| Author | Pereira, Glaucia Vilar | |
| Author | Gibaldi, Daniel | |
| Author | Castaño Barrios, Leda Margarita | |
| Author | Silva, Andrea Alice da | |
| Author | Pereira, Isabela Resende | |
| Author | Moreira, Otacílio Cruz | |
| Author | Britto, Constança Felícia De Paoli de Carvalho | |
| Author | Santos, Hílton Antônio Mata dos | |
| Author | Lopes, Raquel de Oliveira | |
| Author | Tinoco, Luzineide Wanderley | |
| Author | Oliveira Junior, Wilson | |
| Author | Vieira, Joseli Lannes | |
| Access date | 2024-06-17T14:26:11Z | |
| Available date | 2024-06-17T14:26:11Z | |
| Document date | 2024 | |
| Citation | PEREIRA, Glaucia Vilar et al. The beneficial effect of fluoxetine on behavioral and cognitive changes in chronic experimental Chagas disease unveils the role of serotonin fueling astrocyte infection by Trypanosoma cruzi. PLoS Neglected Tropical Diseases, v. 18, n. 5, p. 1-32, 22 May 2024. | en_US |
| ISSN | 1935-2727 | en_US |
| URI | https://www.arca.fiocruz.br/handle/icict/64509 | |
| Description | Produção científica do Laboratório de Biologia das Interações. | pt_BR |
| Description | Produção científica do Laboratório de Biologia Molecular e Doenças Endêmicas. | pt_BR |
| Description | Produção científica do Laboratório de Virologia e Parasitologia Molecular. | pt_BR |
| Description | Author summary: In chronic Chagas disease, illness caused by Trypanosoma cruzi infection, anxiety, depression, and memory decline are mostly related to social and psychological stressors. Here, we described the sequential onset of behavioral and cognitive changes in T. cruzi-infected mice, supporting a role for biological stressors. Indeed, in chronically infected mice, the behavioral changes parallel increased levels of the neurotransmitters GABA/glutamate and lipid peroxidation products and decreased expression of the neurotrophin BDNF. Therapy with the selective serotonin reuptake inhibitor and antidepressant fluoxetine ameliorated, prevented, or reversed behavioral and cognitive changes, improved neurochemical alterations, and, surprisingly, reduced parasite load in the brain. In vitro, serotonin fueled parasite uptake by U-87 MG cells, a human astrocyte-like cell lineage. Serotonin effects were increased by prior interferon-gamma (IFNγ) and tumor necrosis factor (TNF) stimulation but abrogated by fluoxetine and related to nitric oxide and glutamate levels in culture supernatants. Thus, the cytokine-driven consumption of serotonin may fuel T. cruzi uptake by astrocytes, sustaining brain parasitism, reducing serotonin availability, dysregulating the neurotransmitter and neurotrophin networks, and favoring a neurotoxic milieu, which may contribute to behavioral and cognitive disorders. Therefore, fluoxetine therapy, which interferes with these biological processes, may improve the quality of life of Chagas disease patients. | en_US |
| Sponsorship | This work was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior Brasil (CAPES - Finance Code 001 to Joseli Lannes Vieira); by the Conselho Nacional de Desenvolvimento Científico e Tecnológico, CNPq, CNPq1B (304474/2015-0 and 306037/2019-0 to Joseli Lannes Vieira) and CNPq 1D (311539/2020-3 to Otacílio Cruz Moreira); by the Fundação Carlos Chagas Filho de Amparo à Pesquisa do Rio de Janeiro FAPERJ - Scientist of the State of Rio de Janeiro (CNE E-26/ 210.190/2018 and E-26/202.572/2019 to Joseli Lannes Vieira and CNE E26/201.096/2022 to Otacílio Cruz Moreira); and Grant PAEF2-IOC/Fiocruz to Joseli Lannes Vieira). | en_US |
| Language | eng | en_US |
| Publisher | Public Library of Science | en_US |
| Rights | open access | |
| Title | The beneficial effect of fluoxetine on behavioral and cognitive changes in chronic experimental Chagas disease unveils the role of serotonin fueling astrocyte infection by Trypanosoma cruzi | en_US |
| Type | Article | |
| DOI | 10.1371/journal.pntd.0012199 | |
