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Rosuvastatin reduced brain parasite burden in a chronic toxoplasmosis in vivo model and influenced the neuropathological pattern of ME-49 strain

Published online by Cambridge University Press:  18 November 2019

L. Nishi Open the ORCID record for L. Nishi [Opens in a new window] ,
P. L. Santana ,
F. F. Evangelista ,
L. F. Beletini ,
A. H. Souza ,
F. M. Mantelo ,
A. M. Souza-Kaneshima ,
I. N. Costa Open the ORCID record for I. N. Costa [Opens in a new window]  and
A. L. Falavigna-Guilherme
L. Nishi
Affiliation:
Postgraduate Program in Health Science, Department of Basic Health Sciences, State University of Maringá (UEM), Colombo Avenue, 5790. Bloco I90. CEP: 87020-900. Maringá, Paraná, Brazil
P. L. Santana
Affiliation:
Pathology Laboratory, Department of Basic Health Sciences, State University of Maringa, 5790 Colombo Avenue, Bloco I-90, CEP 87020-900, Maringá, Paraná, Brazil
F. F. Evangelista
Affiliation:
Postgraduate Program in Health Science, Department of Basic Health Sciences, State University of Maringá (UEM), Colombo Avenue, 5790. Bloco I90. CEP: 87020-900. Maringá, Paraná, Brazil
L. F. Beletini
Affiliation:
Postgraduate Program in Health Science, Department of Basic Health Sciences, State University of Maringá (UEM), Colombo Avenue, 5790. Bloco I90. CEP: 87020-900. Maringá, Paraná, Brazil
A. H. Souza
Affiliation:
Department of Basic Health Sciences, State University of Maringá (UEM), 5790 Colombo Avenue, Bloco I-90, CEP: 87020-900. Maringá, Paraná, Brazil
F. M. Mantelo
Affiliation:
Department of Basic Health Sciences, State University of Maringá (UEM), 5790 Colombo Avenue, Bloco I-90, CEP: 87020-900. Maringá, Paraná, Brazil
A. M. Souza-Kaneshima
Affiliation:
Pathology Laboratory, Department of Basic Health Sciences, State University of Maringa, 5790 Colombo Avenue, Bloco I-90, CEP 87020-900, Maringá, Paraná, Brazil
I. N. Costa
Affiliation:
Program of Experimental Pathology, Department of Pathological Sciences, State University of Londrina, Rodovia Celso Garcia Cid – PR 445 Km 380. Campus Universitário. Caixa Postal 10.011. CEP 86.057-970. Londrina, Paraná, Brazil
A. L. Falavigna-Guilherme*
Affiliation:
Parasitology Laboratory, Department of Basic Health Sciences, State University of Maringá, Colombo Avenue, 5790. Bloco I90. CEP: 87020-900. Maringá, Paraná, Brazil
*
Author for correspondence: A. L. Falavigna-Guilherme, E-mail: [email protected]
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Abstract

This study evaluated the effects of rosuvastatin in vivo on toxoplasmosis chronic infection. Thirty-five Swiss mice were orally infected (ME-49 strain). After 50 days, the mice were separated into five groups: GI – non-infected, GII – infected, GIII – infected and treated with pyrimethamine and sulfadiazine (12.5 + 50 mg kg−1 body weight day−1), GIV and GV – infected and treated with rosuvastatin 10 and 40 mg kg−1 body weight day−1, respectively. After 21 days, we collected blood, liver, lungs, femoral biceps and brain were removed for Toxoplasma gondii DNA quantification by qPCR and histopathological analysis. GIV and GV did not present premature death or clinical changes, and the hepatic enzyme levels were lower compared to GI. Toxoplasma gondii DNA was detected mainly in brain and muscle, but the parasite load was significantly lower in GV compared to GII brains (P < 0.05). Histopathological changes were observed in brains, with T. gondii cysts as well as an inflammatory condition, including necrosis areas in GII and GIII. These data confirm active infection with tissue injury. This inflammatory condition was attenuated in the groups treated with rosuvastatin, especially R40 (GV). Our findings demonstrated the in vivo action of rosuvastatin in reducing cerebral parasitic load and indicate that this drug may interfere in chronic toxoplasmosis.

