Clopidogrel combats neuroinflammation and enhances learning behavior and memory in a rat model of Alzheimer's disease

• Published in: Pharmacology, biochemistry and behavior Vol. 195; p. 172956
• Main Authors: Khalaf, Noura El Adle, El Banna, Farida Mohamed, Youssef, Mona Younis, Mosaad, Youssef Mohammed, Daba, Mohamed-Hesham Yousry, Ashour, Rehab Hamdy
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2020
• Subjects: Acetylcholinesterase - metabolism; Aluminum chloride; Aluminum Chloride - adverse effects; Alzheimer Disease - chemically induced; Alzheimer Disease - drug therapy; Alzheimer's disease; Amyloid beta-Protein Precursor - genetics; Animals; Clopidogrel; Clopidogrel - administration & dosage; Cytokines - metabolism; Disease Models, Animal; Gene Expression - drug effects; Hippocampus - drug effects; Hippocampus - metabolism; Male; Maze Learning - drug effects; Neuroinflammation; Neuroprotective Agents - administration & dosage; Plaque, Amyloid - drug therapy; Plaque, Amyloid - metabolism; Rats; Rats, Sprague-Dawley; Recognition, Psychology - drug effects; RNA, Messenger - genetics; Signal Transduction - drug effects; APP; ACh; Al3; CNS; cGMP; ADP; LPS; Aβ; HIF-1; NF-κB; AlCl3; Alzheimer's disease; AChE; MWM; AD; Aluminum chloride; qRT-PCR; Neuroinflammation; IL-1β; NOR; TNF-α; IAL; RI; SPs; Clopidogrel; RL; ATP; RQ
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/j.pbb.2020.172956

Alzheimer's disease (AD) is a progressive neurodegenerative disease. Multiple molecular mechanisms have been employed in its pathogenesis such as Amyloid β (Aβ) formation, tau protein hyperphosphorylation, reduced acetylcholine (ACh) level, and neuroinflammation. This study aimed to assess the possible neuroprotective effect of clopidogrel in AD model induced by aluminum chloride (AlCl3) in rats. Sixty adult male Sprague-Dawley rats were divided into four different groups: Control, AlCl3, AlCl3 + donepezil, and AlCl3 + Clopidogrel. AlCl3 and the drugs were given orally once/day for 42 days. The spatial learning and memory and recognition memory were evaluated using Morris Water Maze (MWM) and Novel Object Recognition (NOR) tests, respectively. After euthanasia, hippocampal acetylcholinesterase (AChE) activity, tumor necrosis factor-alpha (TNF-α), and interleukin-1β (IL-1β) levels were biochemically assessed. Moreover, amyloid precursor protein (APP) mRNA gene expression was analyzed in the hippocampi of all rats. Histopathology for amyloid plaques was done. Clopidogrel co-treatment significantly ameliorated the cognitive deficits induced by AlCl3 in rats. Besides, clopidogrel significantly reduced AChE activity, TNF-α and IL-1β concentrations, and APP mRNA gene expression in the hippocampi of rats compared to AlCl3 rats. The decrease of hippocampal TNF-α and IL-1β concentrations by clopidogrel was significant compared to donepezil co-treated rats. Clopidogrel co-treatment lessened amyloid plaque deposition in the hippocampal tissues of rats compared to AlCl3 rats. These findings demonstrate that clopidogrel could alleviate learning and memory deficit induced by AlCl3 in rats and significantly reduced AChE activity. The neuroprotective outcome of clopidogrel might be assigned to its anti-inflammatory effect. [Display omitted] •Chronic AlCl3 treatment impaired rats' spatial learning and the recognition memory.•AlCl3 augmented pro-inflammatory cytokine release in the hippocampi of these rats.•Clopidogrel co-treatment improved the learning behavior and the recognition memory.•Clopidogrel showed significant anti-inflammatory effect by lowering TNF-α and IL-1β.•Clopidogrel significantly attenuated amyloid plaque deposition provoked by AlCl3.