| Abstract | Background: In Chagas disease (CD), a neglected tropical disease caused by the parasite Trypanosoma cruzi, the development of mental disorders such as anxiety, depression, and memory loss may be underpinned by social, psychological, and biological stressors. Here, we investigated biological factors underlying behavioral changes in a preclinical model of CD. Methodology/Principal Findings: In T. cruzi-infected C57BL/6 mice, a kinetic study (5 to 150 days postinfection, dpi) using standardized methods revealed a sequential onset of behavioral changes: reduced innate compulsive behavior, followed by anxiety and depressive-like behavior, ending with progressive memory impairments. Hence, T. cruzi-infected mice were treated (120 to 150 dpi) with 10 mg/Kg/day of the selective serotonin reuptake inhibitor fluoxetine (Fx), an antidepressant that favors neuroplasticity. Fx therapy reversed the innate compulsive behavior loss, anxiety, and depressive-like behavior while preventing or reversing memory deficits. Biochemical, histological, and parasitological analyses of the brain tissue showed increased levels of the neurotransmitters GABA/glutamate and lipid peroxidation products and decreased expression of brain-derived neurotrophic factor in the absence of neuroinflammation at 150 dpi. Fx therapy ameliorated the neurochemical changes and reduced parasite load in the brain tissue. Next, using the human U-87 MG astroglioma cell line, we found no direct effect of Fx on parasite load. Crucially, serotonin/5-HT (Ser/5-HT) promoted parasite uptake, an effect increased by prior stimulation with IFNγ and TNF but abrogated by Fx. Also, Fx blocked the cytokine-driven Ser/5-HT-promoted increase of nitric oxide and glutamate levels in infected cells. Conclusion/Significance: We bring the first evidence of a sequential onset of behavioral changes in T. cruzi-infected mice. Fx therapy improves behavioral and biological changes and parasite control in the brain tissue. Moreover, in the central nervous system, cytokine-driven Ser/5-HT consumption may favor parasite persistence, disrupting neurotransmitter balance and promoting a neurotoxic environment likely contributing to behavioral and cognitive disorders. | en_US |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ, Brasil. | en_US |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ, Brasil. | en_US |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ, Brasil. | en_US |
| Affilliation | Universidade Federal Fluminense. Faculdade de Medicina. Departamento de Patologia. Laboratório Multidisciplinar de Apoio à Pesquisa em Nefrologia e Ciências Médicas. Niterói, RJ, Brasil. | en_US |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ, Brasil. | en_US |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Virologia e Parasitologia Molecular. Rio de Janeiro, RJ, Brasil. | en_US |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular e Doenças Endêmicas. Rio de Janeiro, RJ, Brasil. | en_US |
| Affilliation | Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Faculdade de Farmácia. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Pesquisas de Produtos Naturais Walter Mors. Laboratório de Análise e Desenvolvimento de Inibidores Enzimáticos. Rio de Janeiro, RJ, Brasil. | en_US |
| Affilliation | Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Ciências Biomédicas. Programa de Pós-Graduação em Farmacologia e Química Medicinal. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Pesquisas de Produtos Naturais Walter Mors. Laboratório Multiusuário de Análises por Ressonância Magnética Nuclear. Rio de Janeiro, RJ, Brasil. | en_US |
| Affilliation | Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Pesquisas de Produtos Naturais Walter Mors. Laboratório Multiusuário de Análises por Ressonância Magnética Nuclear. Rio de Janeiro, RJ, Brasil. | en_US |
| Affilliation | Universidade de Pernambuco. Pronto Socorro Cardiológico Universitário. Ambulatório de Doença de Chagas e Insuficiência Cardíaca. Recife, PE, Brasil. | en_US |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ, Brasil. | en_US |
| Subject | Trypanosoma cruzi | en_US |
| Subject | Parasitic diseases | en_US |
| Subject | Mice | en_US |
| Subject | Animal behavior | en_US |
| Subject | Central nervous system | en_US |
| Subject | Memory | en_US |
| Subject | Depression | en_US |
| Subject | Astrocytes | en_US |
| e-ISSN | 1935-2735 | |
