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Current Topics in Medicinal Chemistry

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ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

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Research Article

The Anthelmintic Effect on Strongyloides venezuelensis Induced by BnSP- 6, a Lys49-phospholipase A2 Homologue from Bothrops pauloensis Venom

Author(s): Jéssica Peixoto Rodrigues*, Fernanda Van Petten Vasconcelos Azevedo, Mariana Alves Pereira Zoia, Larissa Prado Maia, Lucas Ian Veloso Correia, Julia Maria Costa-Cruz, Veridiana de Melo Rodrigues and Luiz Ricardo Goulart*

Volume 19, Issue 22, 2019

Page: [2032 - 2040] Pages: 9

DOI: 10.2174/1568026619666190723152520

Price: $65

Abstract

Background: Phospholipases A2 (PLA2) from snake venoms have a broad potential as pharmacological tools on medicine. In this context, strongyloidiasis is a neglected parasitic disease caused by helminths of the genus Strongyloides. Currently, ivermectin is the drug of choice for treatment, however, besides its notable toxicity, therapeutic failures and cases of drug resistance have been reported. BnSP-6, from Bothorps pauloensis snake venom, is a PLA2 with depth biochemical characterization, reporting effects against tumor cells and bacteria.

Objective: The aim of this study is to demonstrate for the first time the action of the PLA2 on Strongyloides venezuelensis.

Methods: After 72 hours of treatment with BnSP-6 mortality of the infective larvae was assessed by motility assay. Cell and parasite viability was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Furthermore, autophagic vacuoles were labeled with Monodansylcadaverine (MDC) and nuclei of apoptotic cells were labeled with Propidium Iodide (PI). Tissue degeneration of the parasite was highlighted by Transmission Electron Microscopy (TEM).

Results: The mortality index demonstrated that BnSP-6 abolishes the motility of the parasite. In addition, the MTT assay attested the cytotoxicity of BnSP-6 at lower concentrations when compared with ivermectin, while autophagic and apoptosis processes were confirmed. Moreover, the anthelmintic effect was demonstrated by tissue degeneration observed by TEM. Furthermore, we report that BnSP-6 showed low cytotoxicity on human intestinal cells (Caco-2).

Conclusion: Altogether, our results shed light on the potential of BNSP-6 as an anthelmintic agent, which can lead to further investigations as a tool for pharmaceutical discoveries.

Keywords: Strongyloidiasis, S. venezuelensis, BnSP-6, Phospholipases A2, Snake venom, Treatment.

