Synergistic approach of alpha-Asarone (α-asarone) with donepezil in mitigating Alzheimer's disease induced by Aluminium chloride in rats.

Alpha-asarone (α-asarone) and its combination with donepezil (Dnp) exhibit significant therapeutic potential against Alzheimer's disease (AD) by modulating cholinergic activity, synaptic plasticity, neuroinflammation, and oxidative stress while reducing Aβ1–42 aggregation. The present study evaluated the neuroprotective effects of α-asarone (3, 6 mg/kg, p.o.) and Dnp (1 mg/kg, i.p.), individually and in combination, in a rat model of AD induced by aluminium trichloride (4.2 mg/kg, i.p., for 28 days). The treatments improved spatial learning and memory, as assessed by the Morris water maze and passive avoidance tests, and decreased acetylcholinesterase, β-secretase, Aβ1–42, and inflammatory markers. Molecular docking studies demonstrated α-asarone's strong binding affinity to AChE, BACE1, TNF-α, and IL-6. Histopathological analysis revealed restoration of hippocampal pyramidal cells and cortical structures. The study suggests α-asarone, alone or in combination with Dnp, offers neuroprotective, antioxidant, and anti-inflammatory benefits, presenting a promising therapeutic approach for AD management. Thus, the findings of this study provide a framework for the dosages of α-asarone (3 and 6 mg/kg; p.o.) and donepezil (1 mg/kg; i.p.), which are within the safety limits for rodents and correspond to human-equivalent levels, thereby supporting the advancement of future translational research. An illustration of α-asarone's neuroprotective effects in AlCl₃-induced Alzheimer's disease in rats, showing reduced beta-amyloid generation, oxidative stress, neuroinflammation, and improved cholinergic function. This highlights α-asarone's therapeutic potential for Alzheimer's-like neurotoxicity. • . α-Asarone alone or with Donepezil reversed behavioral and neuropathological changes in AlCl₃-induced Alzheimer's rats. • Docking showed strong affinity of α-asarone to AD proteins: AChE, BACE1, TNF-α, and IL-6, crucial in AD pathology. • α-Asarone reduced oxidative stress and inflammation, confirming its antioxidant and anti-inflammatory activities. • α-Asarone improved cognition, reducing AChE, β-secretase, Aβ1-42 levels, and enhancing spatial memory in behavioral tests. • Histopathology confirmed α-asarone’s neuroprotection, increasing hippocampal pyramidal cells and restoring cortical structure.