title: Trypanosoma cruzi-induced depressive-like behavior is independent of meningoencephalitis but responsive to parasiticide and TNF-targeted therapeutic interventions.
abstract: Inflammatory cytokines and microbe-borne immunostimulators have emerged as triggers of depressive behavior. Behavioral alterations affect patients chronically infected by the parasite Trypanosoma cruzi. We have previously shown that C3H/He mice present acute phase-restricted meningoencephalitis with persistent central nervous system (CNS) parasitism, whereas C57BL/6 mice are resistant to T. cruzi-induced CNS inflammation. In the present study, we investigated whether depression is a long-term consequence of acute CNS inflammation and a contribution of the parasite strain that infects the host. C3H/He and C57BL/6 mice were infected with the Colombian (type I) and Y (type II) T. cruzi strains. Forced-swim and tail-suspension tests were used to assess depressive-like behavior. Independent of the mouse lineage, the Colombian-infected mice showed significant increases in immobility times during the acute and chronic phases of infection. Therefore, T. cruzi-induced depression is independent of active or prior CNS inflammation. Furthermore, chronic depressive-like behavior was triggered only by the type I Colombian T. cruzi strain. Acute and chronic T. cruzi infection increased indoleamine 2,3-dioxygenase (IDO) expression in the CNS. Treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine abrogated the T. cruzi-induced depressive-like behavior. Moreover, treatment with the parasiticide drug benznidazole abrogated depression. Chronic T. cruzi infection of C57BL/6 mice increased tumor necrosis factor (TNF) expression systemically but not in the CNS. Importantly, TNF modulators (anti-TNF and pentoxifylline) reduced immobility. Therefore, direct or indirect parasite-induced immune dysregulation may contribute to chronic depressive disorder in T. cruzi infection, which opens a new therapeutic pathway to be explored.
authors: Laboratório de Biologia das Interações, Instituto Oswaldo Cruz - Fiocruz, Av Brasil 4365, Rio de Janeiro 21045-900, Brazil.
authors: Glaucia
authors: G
authors: Vilar-Pereira
authors: Andrea Alice da
authors: AA
authors: Silva
authors: Isabela Resende
authors: IR
authors: Pereira
authors: Rafael Rodrigues
authors: RR
authors: Silva
authors: Otacílio Cruz
authors: OC
authors: Moreira
authors: Luciana Rodrigues
authors: LR
authors: de Almeida
authors: Amanda Santos
authors: AS
authors: de Souza
authors: Monica Santos
authors: MS
authors: Rocha
authors: Joseli
authors: J
authors: Lannes-Vieira
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use; D014355:Chagas Disease / Q000188:drug therapy* / Q000523:psychology*; D003863:Depression / Q000188:drug therapy / Q000209:etiology / Q000523:psychology*; D004644:Emotions / Q000502:physiology; D005106:Exploratory Behavior; D005260:Female; D005473:Fluoxetine / Q000627:therapeutic use; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D019417:Hindlimb Suspension / Q000523:psychology; D007150:Immunohistochemistry; D008590:Meningoencephalitis / Q000523:psychology*; D051379:Mice; D008809:Mice, Inbred C3H; D009043:Motor Activity / Q000502:physiology; D009593:Nitroimidazoles / Q000627:therapeutic use; D010431:Pentoxifylline / Q000627:therapeutic use; D010641:Phenotype; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use; D011597:Psychomotor Performance / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D013550:Swimming / Q000523:psychology; D014344:Trypanocidal Agents / Q000627:therapeutic use*; D014349:Trypanosoma cruzi; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D018687:Antidepressive Agents, Second-Generation; D005904:Glial Fibrillary Acidic Protein; D009593:Nitroimidazoles; D010726:Phosphodiesterase Inhibitors; D014344:Trypanocidal Agents; D014409:Tumor Necrosis Factor-alpha; D005473:Fluoxetine; D010431:Pentoxifylline; C009999:benzonidazole