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[1]
Viney, M. Strongyloides. Parasitology, 2017, 144(3), 259-262.
[http://dx.doi.org/10.1017/S0031182016001773] [PMID: 27759560]
[2]
Viney, M.E.; Lok, J.B. The biology of Strongyloides spp. WormBook, 2015, 1-17.
[http://dx.doi.org/10.1895/wormbook.1.141.2] [PMID: 26183912]
[3]
Buonfrate, D.; Requena-Mendez, A.; Angheben, A.; Muñoz, J.; Gobbi, F.; Van Den Ende, J.; Bisoffi, Z. Severe strongyloidiasis: A systematic review of case reports. BMC Infect. Dis., 2013, 13, 78.
[http://dx.doi.org/10.1186/1471-2334-13-78] [PMID: 23394259]
[4]
Kuriakose, K.; Carpenter, K.; Wanjalla, C.; Pettit, A. Case of Strongyloides hyperinfection syndrome. BMJ Case Rep., 2017, 2017bcr2016218320
[http://dx.doi.org/10.1136/bcr-2016-218320]
[5]
Toledo, R.; Muñoz-Antoli, C.; Esteban, J.G. Strongyloidiasis with emphasis on human infections and its different clinical forms. Adv. Parasitol., 2015, 88, 165-241.
[http://dx.doi.org/10.1016/bs.apar.2015.02.005] [PMID: 25911368]
[6]
Luvira, V.; Watthanakulpanich, D.; Pittisuttithum, P. Management of Strongyloides stercoralis: A puzzling parasite. Int. Health, 2014, 6(4), 273-281.
[http://dx.doi.org/10.1093/inthealth/ihu058] [PMID: 25173343]
[7]
Panic, G.; Duthaler, U.; Speich, B.; Keiser, J. Repurposing drugs for the treatment and control of helminth infections. Int. J. Parasitol. Drugs Drug Resist., 2014, 4(3), 185-200.
[http://dx.doi.org/10.1016/j.ijpddr.2014.07.002] [PMID: 25516827]
[8]
Igual-Adell, R.; Oltra-Alcaraz, C.; Soler-Company, E.; Sánchez-Sánchez, P.; Matogo-Oyana, J.; Rodríguez-Calabuig, D. Efficacy and safety of ivermectin and thiabendazole in the treatment of strongyloidiasis. Expert Opin. Pharmacother., 2004, 5(12), 2615-2619.
[http://dx.doi.org/10.1517/14656566.5.12.2615] [PMID: 15571478]
[9]
Mendes, T.; Minori, K.; Ueta, M.; Miguel, D.C.; Allegretti, S.M. Strongyloidiasis Current status with emphasis in diagnosis and drug research. J. Parasitol. Res., 2017, 20175056314
[http://dx.doi.org/10.1155/2017/5056314] [PMID: 28210503]
[10]
Bourguinat, C.; Kamgno, J.; Boussinesq, M.; Mackenzie, C.D.; Prichard, R.K.; Geary, T.G. Analysis of the mdr-1 gene in patients co-infected with Onchocerca volvulus and Loa loa who experienced a post-ivermectin serious adverse event. Am. J. Trop. Med. Hyg., 2010, 83(1), 28-32.
[http://dx.doi.org/10.4269/ajtmh.2010.09-0734] [PMID: 20595473]
[11]
Carvalho, E.M.; Da Fonseca Porto, A. Epidemiological and clinical interaction between HTLV-1 and Strongyloides stercoralis. Parasite Immunol., 2004, 26(11-12), 487-497.
[http://dx.doi.org/10.1111/j.0141-9838.2004.00726.x] [PMID: 15771684]
[12]
Gobbi, F.; Rossanese, A.; Buonfrate, D.; Angheben, A.; Lunardi, G.; Bisoffi, Z. Failure of malaria chemoprophylaxis with mefloquine in an oversize traveller to Mozambique. Malar. J., 2013, 12, 451.
[http://dx.doi.org/10.1186/1475-2875-12-451] [PMID: 24350652]
[13]
Vercruysse, J.; Albonico, M.; Behnke, J.M.; Kotze, A.C.; Prichard, R.K.; McCarthy, J.S.; Montresor, A.; Levecke, B. Is anthelmintic resistance a concern for the control of human soil-transmitted helminths? Int. J. Parasitol. Drugs Drug Resist., 2011, 1(1), 14-27.
[http://dx.doi.org/10.1016/j.ijpddr.2011.09.002] [PMID: 24533260]
[14]
Teixeira, C.F.; Landucci, E.C.; Antunes, E.; Chacur, M.; Cury, Y. Inflammatory effects of snake venom myotoxic phospholipases A2. Toxicon, 2003, 42(8), 947-962.
[http://dx.doi.org/10.1016/j.toxicon.2003.11.006] [PMID: 15019493]
[15]
