European journal of pharmacology · 2025
The potential mitigating effect of febuxostat alone or with donepezil on scopolamine-induced Alzheimer's disease in rats: The role of TXNIP/NLRP3 inflammasome signaling pathway.
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Taha Dina E, Kabel Ahmed M, Yassin Ahmed I, Abdin Amany A
Аннотация
BACKGROUND: Alzheimer's disease (AD) is a pervasive neurodegenerative disorder. Despite extensive research, its multifactorial etiology remains complex and not fully understood. The present study was performed to investigate the potential ameliorative effect of febuxostat and donepezil each alone or in combination on scopolamine-induced AD in male Wistar rats via targeting Thioredoxin-interacting protein (TXNIP)/NOD-like receptor protein-3 (NLRP3) inflammasome pathway.
METHODS: In a rat model of scopolamine-induced AD, the changes in the behavioral tests, biochemical parameters, and the histopathological picture in the hippocampal and cerebral tissues were assessed.
RESULTS: Administration of either donepezil or febuxostat to scopolamine-induced AD rats significantly improved the behavioral changes, decremented TXNIP levels with amelioration of the neuroinflammation by decreased NLRP3, and IL-1β levels, restoration of the oxidant/antioxidant balance and inhibition of apoptosis by increasing expression of anti-apoptotic protein Bcl-2 with restoration of ACh levels. Notably, only febuxostat causes normalization of fasting blood glucose levels. These changes were positively reflected on the histopathological picture and scoring in both tissues. These beneficial effects were significantly more evidenced in rats treated with donepezil/febuxostat combination relative to monotherapy by either donepezil or febuxostat. The impact of the tested parameters in the disease outcome was evidenced by their significant correlation and moreover the causality by the significant regression, shedding light particularly for the glycemic state and the neuroinflammatory reactions.
CONCLUSION: These elaborated data signified the neuroprotective effect of febuxostat and indicated that donepezil/febuxostat combination strengthened each other as they act by different mechanisms to counteract AD.
METHODS: In a rat model of scopolamine-induced AD, the changes in the behavioral tests, biochemical parameters, and the histopathological picture in the hippocampal and cerebral tissues were assessed.
RESULTS: Administration of either donepezil or febuxostat to scopolamine-induced AD rats significantly improved the behavioral changes, decremented TXNIP levels with amelioration of the neuroinflammation by decreased NLRP3, and IL-1β levels, restoration of the oxidant/antioxidant balance and inhibition of apoptosis by increasing expression of anti-apoptotic protein Bcl-2 with restoration of ACh levels. Notably, only febuxostat causes normalization of fasting blood glucose levels. These changes were positively reflected on the histopathological picture and scoring in both tissues. These beneficial effects were significantly more evidenced in rats treated with donepezil/febuxostat combination relative to monotherapy by either donepezil or febuxostat. The impact of the tested parameters in the disease outcome was evidenced by their significant correlation and moreover the causality by the significant regression, shedding light particularly for the glycemic state and the neuroinflammatory reactions.
CONCLUSION: These elaborated data signified the neuroprotective effect of febuxostat and indicated that donepezil/febuxostat combination strengthened each other as they act by different mechanisms to counteract AD.