Keywords

StatinsSwiss micetoxoplasmosis treatment
Type
Research Article
Information
Parasitology , Volume 147 , Issue 3 , March 2020 , pp. 303 - 309
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Copyright
Copyright © Cambridge University Press 2019

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References

Avelino, MM, Amaral, WN, Rodrigues, IM, Rassi, AR, Gomes, MB, Costa, TL and Castro, AM (2014) Congenital toxoplasmosis and prenatal care state programs. BMC Infectious Diseases 14, 1–13.CrossRefGoogle ScholarPubMed
Bharti, AR, McCutchan, A, Deutsch, R, Smith, DM, Ellis, RJ, Cherner, M, Woods, SP, Heaton, RK, Grant, I and Letendre, SL (2016) Latent Toxoplasma infection and higher Toxoplasma gondii immunoglobulin G levels are associated with worse neurocognitive functioning in HIV-infected adults. Journal of Biochemistry and Molecular Biology 63, 1655–1660.Google ScholarPubMed
Burg, JL, Grover, CM, Pouletty, P and Boothroyd, JC (1989) Direct and sensitive detection of a pathogenic protozoan, Toxoplasma gondii, by polymerase chain reaction. Journal of Clinical Microbiology 27, 1787–1792.CrossRefGoogle ScholarPubMed
Cho, O, Jang, YJ, Park, KY and Heo, TH (2019) Beneficial anti-inflammatory effects of combined rosuvastatin and cilostazol in a TNF-driven inflammatory model. Pharmacological Reports 71, 266–271.CrossRefGoogle Scholar
Cuervo, G, Simonetti, AF, Alegre, O, Sanchez-Salado, JC and Podzamczer, D (2016) Toxoplasma myocarditis: a rare but serious complication in an HIV-infected late presenter. AIDS (London, England) 30, 2253–2254.CrossRefGoogle Scholar
Dincel, GC (2017) First description of enhanced expression of glia maturation factor-beta in experimental toxoplasmic encephalitis. Journal of International Medical Research 45, 1670–1679.CrossRefGoogle ScholarPubMed
Dincel, GC and Atmaca, HT (2016) Role of oxidative stress in the pathophysiology of Toxoplasma gondii infection. International Journal of Immunopathology and Pharmacology 29, 226–240.CrossRefGoogle ScholarPubMed
Dubey, JP (2016) Toxoplasmosis of Animals and Humans, 2nd Edn. Boca Raton, Flórida: CRC Press. 336 p.CrossRefGoogle Scholar
El-Zawawy, LA, El-Said, D, Mossallam, SF, Ramadan, HS and Younis, SS (2015 a) Preventive prospective of triclosan and triclosan-liposomal nanoparticles against experimental infection with a cystogenic ME49 strain of Toxoplasma gondii. Acta Tropica 141, 103–111.CrossRefGoogle ScholarPubMed
El-Zawawy, LA, El-Said, D, Mossallam, SF, Ramadan, HS and Younis, SS (2015 b) Triclosan and triclosan-loaded liposomal nanoparticles in the treatment of acute experimental toxoplasmosis. Experimental Parasitology 149, 54–64.CrossRefGoogle ScholarPubMed
Franco, PS, Silva, DA, Costa, IN, Gomes, AO, Silva, AL, Pena, JD, Mineo, JR and Ferro, EA (2011) Evaluation of vertical transmission of Toxoplasma gondii in Calomys callosus model after reinfection with heterologous and virulent strain. Placenta 32, 116–120.CrossRefGoogle ScholarPubMed
Fraulob, JC, Souza-Mello, V, Aguila, MB and Mandarim-de-Lacerda, CA (2012) Beneficial effects of rosuvastatin on insulin resistance, adiposity, inflammatory markers and non-alcoholic fatty liver disease in mice fed on a high-fat diet. Clinical Science 123, 259–270.CrossRefGoogle ScholarPubMed
Gomella, TL, Eyal, FG and Zenk, KE (2004) Neonatology: Management, Procedures, On-Call Problems, Diseases, and Drugs, 5th Edn. New York: The McGraw-Hill Companies, Inc.Google Scholar
