Evaluate the effect of auranofin on the early and late stages of chronic infection with Toxoplasma gondii avirulent ME49 strain.
Swiss albino mice were orally inoculated with 10 cysts of Toxoplasma gondii, and orally treated with auranofin or septazole in daily doses of 20 mg/kg or 100 mg /kg, respectively, for 30 days. Treatment began either on the same day of infection and mice were sacrificed at the 60th day postinfection or the treatment started after 60 days of infection and mice were sacrificed at the 90th day postinfection.
Auranofin significantly reduced the brain cyst burden and inflammatory reaction at both stages of infection compared to the infected non-treated control. More remarkably, auranofin significant reduced the brain cyst burden in the late stage, while septazole failed. Hydrogen peroxide level was significantly increased in the brain homogenate of mice treated with auranofin only at the early stage of infection. Ultrastructral studies revealed that the anti-Toxoplasma effect of auranofin is achieved by changing the membrane permeability and inducing apoptosis.
Thus, auranofin could be an alternative for the standard treatment regimen of toxoplasmosis and these results are considered another achievement for the drug against parasitic infection. Being a FDA-approved drug, it can be rapidly evaluated in clinical trials.
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Mordue DG, Sibley LD (1997) Intracellular fate of vacuoles containing Toxoplasma gondii is determined at the time of formation and depends on the mechanism of entry. J Immunol 159(9):4452–4459
Robert-Gangneux F, Murat JB, Fricker-Hidalgo H, Brenier-Pinchart MP, Gangneux JP, Pelloux H (2011) The placenta: a main role in congenital toxoplasmosis? Trends Parasitol 27(12):530–536. https://doi.org/10.1016/j.pt.2011.09.005
Dubey JP, Lindsay DS, Speer CA (1998) Structures of Toxoplasma gondii tachyzoites, bradyzoites, and sporozoites and biology and development of tissue cysts. Clin Microbiol Rev 11:267–299
Skariah S, McIntyre MK, Mordue DG (2010) Toxoplasma gondii: determinants of tachyzoite to bradyzoite conversion. Parasitol Res 107:253–260
Luft BJ, Remington JS (1992) Toxoplasmic encephalitis in AIDS (AIDS commentary). Clin Infect Dis 15:211–222
Pearce BD, Kruszon-Moran D, Jones JL (2012) The relationship between Toxoplasma gondii infection and mood disorders in the third national health and nutrition survey. Biol Psychiatry 72:290–295
Fajard HV, D’ávila S, Bastos RR, Cyrino CD, De Lima Detoni M, Garcia JL, Das Neves LB, Nicolau JL, Amendoeira MR (2013) Seroprevalence and risk factors of toxoplasmosis in cattle from extensive and semi-intensive rearing systems at Zona da Mata, Minas Gerais state. Southern Brazil. Parasit Vectors 6:191. https://doi.org/10.1186/1756-3305-6-191
Wei HX, Wei SS, Lindsay DS, Peng HJ (2015) A systematic review and meta-analysis of the efficacy of anti-Toxoplasma gondii medicines in humans. PLoS ONE 10:e0138204. https://doi.org/10.1371/journal.pone.0138204
Reynolds MG, Oh J, Roos DS (2001) In vitro generation of novel pyrimethamine resistance mutations in the Toxoplasma gondii dihydrofolate reductase. Antimicrob Agents Chemother 45:1271–1277
Sordet F, Aumjaud Y, Fessi H, Derouin F (1998) Assessment of the activity of atovaquone-loaded nanocapsules in the treatment of acute and chronic murine toxoplasmosis. Parasite 5(3):223–229
Dike SY, Singh D, Thankachen BN, Sharma B, Mathur PK, Kore S, Kumar AA (2014) Single-pot synthesis of atovaquone: an antiparasitic drug of choice. Org Process Re Dev 18:618–625
Abou-El-Naga IF, El Kerdany ED, Mady RF, Shalaby TI, Zaytoun EM (2017) The effect of lopinavir/ritonavir and lopinavir/ritonavir loaded PLGA nanoparticles on experimental toxoplasmosis. Parasitol Int 66(6):735–747. https://doi.org/10.1016/j.parint.2017.08.007
