The involvement of neuroinflammation in an animal model of dementia and depression

• Published in: Progress in neuro-psychopharmacology & biological psychiatry 2024-07, Vol.133, p.110999-110999, Article 110999
• Main Authors: Zabot, Gabriel Casagrande, Medeiros, Eduarda Behenck, Macarini, Bárbara Machado Naspolini, Peruchi, Bruno Búrigo, Keller, Gabriela Serafim, Lídio, Adrielly Vargas, Boaventura, Amanda, de Jesus, Laura Ceolin, de Bem Silveira, Gustavo, Silveira, Paulo Cesar Lock, Chede, Beatriz Costa, Réus, Gislaine Zilli, Budni, Josiane
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Chronic mild stress; Cytokines; Depression; Donepezil; Fluoxetine; Galantamine; Inflammation
• ISSN: 0278-5846; 1878-4216
• DOI: 10.1016/j.pnpbp.2024.110999

Alzheimer's disease (AD) and depression are inflammatory pathologies, leading to increased inflammatory response and neurotoxicity. Therefore, this study aimed to evaluate the effect of the treatment with fluoxetine and/or galantamine and/or donepezil on the levels of proinflammatory and anti-inflammatory cytokines in a mixed animal model of depression and dementia. Adult male Wistar rats underwent chronic mild stress (CMS) protocol for 40 days and were subjected to stereotaxic surgery for intra-hippocampal administration of amyloid-beta (Aꞵ) peptide or artificial cerebrospinal fluid (ACSF) to mimic the dementia animal model. On the 42nd day, animals were treated with water, galantamine, donepezil, and/or fluoxetine, orally for 17 days. On the 57th and 58th days, the Splash and Y-maze tests for behavior analysis were performed. The frontal cortex and hippocampus were used to analyze the tumor necrosis factor alfa (TNF-α), interleukin 1 beta (IL-1ꞵ), IL-6, and IL-10 levels. The results of this study show that animals subjected to CMS and administration of Aꞵ had anhedonia, cognitive impairment, increased TNF-α and IL-1ꞵ levels in the frontal cortex, and reduced IL-10 levels in the hippocampus. All treatment groups were able to reverse the cognitive impairment. Only donepezil did not decrease the TNF-α levels in the hippocampus. Fluoxetine + galantamine and fluoxetine + donepezil reversed the anhedonia. Fluoxetine reversed the anhedonia and IL-1ꞵ levels in the frontal cortex. In addition, fluoxetine + donepezil reversed the reduction of IL-10 levels in the hippocampus. The results indicate a pathophysiological interaction between AD and depression, and the association of medications in the future may be a possible therapeutic strategy to reduce inflammation, especially the fluoxetine-associated treatments. •CMS + Aβ can be an important animal model to study MDD and AD.•CMS + Aβ induces cognitive impairment.•CMS + Aβ induces anhedonic behavior.•CMS + Aβ increase TNF-α and IL-1β levels in the frontal cortex.•Fluoxetine treatment had the best effect in this double animal model.