Gulinello, M, Acquarone, M, Kim, JH, Spray, DC, Barbosa, HS, Sellers, R, Tanowitz, HB and Weiss, LM (2010) Acquired infection with Toxoplasma gondii in adult mice results in sensorimotor deficits but normal cognitive behavior despite widespread brain pathology. Microbes and Infection 12, 528–537.CrossRefGoogle ScholarPubMed
Hamilton, CM, Black, L, Oliveira, S, Burrells, A, Bartley, PM, Melo, RPB, Chianini, F, Palarea-Albaladejo, J, Innes, EA, Kelly, PJ and Katzer, F (2019) Comparative virulence of Caribbean, Brazilian and European isolates of Toxoplasma gondii. Parasites & Vectors 12, 104.CrossRefGoogle ScholarPubMed
Jauregui, LH, Higgins, J, Zarlenga, D, Dubey, JP and Lunney, JK (2001) Development of a real-time PCR assay for detection of Toxoplasma gondii in pig and mouse tissues. Journal of Clinical Microbiology 39, 2065–2071.CrossRefGoogle ScholarPubMed
Li, ZH, Ramakrishnan, S, Striepen, B and Moreno, SN (2013) Toxoplasma gondii relies on both host and parasite isoprenoids and can be rendered sensitive to atorvastatin. PLoS Pathogens 9, e1003665.CrossRefGoogle ScholarPubMed
Li, ZH, Li, C, Szajnman, SH, Rodriguez, JB and Moreno, SNJ (2017) Synergistic activity between statins and bisphosphonates against acute experimental toxoplasmosis. Antimicrobial Agents and Chemotherapy 61, e02628–16.CrossRefGoogle ScholarPubMed
Lu, D, Shen, L, Mai, H, Zang, J, Liu, Y, Tsang, CK, Li, K and Xu, A (2019) HMG-CoA reductase inhibitors attenuate neuronal damage by suppressing oxygen glucose deprivation-induced activated microglial cells. Neural Plasticity 15, 1–15.Google Scholar
Montazeri, M, Sharif, M, Sarvi, S, Mehrzadi, S, Ahmadpour, E and Daryani, A (2017) A systematic review of in vitro and in vivo activities of anti-Toxoplasma drugs and compounds (2006–2016). Frontiers in Microbiology 8, 1–31.CrossRefGoogle Scholar
Montazeri, M, Mehrzadi, S, Sharif, M, Sarvi, S, Shahdin, S and Daryani, A (2018) Activities of anti-Toxoplasma drugs and compounds against tissue cysts in the last three decades (1987 to 2017), a systematic review. Parasitology Research 117, 3045–3057.CrossRefGoogle ScholarPubMed
Mordue, DG, Monroy, F, La Regina, M, Dinarello, CA and Sibley, LD (2001) Acute toxoplasmosis leads to lethal overproduction of Th1 cytokines. Journal of Immunology 167, 4574–4584.CrossRefGoogle ScholarPubMed
Murata, Y, Sugi, T, Weiss, LM and Kato, K (2017) Identification of compounds that suppress Toxoplasma gondii tachyzoites and bradyzoites. PLoS ONE 12, e0178203.CrossRefGoogle ScholarPubMed
Nanassy, OZ, Haydock, PV and Reed, MW (2007) Capture of genomic DNA on glass microscope slides. Analytical Biochemistry 365, 240–245.CrossRefGoogle ScholarPubMed
Neto-Ferreira, R, Rocha, VN, Souza-Mello, V, Mandarim-de-Lacerda, CA and De Carvalho, JJ (2013) Pleiotropic effects of rosuvastatin on the glucose metabolism and the subcutaneous and visceral adipose tissue behavior in C57Bl/6 mice. Diabetology & Metabolic Syndrome 5, 32.CrossRefGoogle ScholarPubMed
Pereira, ACA, Silva, RJ, Franco, PS, de Oliveira Gomes, A, Souza, G, Milian, ICB, Ribeiro, M, Rosini, AM, Guirelli, PM, Ramos, ELP, Mineo, TWP, Mineo, JR, Silva, NM, Ferro, EAV and Barbosa, BF (2019) Cyclooxygenase (COX)-2 inhibitors reduce Toxoplasma gondii infection and upregulate the pro-inflammatory immune response in Calomys callosus rodents and human monocyte cell line. Frontiers in Microbiology 10, 225.CrossRefGoogle ScholarPubMed