Azevedo, F.V.; Lopes, D.S.; Cirilo Gimenes, S.N.; Achê, D.C.; Vecchi, L.; Alves, P.T. Guimarães, Dde.O.; Rodrigues, R.S.; Goulart, L.R.; Rodrigues, Vde.M.; Yoneyama, K.A. Human breast cancer cell death induced by BnSP-6, a Lys-49 PLA2 homologue from Bothrops pauloensis venom. Int. J. Biol. Macromol., 2016, 82, 671-677.
[http://dx.doi.org/10.1016/j.ijbiomac.2015.10.080] [PMID: 26519876]
[16]
Nunes, D.C.; Figueira, M.M.; Lopes, D.S.; De Souza, D.L.; Izidoro, L.F.; Ferro, E.A.; Souza, M.A.; Rodrigues, R.S.; Rodrigues, V.M.; Yoneyama, K.A. BnSP-7 toxin, a basic phospholipase A2 from Bothrops pauloensis snake venom, interferes with proliferation, ultrastructure and infectivity of Leishmania (Leishmania) amazonensis. Parasitology, 2013, 140(7), 844-854.
[http://dx.doi.org/10.1017/S0031182013000012] [PMID: 23442579]
[17]
Rodrigues, V.M.; Marcussi, S.; Cambraia, R.S.; de Araújo, A.L.; Malta-Neto, N.R.; Hamaguchi, A.; Ferro, E.A.; Homsi-Brandeburgo, M.I.; Giglio, J.R.; Soares, A.M. Bactericidal and neurotoxic activities of two myotoxic phospholipases A2 from Bothrops neuwiedi pauloensis snake venom. Toxicon, 2004, 44(3), 305-314.
[http://dx.doi.org/10.1016/j.toxicon.2004.06.008] [PMID: 15302537]
[18]
Król, A.; Ostrowski, M. Enzymatic and non-enzymatic functions of secreted phospholipases A2. Postepy Biochem., 2017, 63(3), 198-204.
[PMID: 29294264]
[19]
Rodrigues, V.M.; Lopes, D.S.; Castanheira, L.E.; Gimenes, S.N.; Naves de Souza, D.L.; Ache, D.C.; Borges, I.P.; Yoneyama, K.A.; Rodrigues, R.S. Bothrops pauloensis snake venom toxins: the search for new therapeutic models. Curr. Top. Med. Chem., 2015, 15(7), 670-684.
[http://dx.doi.org/10.2174/1568026615666150217120347] [PMID: 25686731]
[20]
Waheed, H.; Moin, S.F.; Choudhary, M.I. Snake venom: From deadly toxins to life-saving therapeutics. Curr. Med. Chem., 2017, 24(17), 1874-1891.
[http://dx.doi.org/10.2174/0929867324666170605091546] [PMID: 28578650]
[21]
Almeida, J.R.; Lancellotti, M.; Soares, A.M.; Calderon, L.A.; Ramírez, D.; González, W.; Marangoni, S.; Da Silva, S.L. CoaTx-II, a new dimeric Lys49 phospholipase A2 from Crotalus oreganus abyssus snake venom with bactericidal potential: Insights into its structure and biological roles. Toxicon, 2016, 120, 147-158.
[http://dx.doi.org/10.1016/j.toxicon.2016.08.007] [PMID: 27530662]
[22]
Russo, R.R.; Dos Santos Júnior, N.N.; Cintra, A.C.O.; Figueiredo, L.T.M.; Sampaio, S.V.; Aquino, V.H. Expression, purification and virucidal activity of two recombinant isoforms of phospholipase A2 from Crotalus durissus terrificus venom. Arch. Virol., 2019, 164(4), 1159-1171.
[http://dx.doi.org/10.1007/s00705-019-04172-6] [PMID: 30809709]
[23]
Muller, V.D.; Soares, R.O.; dos Santos, N.N., Jr; Trabuco, A.C.; Cintra, A.C.; Figueiredo, L.T.; Caliri, A.; Sampaio, S.V.; Aquino, V.H. Phospholipase A2 isolated from the venom of Crotalus durissus terrificus inactivates dengue virus and other enveloped viruses by disrupting the viral envelope. PLoS One, 2014, 9(11)e112351
[http://dx.doi.org/10.1371/journal.pone.0112351] [PMID: 25383618]
[24]
Rey-Suárez, P.; Núñez, V.; Saldarriaga-Córdoba, M.; Lomonte, B. Primary structures and partial toxicological characterization of two phospholipases A2 from Micrurus mipartitus and Micrurus dumerilii coral snake venoms. Biochimie, 2017, 137, 88-98.
[http://dx.doi.org/10.1016/j.biochi.2017.03.008] [PMID: 28315380]
[25]
Dutta, S.; Gogoi, D.; Mukherjee, A.K. Anticoagulant mechanism and platelet deaggregation property of a non-cytotoxic, acidic phospholipase A2 purified from Indian cobra (Naja naja) venom: inhibition of anticoagulant activity by low molecular weight heparin. Biochimie, 2015, 110, 93-106.
[http://dx.doi.org/10.1016/j.biochi.2014.12.020] [PMID: 25576831]
[26]