Cox AG, Brown KK, Arner ES, Hampton MB (2008) The thioredoxin reductase inhibitor auranofin triggers apoptosis through a Bax/Bak-dependent process that involves peroxiredoxin 3 oxidation. Biochem Pharmacol 76:1097–1109. https://doi.org/10.1016/j.bcp.2008.08.021
Katz WA, Alexander S, Bland JH, Blechman W, Bluhm GB, Bonebrake RA et al (1982) The efficacy and safety of auranofin compared to placebo in rheumatoid arthritis. J Rheumatol Suppl 8:173–178
Madeira JM, Schindler SM, Klegeris AA (2015) New look at auranofin, dextromethorphan and rosiglitazone for reduction of glia-mediated inflammation in neurodegenerative diseases. Neural Regen Res 10(3):391–393. https://doi.org/10.4103/1673-5374.153686
Abou-El-Naga IF, Gaafar MR, Gomaa MM, Khedr SI, El Achy SN (2019) Encephalitozoon intestinalis: A new target for auranofin in a mice model. Med Mycol. https://doi.org/10.1093/mmy/myz126 (myz126)
Abou-El-Naga IF, Mady RF, Mogahed NMFH (2020) In vitro effectivity of three approved drugs and their synergistic interaction against Leishmania infantum. Biomédica 40(Supl.1):89–101
Debnath A, Ndao M, Reed SL (2013) Reprofiled drug targets ancient protozoans. Gut Microbes 4(1):66–71
Peroutka-Bigus N, Bellaire BH (2019) Antiparasitic activity of auranofin against pathogenic Naegleria fowleri. J Eukaryot Microbiol. https://doi.org/10.1111/jeu.12706
Tejman-Yarden N, Miyamoto Y, Leitsch D, Santini J, Debnath A, Gut J et al (2013) A reprofiled drug, auranofin, is effective against metronidazole-resistant Giardia lamblia. Antimicrob Agents Chemother 57(5):2029–2035. https://doi.org/10.1128/AAC.01675-12
da Silva MT, Silva-Jardim I, Portapilla GB, de Lima GM, Costa FC, Anibal FF, Thiemann OH (2016) In vivo and in vitro auranofin activity against Trypanosoma cruzi: Possible new uses for an old drug. Exp Parasitol 166:189–193. https://doi.org/10.1016/j.exppara.2015.05.012
Sharlow ER, Leimgruber S, MurrayS LA, Sciotti RJ, Hickman M et al (2014) Auranofin is an apoptosis-simulating agent Auranofin with in vitro and in vivo anti-leishmanial activity. ACS Chem Biol 9(3):663–672
Andrade RM, Chaparro JD, Capparelli E, Reed SL (2014) Auranofin is highly efficacious against Toxoplasma gondii in vitro and in an in vivo experimental model of acute toxoplasmosis. PLoS Negl Trop Dis 8(7):e2973. https://doi.org/10.1371/journal.pntd.0002973
Pessetto ZY, Weir SJ, Sethi G, Broward MA, Godwin AK (2013) Drug repurposing for gastrointestinal stromal tumor. Mol Cancer Ther 12(7):1299–1309. https://doi.org/10.1158/1535-7163.mct-12-0968
Angelucci F, Sayed AA, Williams DL, Boumis G, Brunori M, Dimastrogiovanni D et al (2009) Inhibition of Schistosoma mansoni thioredoxin-glutathione reductase by auranofin: structural and kinetic aspects. J Biol Chem 284:28977–28985. https://doi.org/10.1074/jbc.M109.020701
Parsonage D, Sheng F, Hirata K, Debnath A, Mckerrow JH, Reed SL et al (2016) X-ray structures of thioredoxin and thioredoxin reductase from Entamoeba histolytica and prevailing hypothesis of the mechanism of Auranofin action. J Struct Biol 194:180–190. https://doi.org/10.1016/j.jsb.2016.02.015
Capparelli EV, Bricker-Ford R, Rogers MJ, McKerrow JH, Reed SL (2017) Phase I clinical trial results of auranofin, a novel antiparasitic agent. Antimicrob Agents Chemother 61(1):e01947-e2016. https://doi.org/10.1128/AAC.01947-16
Gamberi T, Fiaschi T, Modesti A, Massai L, Messori L, Balzi M et al (2015) Evidence that the antiproliferative effects of auranofin in Saccharomyces cerevisiae arise from inhibition of mitochondrial respiration. Int J Biochem Cell Biol 65:61–71. https://doi.org/10.1016/j.biocel.2015.05.016
Dubey JP, Frenkel JK (1976) Feline toxoplasmosis from acutely infected mice and the development of Toxoplasma cysts. J Protozool 23(4):537–546
Hermes G, Ajioka JW, Kelly KA, Mui E, Roberts F, Kasza K et al (2008) Neurological and behavioral abnormalities, ventricular dilatation, altered cellular functions, inflammation, and neural injury in brains of mice due to common, persistent, parasitic infection. J Neuroinflammation 5:48–85