Petersen, E and Schmidt, DR (2003) Sulfadiazine and pyrimethamine in the postnatal treatment of congenital toxoplasmosis: what are the options? Expert Review of Anti-Infective Therapy 1, 175–182.CrossRefGoogle ScholarPubMed
Reagan-Shaw, S, Nihal, M and Ahmad, N (2008) Dose translation from animal to human studies revisited. The FASEB Journal 22, 659–661.CrossRefGoogle ScholarPubMed
Remington, JS, Klein, JO, Wilson, CB and Baker, CJ (2011). Infectious Disease of the Fetus and Newborn Infant, 7th Edn. Philadelphia: Elsevier Saunders.Google Scholar
Robert-Gangneux, F (2014) It is not only the cat that did it: how to prevent and treat congenital toxoplasmosis. The Journal of Infection 68(Suppl 1), S125–S133.CrossRefGoogle ScholarPubMed
Sanfelice, RA, da Silva, SS, Bosqui, LR, Miranda-Sapla, MM, Barbosa, BF, Silva, RJ, Ferro, EAV, Panagio, LA, Navarro, IT, Bordignon, J, Conchon-Costa, I, Pavanelli, WR, Almeida, RS and Costa, IN (2017 a) Pravastatin and simvastatin inhibit the adhesion, replication and proliferation of Toxoplasma gondii (RH strain) in HeLa cells. Acta Tropica 167, 208–215.CrossRefGoogle Scholar
Sanfelice, RA, Machado, LF, Bosqui, LR, Miranda-Sapla, MM, Tomiotto-Pellissier, F, de Alcântara Dalevedo, G, Ioris, D, Reis, GF, Panagio, LA, Navarro, IT, Bordignon, J, Conchon-Costa, I, Pavanelli, WR, Almeida, RS and Costa, IN (2017 b) Activity of rosuvastatin in tachyzoites of Toxoplasma gondii (RH strain) in HeLa cells. Experimental Parasitology 181, 75–81.CrossRefGoogle Scholar
Sanfelice, RA, Bosqui, LR, da Silva, SS, Miranda-Sapla, MM, Panagio, LA, Navarro, IT, Conchon-Costa, I, Pavanelli, WR, Almeida, RS and Costa, IN (2018) Proliferation of Toxoplasma gondii (RH strain) is inhibited by the combination of pravastatin and simvastatin with low concentrations of conventional drugs used in toxoplasmosis. Journal of Applied Biomedicine 16, 29–33.CrossRefGoogle Scholar
Shiojiri, D, Kinai, E, Teruya, K, Kikuchi, Y and Oka, S (2019) Combination of clindamycin and azithromycin as alternative treatment for Toxoplasma gondii encephalitis. Emerging Infectious Diseases 25, 841–843.CrossRefGoogle ScholarPubMed
Shwab, EK, Jiang, T, Pena, HF, Gennari, SM, Dubey, JP and Su, C (2016) The ROP18 and ROP5 gene allele types are highly predictive of virulence in mice across globally distributed strains of Toxoplasma gondii. International Journal for Parasitology 46, 141–146.CrossRefGoogle ScholarPubMed
Tagel, M, Lassen, B, Viltrop, A and Jokelainen, P (2019) Large-scale epidemiological study on Toxoplasma gondii seroprevalence and risk factors in sheep in Estonia: age, farm location, and breed associated with seropositivity. Vector Borne and Zoonotic Diseases 19, 421–429.CrossRefGoogle ScholarPubMed
Torgerson, PR and Mastroiacovo, P (2013) The global burden of congenital toxoplasmosis: a systematic review. Bulletin of the World Health Organization 91, 501–508.CrossRefGoogle ScholarPubMed
Zhang, Y, Lin, X and Lu, F (2018) Current treatment of ocular toxoplasmosis in immunocompetent patients: a network meta-analysis. Acta Tropica 185, 52–62.CrossRefGoogle ScholarPubMed
Zhang, JL, Si, HF, Shang, XF, Zhang, XK, Li, B, Zhou, XZ and Zhang, JY (2019) New life for an old drug: in vitro and in vivo effects of the anthelmintic drug niclosamide against Toxoplasma gondii RH strain. International Journal for Parasitology. Drugs and Drug Resistance 9, 27–34.CrossRefGoogle ScholarPubMed