1. Fluoxetine ameliorates Alzheimer's disease progression and prevents the exacerbation of cardiovascular dysfunction of socially isolated depressed rats through activation of Nrf2/HO-1 and hindering TLR4/NLRP3 inflammasome signaling pathway.
- Author
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Abu-Elfotuh K, Al-Najjar AH, Mohammed AA, Aboutaleb AS, and Badawi GA
- Subjects
- Alzheimer Disease metabolism, Alzheimer Disease pathology, Animals, Antidepressive Agents pharmacology, Antioxidants metabolism, Behavior, Animal drug effects, Biogenic Monoamines metabolism, Brain drug effects, Brain metabolism, Brain pathology, Depression metabolism, Depression pathology, Disease Progression, Fluoxetine pharmacology, Heme Oxygenase (Decyclizing) metabolism, Inflammasomes metabolism, Male, Myocardium pathology, NF-E2-Related Factor 2 metabolism, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Neuroprotective Agents pharmacology, Rats, Sprague-Dawley, Signal Transduction drug effects, Social Isolation, Toll-Like Receptor 4 metabolism, Rats, Alzheimer Disease drug therapy, Antidepressive Agents therapeutic use, Depression drug therapy, Fluoxetine therapeutic use, Neuroprotective Agents therapeutic use
- Abstract
Depression is a risk factor for Alzheimer's (AD) and cardiovascular diseases (CVD). Therefore, depression treatment restricts its deteriorating effects on mood, memory and CV system. Fluoxetine is the most widely used antidepressant drug, it has neuroprotective effect through its antioxidant/anti-inflammatory properties. The current study investigated for the first-time the cross link between depression, AD and CVD besides, role of fluoxetine in mitigating such disorders. Depression was induced in rats by social isolation (SI) for 12 weeks, AlCL3 (70 mg/kg/day, i.p.) was used to induce AD which was administered either in SI or normal control (NC) grouped rats starting at 8th week till the end of the experiment, fluoxetine (10 mg/kg/day, p.o) treatment also was started at 8th week. SI and AD showed a statistically significant deteriorated effect on behavioral, neurochemical and histopathological analysis which was exaggerated when two disorder combined than each alone. Fluoxetine treatment showed protective effect against SI, AD and prevents exacerbation of CVD. Fluoxetine improved animals' behavior, increased brain monoamines, BDNF besides increased antioxidant defense mechanism of SOD, TAC contents and increased protein expression of Nrf2/HO-1 with significant decrease of AChE activity, β-amyloid, Tau protein, MDA, TNF-α, IL1β contents as well as decreased protein expression of NF-kB, TLR4, NLRP3 and caspase1. It also showed cardioprotective effects as it improved lipid profile with pronounced decrease of cardiac enzymes of CK-MB, troponin and MEF2. In conclusion, fluoxetine represents as a promising drug against central and peripheral disorders through its anti-inflammatory/antioxidant effects via targeting antioxidant Nrf2/HO-1 and hindering TLR4/NLRP3 inflammasome signaling pathways., (Copyright © 2021 Elsevier B.V. All rights reserved.)
- Published
- 2022
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