Bottari NB, Baldissera MD, Tonin AA, Rech VC, Nishihira VS, Thomé GR et al (2015) Sulfamethoxazole-trimethoprim associated with resveratrol for the treatment of toxoplasmosis in mice: influence on the activity of enzymes involved in brain neurotransmission. Microb Pathog 79:17–23
El-Zawawy LA, El-Said D, Mossallam SF, Ramadan HS, Younis SS (2015) Preventive prospective of triclosan and triclosan-liposomal nanoparticles against experimental infection with a cystogenic ME49 strain of Toxoplasma gondii. Acta Trop 141(Pt A):103–111. https://doi.org/10.1016/j.actatropica.2014.09.020
Eissa MH, Antnious SN, Salama MM, Fikry AA, Morsy TA (1990) Histopathological studies of acute, chronic and congenital infection of toxoplasmosis in mice. J Egy Soc Parasitol 20(2):805–816
Marzano C, Gandin V, Folda A, Scutari G, Bindoli A, Rigobello MP (2007) Inhibition of thioredoxin reductase by auranofin induces apoptosis in cisplatin-resistant human ovarian cancer cells. Free Radic Biol Med 42(6):872–881
Sun D, Crowell SA, Harding CM, De Silva PM, Harrison A, Fernando DM et al (2016) KatG and KatE confer Acinetobacter resistance to hydrogen peroxide but sensitize bacteria to killing by phagocytic respiratory burst. Life Sci 148:31–40. https://doi.org/10.1016/j.lfs.2016.02.015
Hayat MA (2000) Principles and techniques of electron microscopy: biological applications. VNR Company, New York, USA
Kirkpatrick LA, Feeney BC (2013) A simple guide to IBM SPSS statistics for version 20.0. Student ed. Belmont, Calif. Wadsworth, Cengage Learning 115
Innes EA (2010) Vaccination against Toxoplasma gondii: an increasing priority for collaborative research? Expert Rev Vaccines 9(10):1117–1119. https://doi.org/10.1586/erv.10.113
Chew WK, Wah MJ, Ambu S, Segarra I (2012) Toxoplasma gondii: determination of the onset of chronic infection in mice and the in vitro reactivation of brain cysts. Exp Parasitol 130:22–25
Djurković-Djaković O, Milenković V, NikolićBobić AB, Grujić J (2002) Efficacy of atovaquone combined with clindamycin against murine infection with a cystogenic (Me49) strain of Toxoplasma gondii. JAntimicrob Chemother 50(6):981–987
Israelski DM, Remington JS (1993) Toxoplasma gondii is an intracellular protozoan parasite: toxoplasmosis in the non-AIDS immunocompromised host. Curr Clin Top Infect 13:322–356
Faucher B, Moreau J, Zaegel O, Frank J, Piarroux P (2011) Failure of conventional treatment with pyrimethamine and sulfadiazine for secondary prophylaxis of cerebral toxoplasmosis in a patient with AIDS. J Antimicrob Chemother 66:1654–1656
Carruthers VB, Suzuki Y (2007) Effects of Toxoplasma gondii infection on the brain. Schizophr Bull 33:745–751
AraujoFG H-M, Gutteridge WE, Remington JS (1992) In vitro and in vivo activities of the hydroxynaphthoquinone 566C80 against the cyst form of Toxoplasma gondii. Antimicrob Agents Chemother 36(2):326–330
Costa IN, Angeloni MB, Santana LA, Barbosa BF, Silva MC, Rodrigues AA et al (2009) Azithromycin inhibits vertical transmission of Toxoplasma gondii in Calomys callosus (Rodentia: Cricetidae). Placenta 30(10):884–890. https://doi.org/10.1016/j.placenta.2009.08.002
Xue J, Jiang W, Chen Y, Gong F, Wang M, Zeng P et al (2017) Thioredoxin reductase from Toxoplasma gondii: an essential virulence effector with antioxidant function. FASEB J 31(10):4447–4457. https://doi.org/10.1096/fj.201700008R
Carvalho AP, Fernandes PA, Ramos MJ (2006) Similarities and differences in the thioredoxin superfamily. Prog Biophys Mol Biol 91:229–248
Stewart EJ, Aslund F, Beckwith J (1998) Disulfide bond formation in the Escherichia coli cytoplasm: an in vivo role reversal for the thioredoxins. EMBO J 17:5543–5550. https://doi.org/10.1093/emboj/17.19.5543
