Targeting Fyn Kinase for Alleviation of Cognitive Impairment in Streptozocin-Induced Alzheimer’s Disease in Mice by Loperamide; An Experimental and in Silico Analysis

Alzheimer’s disease (AD) is a complex, progressive neurodegenerative disorder that leads to irreversible deterioration of neuronal cells over time. It is the most frequent cause of dementia in elderly individuals globally. Current treatment drugs exhibit modest effect on AD patients. Fyn kinase is implicated in AD pathogenesis, and its interactions with both AD hallmarks Aβ and tau make it a unique therapeutic target. To explore small molecule inhibitors effective in treating AD, FDA-approved drugs were evaluated using molecular docking to determine their affinity for Fyn kinase. The findings of molecular simulations support the repurposing of loperamide for treating AD. Swiss albino mice were divided into six groups, including sham control, STZ group, donepezil-treated positive control, and three loperamide-treated groups with varying doses (2.5, 5, 10 mg/kg). Cognitive functions were assessed using Novel Object Recognition (NOR), Morris Water Maze (MWM), and Elevated plus Maze (EPM) tests. Histological analyses were performed using Congo red, haematoxylin-eosin, and nissl staining. Gene expression of AD markers including Fyn, App, tau, Dlg4, Gfap, Bdnf, Cal1, Ide, Nep, and Sv2a were evaluated using qPCR. For protein quantification, amyloid beta 42 levels were measured using ELISA, while tau phosphorylation was assessed by immunohistochemistry. Our results show that loperamide treatment significantly improved cognitive function in mice, reduced amyloid accumulation and neuronal loss, and enhanced Aβ clearance most probably by upregulating Nep and Ide. Additionally, qPCR results revealed a significant decrease in Fyn expression. Amyloid beta 42 levels were significantly reduced by loperamide treatment, accompanied by decreased phosphorylated tau immunoreactivity in the cortex, dentate gyrus, and cornu ammonis 1 region. We conclude from these investigations that loperamide may serve as a promising therapeutic agent for AD by potentially targeting Fyn kinase, suggesting that further research is needed to explore its effectiveness in treating AD.