Deka, A.; Sharma, M.; Sharma, M.; Mukhopadhyay, R.; Doley, R. Purification and partial characterization of an anticoagulant PLA2 from the venom of Indian Daboia russelii that induces inflammation through upregulation of proinflammatory mediators. J. Biochem. Mol. Toxicol., 2017, 31(10)
[http://dx.doi.org/10.1002/jbt.21945] [PMID: 28608598]
[27]
Mukherjee, A.K.; Kalita, B.; Thakur, R. Two acidic, anticoagulant PLA2 isoenzymes purified from the venom of monocled cobra Naja kaouthia exhibit different potency to inhibit thrombin and factor Xa via phospholipids independent, non-enzymatic mechanism. PLoS One, 2014, 9(8)e101334
[http://dx.doi.org/10.1371/journal.pone.0101334] [PMID: 25118676]
[28]
Fatah, C.; Samah, S.; Fatima, L.D. Antiplatelet and anticoagulant activities of two phospholipase A2s purified from Cerastes cerastes venom: Structure-function relationship. J. Biochem. Mol. Toxicol., 2018, 32(12)e22219
[http://dx.doi.org/10.1002/jbt.22219] [PMID: 30239061]
[29]
Rodrigues, R.S.; Boldrini-França, J.; Fonseca, F.P.; de la Torre, P.; Henrique-Silva, F.; Sanz, L.; Calvete, J.J.; Rodrigues, V.M. Combined snake venomics and venom gland transcriptomic analysis of Bothropoides pauloensis. J. Proteomics, 2012, 75(9), 2707-2720.
[http://dx.doi.org/10.1016/j.jprot.2012.03.028] [PMID: 22480909]
[30]
Silva, M.A.; Lopes, D.S.; Teixeira, S.C.; Gimenes, S.N.C.; Azevedo, F.; Polloni, L.; Borges, B.C.; da Silva, M.S.; Barbosa, M.J.; Oliveira, R.J. Junior; Elias, M.C.; da Silva, C.V.; Yoneyama, K.A.G.; Rodrigues, V.M.; Rodrigues, R.S. Genotoxic effects of BnSP-6, a Lys-49 phospholipase A2 (PLA2) homologue from Bothrops pauloensis snake venom, on MDA-MB-231 breast cancer cells. Int. J. Biol. Macromol, 2018. 118(Pt A), 311-319.
[31]
Rugai, E.; Mattos, T.; Brisola, A.P. A new technic for the isolation of nematode larvae from feces; modification of Baermann’s method. Rev. Inst. Adolfo Lutz, 1954, 14(1), 5-8.
[PMID: 14372416]
[32]
Olounladé, P.A.; Azando, E.V.; Hounzangbé-Adoté, M.S.; Ha, T.B.; Leroy, E.; Moulis, C.; Fabre, N.; Magnaval, J.F.; Hoste, H.; Valentin, A. In vitro anthelmintic activity of the essential oils of Zanthoxylum zanthoxyloides and Newbouldia laevis against Strongyloides ratti. Parasitol. Res., 2012, 110(4), 1427-1433.
[http://dx.doi.org/10.1007/s00436-011-2645-4] [PMID: 21960378]
[33]
Rebollo, C.D.; Taira, N.; Ura, S.; Williams, J.C. Larvicidal effects of several chemicals on Strongyloides infective larvae. Vet. Parasitol., 2003, 118(1-2), 165-168.
[http://dx.doi.org/10.1016/j.vetpar.2003.08.009] [PMID: 14651886]
[34]
Olsen, A.; van Lieshout, L.; Marti, H.; Polderman, T.; Polman, K.; Steinmann, P.; Stothard, R.; Thybo, S.; Verweij, J.J.; Magnussen, P. Strongyloidiasis--the most neglected of the neglected tropical diseases? Trans. R. Soc. Trop. Med. Hyg., 2009, 103(10), 967-972.
[http://dx.doi.org/10.1016/j.trstmh.2009.02.013] [PMID: 19328508]
[35]
Montes, M.; Sanchez, C.; Verdonck, K.; Lake, J.E.; Gonzalez, E.; Lopez, G.; Terashima, A.; Nolan, T.; Lewis, D.E.; Gotuzzo, E.; White, A.C., Jr Regulatory T cell expansion in HTLV-1 and strongyloidiasis co-infection is associated with reduced IL-5 responses to Strongyloides stercoralis antigen. PLoS Negl. Trop. Dis., 2009, 3(6)e456
[http://dx.doi.org/10.1371/journal.pntd.0000456] [PMID: 19513105]
[36]
Rodriguez, E.A.; Abraham, T.; Williams, F.K. Severe strongyloidiasis with negative serology after corticosteroid treatment. Am. J. Case Rep., 2015, 16, 95-98.
[http://dx.doi.org/10.12659/AJCR.892759] [PMID: 25690926]
[37]
Ashour, D.S. Ivermectin: From theory to clinical application. Int. J. Antimicrob. Agents, 2019, 54(2), 134-142.
[PMID: 31071469]
[38]