Harbut MB, Vilchèze C, Luo X, Hensler ME, Guo H, Yang B et al (2015) Auranofin exerts broad-spectrum bactericidal activities by targeting thiol-redox homeostasis. Proc Natl Acad Sci USA 112:4453–4458. https://doi.org/10.1073/pnas.1504022112
Madeira JM, Gibson DL, Kean WF, Klegeris A (2012) The biological activity of auranofin: implications for novel treatment of diseases. Inflammopharmacology 20:297–306. https://doi.org/10.1007/s10787-012-0149-1
Madeira JM, Renschler CJ, Mueller B, Hashioka S, Gibson DL, Klegeris A (2013) Novel protective properties of auranofn: inhibition of human astrocyte cytotoxic secretions and direct neuroprotection. Life Sci 92:1072–1080. https://doi.org/10.1016/j.lfs.2013.04.005
Madeira JM, Bajwa E, Stuart MJ, Hashioka S, Klegeris A (2014) Gold drug auranofn could reduce neuroinflammation by inhibiting microglia cytotoxic secretions and primed respiratory burst. J Neuroimmunol 276:71–79
Hammouda NA, Rashwan EA, Hussien ED, Abo el-Naga I, Fathy FM (1995) Measurement of respiratory burst of TNF and IL-1 cytokine activated murine peritoneal macrophages challenged with Toxoplasma gondii. J Egypt Soc Parasitol 25(3):683–691
Engin AB, Dogruman-Al F, Ercin U, Celebi B, Babur C, Bukan N (2012) Oxidative stress and tryptophan degradation pattern of acute Toxoplasma gondii infection in mice. Parasitol Res 111:1725–1730
Gais A, Beinert N, Gross U, Lüder CG (2008) Transient inhibition of poly (ADP-ribose) polymerase expression and activity by Toxoplasma gondii is dispensable for parasite-mediated blockade of host cell apoptosis and intracellular parasite replication. Microbes Infect 10(4):358–366. https://doi.org/10.1016/j.micinf.2007.12.010
De Rocher AE, Coppens I, Karnataki A, Gilbert LA, Rome ME, Feagin JE et al (2008) A thioredoxin family protein of the apicoplast periphery identifies abundant candidate transport vesicles in Toxoplasma gondii. Eukaryot Cell 7(9):1518–1529. https://doi.org/10.1128/EC.00081-08
Gajria B, Bahl A, Brestelli J, Dommer J, Fischer S, Gao X et al (2008) ToxoDB: an integrated Toxoplasma gondii database resource. Nucleic Acids Res 36:D553-556
Portes JA, Souza TG, dos Santos TA, da Silva LL, RibeiroTP PMD et al (2015) Reduction of toxoplasma gondii development due to inhibition of parasite antioxidant enzymes by a dinuclear iron(III) compound. Antimicrob Agents Chemother 59(12):7374–7386. https://doi.org/10.1128/AAC.00057-15
Moncada D, Arenas A, Acosta A, Molina D, Hernandez A, Cardona N et al (2016) Role of the 52 KDa thioredoxin protein disulfide isomerase of Toxoplasma gondii during infection to human cells. Exp Parasitol 164:36–42
Rigobello MP, Scutari G, Boscolo R, Bindoli A (2002) Induction of mitochondrial permeability transition by auranofin, a gold (I)-phosphine derivative. Br J Pharmacol 136:1162–1168
Ilari A, Baiocco P, Messori L, Fiorillo A, Boffi A, Gramiccia M et al (2012) A gold-containing drug against parasitic polyamine metabolism: the X-ray structure of trypanothione reductase from Leishmania infantumin complex with auranofin reveals a dual mechanism of enzyme inhibition. Amino Acids 42(2–3):803–811
Chircorian A, Barrios AM (2004) Inhibition of lysosomal cysteine proteases by chrysotherapeutic compounds: a possible mechanism for the antiarthritic activity of Au (I). Bioorg Med Chem Lett 14(20):5113–5116
Krishnamurthy D, Karver MR, Fiorillo E, Orrú V, Stanford SM, Bottini N, Barrios AM (2008) Gold(I)-mediated inhibition of protein tyrosine phosphatases: a detailed in vitro and cellular study. J Med Chem 51(15):4790–4795. https://doi.org/10.1021/jm800101w
Dr Ashraf Barakat, Professor of Epidemiology and Zoonotic Diseases, National Research Centre, Dokii, Giza, Egypt for providing us with Me49 strain.
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Abou-El-Naga, I.F., Mogahed, N.M.F.H. Repurposing auranofin for treatment of Experimental Cerebral Toxoplasmosis. Acta Parasit. (2021). https://doi.org/10.1007/s11686-021-00337-z
- Cerebral toxoplasmosis
- Toxoplasma cyst