Background and aim: Alzheimer's disease (AD) is a common progressive disease characterized by neurodegeneration. Multiple molecular mechanisms such as amyloid β (Aβ) formation, tau protein hyperphosphorylation, reduced cholinergic neurotransmission, oxidative stress, and neuroinflammation are involved in the disease pathophysiology. The purpose of this study was to assess potential neuroprotective effect of clopidogrel in AD model induced by aluminum chloride (AlCl3) in rats Methods: Forty adult male Sprague-Dawley rats were haphazardly separated into four groups of ten rats each: Control, AlCl3 (100 mg/kg orally), AlCl3 + Memantine (10 mg/kg orally), and AlCl3 + Clopidogrel groups (20 mg/kg orally). AlCl3 and drugs were administrated once every day for 42 days. The spatial learning and memory were evaluated using Morris Water Maze (MWM) test. After euthanization, hippocampal acetylcholinesterase (AChE) activity, tumor necrosis factor alpha (TNF-α), and interleukin-1beta (IL-1β) concentrations were biochemically assessed in all groups. Moreover, amyloid precursor protein (APP) mRNA gene expression was analyzed in the hippocampus of all groups with Real-time quantitative polymerase chain reaction (qPCR). Histopathology for amyloid plaques was done in all groups' hippocampus using hematoxylin and eosin and Congo stain. Results: AlCl 3 and clopidogrel co-treatment significantly ameliorated the cognitive deficits induced by AlCl3 in rats. Moreover, AlCl3 and clopidogrel co-treatment significantly reduced AChE activity, TNF-α and IL-1β concentrations, and APP mRNA gene expression in the rat hippocampi compared to AlCl3-treated rats. AlCl3 and clopidogrel co-treatment significantly reduced TNF-α and IL-1β concentrations in the rat hippocampi compared to AlCl3 and memantine co-treated rats. In addition, AlCl3 and clopidogrel cotreatment alleviated amyloid plaque deposition in the rat hippocampal tissues stained with hematoxylin and eosin and Congo stains compared to AlCl3-treated rats. Conclusion: These results showed that clopidogrel could improve cognitive deficits triggered by AlCl3 in rats. The neuronal protection influence of clopidogrel in AlCl3-triggered AD might be mediated through its antiinflammatory effect as demonstrated by its ability to decrease hippocampal TNF-α and IL-1β concentrations. It might also be mediated through its lowering effect on AChE activity and/or decreasing mRNA gene expression of APP gene in the hippocampus
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