Influence of long-term treatment with pravastatin on the survival, evolution of cutaneous lesion and weight of animals infected by Leishmania amazonensis Carlos S Kückelhaus a,b , Selma AS Kückelhaus a,c , Maria Imaculada Muniz-Junqueira a,b,⇑ a Laboratory of Cellular Immunology, Pathology, Faculty of Medicine, University of Brasilia, Brasilia, DF 70.910-900, Brazil b Nucleus of Tropical Medicine, Faculty of Medicine, University of Brasilia, Brasilia, DF 70.910-900, Brazil c Laboratory of Morphology, Faculty of Medicine, University of Brasilia, Brasilia, DF 70.910-900, Brazil article info Article history: Received 9 October 2010 Received in revised form 16 November 2010 Accepted 14 December 2010 Available online 19 December 2010 Keywords: Pravastatin Leishmania (L.) amazonensis Leishmaniasis abstract The high toxicity of current drugs for treatment of leishmaniasis is a major hindrance for controlling the disease. Pravastatin is a well-known drug with anti-inflammatory and immunomodulatory properties that may modulate host defense mechanisms against Leishmania. We evaluated the influence of pro- longed pravastatin treatment on the survival of Leishmania amazonensis-infected animals (BALB/c, C57BL6 mice and Syrian hamsters), including weekly measurement of cutaneous lesions (footpad thick- ness) and weight. Pravastatin improved survival of Leishmania-infected BALB/c mice but not of infected C57BL6 mice or hamsters. On the 50th week of follow-up, 71% of pravastatin-treated Leishmania-infected BALB/c mice were alive against 29% of control group (p < 0.01). Low footpad thickness was found on BALB/c pravastatin treated mice from the 14th week (p < 0.05), and 20th week onward for C57BL6 treated mice. Pravastatin treatment decreased weight loss in Leishmania-infected C57BL6 mice and Syrian ham- sters, but not infected BALB/c mice. Our results points to beneficial effects of pravastatin on the evolution of the disease in the murine leishmaniasis model. Ó 2010 Elsevier Inc. All rights reserved. 1. Introduction Leishmaniasis is a group of diseases with different clinical forms depending on the host, parasite species, and immunological re- sponse to infection (Müller et al., 1989; Ribeiro-de-Jesus et al., 1998). The disseminated form of the disease frequently leads to death, while localized disease is less severe, but frequently causes deforming ulcers that are difficult to heal (Müller et al., 1989; Ribe- iro-de-Jesus et al., 1998). The best studied animal model of leishmaniasis is the murine model of infection by Leishmania major. Murine models of leish- maniasis show different immunological responses depending on host species. Leishmania major-resistant C57BL6 mice present localized lesions that heal in few months. These animals show a strong Th1 response, with production of high levels of tumor necrosis factor-a (TNF-a), interferon-c (INF-c), interleukin-1 (IL- 1) and interleukin-12 (IL-12) (Müller et al., 1989; Ribeiro-de-Jesus et al., 1998; Noben-Trauth, 2000). On the other hand, Leishmania major-susceptible BALB/c mice present disseminated disease, which leads to death in few months. They have a Th2 response with high production of IL-4 and IL-10, and increased levels of TGF-b (Müller et al., 1989; Ribeiro-de-Jesus et al., 1998; Noben- Trauth, 2000). Human disease caused by different Leishmania spe- cies may present variations of Th1 and Th2 cytokines profiles ob- served in the two extremes of murine L. major infections. Murine infections with Leishmania (L.) amazonensis show several features similar to clinical disease in humans (Awasthi et al., 2004). BALB/c mice are highly susceptible to development of characteristic chronic lesions induced by L. amazonensis, whereas C57BL/6 mice are less susceptible (Calabrese and Da-Costa, 1992; Jones et al., 2002). In mouse models of L. amazonensis infection, susceptibility of C57BL/ 10, BALB/c and C3H mice is associated with absence of a Th1 re- sponse, rather than to the presence of a Th2 cell response (Afonso and Scott, 1993; Ji et al., 2005; Maioli et al., 2004). For decades, antimonials and amphotericin-B have been used to treat leishmaniasis. Both drugs are toxic and difficult to use in clin- ical practice, and resistance to these drugs has been described (Dietze et al., 1985; Sampaio and Marsden, 1997). Immunomodu- latory drugs, such as HMG CoA inhibitors, may have some potential as anti-parasite drugs (Kaneta et al., 2003; Liao, 2002; Kaesemeyer et al., 1999; Grip et al., 2000). Pravastatin reduces phagocytosis, hydrogen peroxide, TNF-a and chemo-attraction of peripheral blood monocytes of healthy individuals (Kaesemeyer et al., 1999; Grip et al., 2000; Muniz-Junqueira et al., 2006). It also increases ni- tric oxide production on endothelial cells by increasing the endo- thelial nitric oxide synthase (eNOS) and decreasing 0014-4894/$ - see front matter Ó 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.exppara.2010.12.003 ⇑ Corresponding author at: Laboratory of Cellular Immunology, Pathology, Faculty of Medicine, University of Brasilia, Brasilia, DF 70.910-900, Brazil. Fax: +55 61 3273 3907. E-mail addresses: cscarlos@unb.br (C.S Kückelhaus), selmak@unb.br (S.AS Kückelhaus), mimjunqueira@unb.br (M.I. Muniz-Junqueira). Experimental Parasitology 127 (2011) 658–664 Contents lists available at ScienceDirect Experimental Parasitology journal homepage: www.elsevier.com/locate/yexpr