Ikeda, T. Pharmacological effects of ivermectin, an antiparasitic agent for intestinal strongyloidiasis: Its mode of action and clinical efficacy. Nippon Yakurigaku Zasshi, 2003, 122(6), 527-538.
[http://dx.doi.org/10.1254/fpj.122.527] [PMID: 14639007]
[39]
Atif, M.; Smith, J.J.; Estrada-Mondragon, A.; Xiao, X.; Salim, A.A.; Capon, R.J.; Lynch, J.W.; Keramidas, A. GluClR-mediated inhibitory postsynaptic currents reveal targets for ivermectin and potential mechanisms of ivermectin resistance. PLoS Pathog., 2019, 15(1)e1007570
[http://dx.doi.org/10.1371/journal.ppat.1007570] [PMID: 30695069]
[40]
Rodrigues, V.M.; Soares, A.M.; Mancin, A.C.; Fontes, M.R.; Homsi-Brandeburgo, M.I.; Giglio, J.R. Geographic variations in the composition of myotoxins from Bothrops neuwiedi snake venoms: biochemical characterization and biological activity. Comp. Biochem. Physiol. A Mol. Integr. Physiol., 1998, 121(3), 215-222.
[http://dx.doi.org/10.1016/S1095-6433(98)10136-8] [PMID: 9972319]
[41]
Dal Mas, C.; Moreira, J.T.; Pinto, S.; Monte, G.G.; Nering, M.B.; Oliveira, E.B.; Gazarini, M.L.; Mori, M.A.; Hayashi, M.A. Anthelmintic effects of a cationic toxin from a South American rattlesnake venom. Toxicon, 2016, 116, 49-55.
[http://dx.doi.org/10.1016/j.toxicon.2015.11.021] [PMID: 26713409]
[42]
Zouari-Kessentini, R.; Srairi-Abid, N.; Bazaa, A.; El Ayeb, M.; Luis, J.; Marrakchi, N. Antitumoral potential of Tunisian snake venoms secreted phospholipases A2. BioMed Res. Int., 2013, 2013391389
[http://dx.doi.org/10.1155/2013/391389] [PMID: 23509718]
[43]
Corrêa, E.A.; Kayano, A.M.; Diniz-Sousa, R.; Setúbal, S.S.; Zanchi, F.B.; Zuliani, J.P.; Matos, N.B.; Almeida, J.R.; Resende, L.M.; Marangoni, S.; da Silva, S.L.; Soares, A.M.; Calderon, L.A. Isolation, structural and functional characterization of a new Lys49 phospholipase A2 homologue from Bothrops neuwiedi urutu with bactericidal potential. Toxicon, 2016, 115, 13-21.
[http://dx.doi.org/10.1016/j.toxicon.2016.02.021] [PMID: 26927324]
[44]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]
[45]
Legarda-Ceballos, A.L.; López-Abán, J.; Del Olmo, E.; Escarcena, R.; Bustos, L.A.; Rojas-Caraballo, J.; Vicente, B.; Fernández-Soto, P.; San Feliciano, A.; Muro, A. In vitro and in vivo evaluation of 2-aminoalkanol and 1,2-alkanediamine derivatives against Strongyloides venezuelensis. Parasit. Vectors, 2016, 9(1), 364.
[http://dx.doi.org/10.1186/s13071-016-1648-5] [PMID: 27353595]
[46]
Legarda-Ceballos, A.L.; Rojas-Caraballo, J.; López-Abán, J.; Ruano, A.L.; Yepes, E.; Gajate, C.; Mollinedo, F.; Muro, A. The alkylphospholipid edelfosine shows activity against Strongyloides venezuelensis and induces apoptosis-like cell death. Acta Trop., 2016, 162, 180-187.
[http://dx.doi.org/10.1016/j.actatropica.2016.07.001] [PMID: 27394030]
[47]
An, G. Small-molecule compounds exhibiting target-mediated drug disposition (TMDD): A Minireview. J. Clin. Pharmacol., 2017, 57(2), 137-150.
[http://dx.doi.org/10.1002/jcph.804] [PMID: 27489162]
[48]
Ruano, A.L.; López-Abán, J.; Gajate, C.; Mollinedo, F.; De Melo, A.L.; Muro, A. Apoptotic mechanisms are involved in the death of Strongyloides venezuelensis after triggering of nitric oxide. Parasite Immunol., 2012, 34(12), 570-580.
[http://dx.doi.org/10.1111/pim.12004] [PMID: 22897441]
[49]
Sant’Anna, V.; Railbolt, M.; Oliveira-Menezes, A.; Calogeropoulou, T.; Pinheiro, J.; de Souza, W. Ultraestructural study of effects of alkylphospholipid analogs against nematodes. Exp. Parasitol., 2018, 187, 49-58.
[http://dx.doi.org/10.1016/j.exppara.2018.02.004] [PMID: 29496523]

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