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

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.

Neuroprotective effects of combined therapy with memantine, donepezil, and vitamin D in ovariectomized female mice subjected to dementia model.

Women older than 60 have a higher risk of dementia, aging-related cognitive decline, and Alzheimer's Disease (AD) than the rest of the population. The main reason is hormonal senescence after menopause, a period characterized by a decline in estrogen levels. Since the effectiveness of drugs currently approved for the treatment of AD is limited, it is necessary to seek the development of new therapeutic strategies. Vitamin D deficiency is prevalent in AD patients and individuals with dementia in general. The supplementation of this vitamin in dementia patients might be an interesting approach for increasing the effectiveness of pre-existing medications for dementia treatment. Thus, the present study aims to investigate the effect of vitamin D treatment associated with memantine and donepezil in female mice submitted to ovariectomy (OVX) for five months and subjected to a dementia animal model induced by intracerebroventricular injection of aggregated amyloid ßeta (Aß1-42). For this purpose, Balb/c mice were divided into five experimental groups, which received 17 days of combined therapy with vitamin D, donepezil, and memantine. Then, animals were subjected to behavioral tests. OVX groups exhibited reduced levels of estradiol (E2) in serum, which was not altered by the combined therapy. Higher levels of vitamin D3 were found in the OVX animals submitted to the triple-association treatment. Mice exposed to both OVX and the dementia animal model presented impairment in short and long-term spatial and habituation memories. Also, female mice exposed to Aß and OVX exhibited a reduction in brain-derived neurotrophic factor (BDNF) and interleukin-4 (IL-4) levels, and an increase in tumor necrose factor-α (TNFα) levels in the hippocampus. Besides, increased levels of IL-1ß in the hippocampus and cerebral cortex were observed, as well as a significant increase in immunoreactivity for glial fibrillary acidic protein (GFAP), an astrocytes marker, in the hippocampus. Notably, triple-association treatment reversed the effects of the exposition of mice to Aß and OVX in the long-term spatial and habituation memories impairment, as well as reversed changes in TNFα, IL-1ß, IL-4, and GFAP immunoreactivity levels in the hippocampus of treated animals. Our results indicate that the therapeutic association of vitamin D, memantine, and donepezil has beneficial effects on memory performance and attenuated the neuroinflammatory response in female mice subjected to OVX associated with a dementia animal model.