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SULFADIAZINE PLUS PYRIMETHAMINE THERAPY REVERSED MULTIPLE BEHAVIORAL AND NEUROCOGNITIVE CHANGES IN LONG-TERM CHRONIC TOXOPLASMOSIS BY REDUCING BRAIN CYST LOAD AND INFLAMMATION-RELATED ALTERATIONS
Ansiedade
Depressão
Hiperatividade
Perda de memória
Neuroinflamação
Citocinas
Anxiety
Depression
Hyperactivity
Memory loss
Neuroinflammation
Cytokines
Autor
Afiliación
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ, Brasil.
Universidade Federal Fluminense. Laboratório Multiusuário para Apoio à Investigação em Nefrologia e Ciências Médicas. Niterói, RJ, Brasil
Faculty of Basic Sciences, University of Santiago de Cali. Cali, Colombia.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ, Brasil.
Universidade Federal de Uberlândia. Instituto de Química. Instituto de Ciências Biomédicas. Uberlândia, MG, Brasil.
Universidade Federal de Uberlândia. Instituto de Química. Instituto de Ciências Biomédicas. Uberlândia, MG, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ, Brasil.
Universidade Federal Fluminense. Laboratório Multiusuário para Apoio à Investigação em Nefrologia e Ciências Médicas. Niterói, RJ, Brasil
Faculty of Basic Sciences, University of Santiago de Cali. Cali, Colombia.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ, Brasil.
Universidade Federal de Uberlândia. Instituto de Química. Instituto de Ciências Biomédicas. Uberlândia, MG, Brasil.
Universidade Federal de Uberlândia. Instituto de Química. Instituto de Ciências Biomédicas. Uberlândia, MG, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ, Brasil.
Resumen en ingles
Toxoplasma gondii infects one-third of the world population. For decades, it has been
considered a silent lifelong infection. However, chronically T. gondii-infected persons may
present psychiatric and neurocognitive changes as anxiety, depression, and memory loss.
In a model of long-term chronic infection, behavioral alterations parallel neuroinflammation
and systemic high cytokine levels, and may reflect brain cyst load. Recent findings support
that in chronic infection an active parasite-host interplay involves an immune-mediated
control of tissue cysts. Here, we tested the idea that etiological treatment in chronic phase
may add advantage to intrinsic immune-mediated cyst control and impact behavioral
changes. Thus, we combined sulfadiazine-plus-pyrimethamine (S+P), the first-choice
therapy for toxoplasmosis, to study the association of brain cyst load and biological
processes related to the immune response (neuroinflammation, blood-brain barrier -BBBdisruption
and serum cytokine levels), with behavioral and neurocognitive changes of
long-term chronic infection. Female C57BL/6 mice (H-2b) were infected (5 cysts, ME-49
strain) and treated with S+P from 30 to 60 days postinfection (dpi), compared with vehicle
(Veh)-treated and noninfected controls. At endpoints (pre-therapy, 30 dpi; S+P therapy,
60 dpi; after ceased therapy, 90 dpi), independent groups were subjected to behavioral
tests, and brain tissues and sera were collected. Multiple behavioral and neurocognitive
changes were detected in the early (30 dpi) and long-term (60 and 90 dpi) chronic
infection. S+P therapy resolved locomotor alterations, anxiety, and depressive-like
behavior, partially or transiently ameliorated hyperactivity and habituation memory loss.
Analysis after therapy cessation showed that S+P therapy reduced the number of stimuli
required for aversive memory consolidation. S+P therapy resulted in reduced brain cyst load, neuroinflammation and BBB disruption, and lowered systemic Th1-cytokine levels.
Correlation analysis revealed association between IFNg, TNF and MCP-1/CCL2 serum
levels, brain cyst load and behavioral and neurocognitive alterations. Moreover, principalcomponent
analysis (PCA-2D and 3D projections) highlighted distinction between clusters
(noninfected; Veh-treated and S+P-treated infected). Thus, our data suggest that S+P
therapy added gain to intrinsic brain cyst control and, direct or indirectly, ameliorated
inflammation-related alterations, traits associated with behavioral and
neurocognitive alterations.
Palabras clave en portugues
Toxoplasma gondiiAnsiedade
Depressão
Hiperatividade
Perda de memória
Neuroinflamação
Citocinas
Palabras clave en ingles
Toxoplasma gondiiAnxiety
Depression
Hyperactivity
Memory loss
Neuroinflammation
Cytokines
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