswaldo Cruz 82(Suppl 4):343–345
Silva MC, Gayer CR, Lopes CS, Calixto NO, Reis PA, Passaes CP, Paes MC, Dalmau SR, Sabino KC, Todeschini AR, Coelho MGP (2004) Acute and topic anti-edematogenic fractions isolated from the seeds of Pterodon pubescens. J Pharm Pharmacol 56:135–141
Soeiro MNC, Souza EM (2007) Programmed cell death and trypanosomatids: a brief review. In: Pérez-Martin JM (ed) Programmed cell death in protozoa. Landes Bioscience, Austin (http://eurekah.com/chapter/3428)
Sperandio S, de Belle I, Bredesen DE (2000) An alternative, nonapoptotic form of programmed cell death. Proc Natl Acad Sci USA 97:14376–14381
Takeda Y, Nakao K, Nakata K, Kawakami A, Ida H, Ichikawa T, Shigeno M, Kajiya Y, Hamasaki K, Kato Y, Eguchi K (2001) Geranylgeraniol, an intermediate product in mevalonate pathway, induces apoptotic cell death in human hepatoma cells: death receptor-independent activation of caspase-8 with down-regulation of Bcl-xL expression. Jpn J Cancer Res 92:918–925
Torrenegra R, Bauereib P, Achenbach H (1989) Homoormosanine-type alkaloids from Bowdichia virgilioides. Phytochemistry 28:2219–2221
Acknowledgement
This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico, Departamento de Ciência e Tecnologia—Secretaria de Ciência, Tecnologia e Insumos Estratégicos—Ministério da Saúde, Faperj, Fundação Oswaldo Cruz, and Universidade do Estado do Rio de Janeiro.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Menna-Barreto, R.F.S., Laranja, G.A.T., Silva, M.C.C. et al. Anti-Trypanosoma cruzi activity of Pterodon pubescens seed oil: geranylgeraniol as the major bioactive component. Parasitol Res 103, 111–117 (2008). https://doi.org/10.1007/s00436-008-0937-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00436-008-0937-0