Leishmania amazonensis infection induces behavioral alterations and modulates cytokine and neurotrophin production in the murine cerebral cortex Alex Portes a , Elizabeth Giestal-de-Araujo b , Aline Fagundes c , Pablo Pandolfo d , Arnaldo de Sá Geraldo d , Marie Luce Flores Lira a , Veronica Figueiredo Amaral a, ⁎ ,1 , Jussara Lagrota-Candido a, ⁎ ,1 a Laboratório de Imunopatologia, Departamento de Imunobiologia, Universidade Federal Fluminense, Rio de Janeiro, Brazil b Laboratório de Cultura de Tecidos Hertha Meyer, Departamento de Neurobiologia, Universidade Federal Fluminense, Rio de Janeiro, Brazil c Laboratório de Vigilância em Leishmanioses, Instituto Oswaldo Cruz – Fiocruz, Rio de Janeiro, Brazil d Laboratório de Neurobiologia do Comportamento Animal, Departamento de Neurobiologia, Universidade Federal Fluminense, Brazil abstract article info Article history: Received 20 June 2016 Received in revised form 8 November 2016 Accepted 11 November 2016 Available online xxxx Neurological symptoms have been associated with Leishmania infection, however little is known about how the nervous system is affected in leishmaniasis. This work aimed to analyze parasitic load, production of cytokines/ neurotrophins in the prefrontal cortex and behavioral changes in BALB/c mice infected with Leishmania amazonensis. At 2 and 4 months post-infection, infected mice showed a decrease in IFN-γ, IL-1, IL-6, IL-4, IL-10 cytokines and BDNF and NGF neurotrophins in prefrontal cortex associated with increased anxiety behavior. Par- asite DNA was found in brain of all animals at 4 months post-infection, when the levels of IBA-1 (activated mac- rophage/microglia marker) and TNF-α was increased in the prefrontal cortex. However TNF-α returned to normal levels at 6 months post-infection suggesting a neuroprotective mechanism. © 2016 Elsevier B.V. All rights reserved. Keywords: Leishmania amazonensis Central nervous system Cytokines Anxiety Neurotrophic factors 1. Introduction Leishmaniasis is a neglected tropical disease affecting millions of people worldwide with great social impact (Desjeux, 2004). This dis- ease is endemic in 98 countries and distributed in 5 continents. In addi- tion, it is considered one of the six most important infectious diseases, affecting mainly the poorest people in developing countries (Alvar et al., 2012). Infections caused by Leishmania are characterized in three primary clinical forms: visceral, cutaneous, and mucocutaneous. The clinical form of disease is determined by species of infecting parasite, immune response and genetic background of the host (McGwire and Satoskar, 2014). Leishmania amazonensis is commonly associated with the cutaneous form of the disease, but it has also been found in mucocu- taneous, diffuse and visceral clinical forms (Aleixo et al., 2006; de Oliveira Cardoso et al., 2010). The host immune response infection is a determining factor in leish- maniasis and it is responsible for control or progression of disease. Clas- sical immune response to Leishmania, in particular to L. major infection, is described by the Th1 or Th2 activation associated to resistance or sus- ceptibility respectively (Sacks and Noben-Trauth, 2002). The develop- ment of Th1 immunity induces production of cytokines as IL-2, IFN-γ, TNF-αand IL-12 promoting activation of macrophages and intracellular parasite killing. In contrast, Th2 immune response controls Th1 func- tions and macrophage activation via production of IL-10 and IL-4 favors disease progression (Awasthi et al., 2004). Mice infected by L. amazonensis have progressive and non-healing cutaneous lesions whereas histological examination demonstrated cel- lular infiltration rich in macrophages within spacious parasitophorous vacuoles, which may contain numerous parasites (Wanasen and Soong, 2008). Some reports showed that the susceptibility of mice to L. amazonensis was associated to lack of Th1 cells and predominance of Th2 cells (Charret et al., 2013; Soong et al., 1997). It is recognized that a susceptibility to L. amazonensis is dependent on IL-4 but is contro- versial about IL-10 production (Padigel et al., 2003). Successful macro- phage activation to kill parasite consists of high nitric oxide production, however L. amazonensis is more resistant to the nitric oxide effects in relation to others Leishmania species (Gibson-Corley et al., 2014). The leishmaniasis is not classically associated with nervous system commitment. Despite this, there are several reports of neurological manifestations in humans and animal models (Llanos-Cuentas et al., 2013; Maia et al., 2015; Petersen and Greenlee, 2011). In Africa, it is Journal of Neuroimmunology xxx (2016) xxx–xxx ⁎ Corresponding authors at: Department of Immunobiology, Institute of Biology, Fluminense Federal University, Niterói, RJ 24 020-141, Brazil. E-mail addresses: veronicadoamaral@gmail.com (V.F. Amaral), jlagrota@id.uff.br (J. Lagrota-Candido). 1 These authors contributed equally. JNI-476463; No of Pages 9 http://dx.doi.org/10.1016/j.jneuroim.2016.11.003 0165-5728/© 2016 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim Please cite this article as: Portes, A., et al., Leishmania amazonensis infection induces behavioral alterations and modulates cytokine and neurotrophin production in the murine cerebral cortex..., J. Neuroimmunol. (2016), http://dx.doi.org/10.1016/j.jneuroim.2016.11.003