The involvement of inflammation in the effect of the administration of donepezil, galantamine, memantine and/or fluoxetine in an animal model of depression and dementia.

Abstract

Alzheimer's disease (AD) and major depressive disorder (MDD) can share the same inflammatory theory in their pathophysiology, indicating that MDD may not only be a symptom, but a risk factor for AD. Therefore, the present study evaluated the levels of cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL) -1β, IL-6 and IL-10 in the frontal cortex and hippocampus of Wistar rats subjected to chronic mild stress protocol (CMS) for induction of an animal model of depression and administration of intra-hippocampal β-amyloid (βA) oligomers for induction of the dementia model. 60-day-old Wistar rats went subjected to CMS protocol for 40 days. After the CMS, the animals were subjected to stereotaxic surgery for intra-hippocampal administration of βA or artificial cerebrospinal fluid (ACSF). The next day, it was started the treatment with water, memantine, galantamine, donepezil and/or fluoxetine orally for 17 days. On the 59th day of the experimental protocol, euthanasia was performed, and the frontal cortex and hippocampus were dissected for later measurements of the TNF-α, IL-1β, IL-6 and IL-10. The results of this study show that animals subjected to CMS and administration of βA showed increased levels of TNF-α and IL-1β in the frontal cortex and reduced IL-10 level in the hippocampus. Fluoxetine reversed the levels of TNF-α and IL-1β in the frontal cortex. In addition, the fluoxetine + donepezil combination reversed the reduction of IL-10 levels in the hippocampus. Galantamine was also effective in reversing TNF-α levels in the cortex, as well as its association with fluoxetine and the association of donepezil with fluoxetine. The animals treated with memantine, as well as their association with fluoxetine, association of galantamine and fluoxetine and the association of donepezil with fluoxetine had levels of IL-10 significantly increased in the frontal cortex. In the hippocampus, only treatments with donepezil were able to raise the levels of IL-1β and IL-10. The results obtained in the present study indicate that there is a pathophysiological interaction between diseases, and that the association of medications in the future may be a possible therapeutic strategy to reduce the inflammation, especially in association with fluoxetine.