Synergistic Effects of Sinomenine Hydrochloride and Low-Dose Donepezil on Cognitive Decline: Combined Modulation of Cholinergic Function and Nrf2-Mediated Antioxidant Response

Background and Objective: Cognitive decline, a hallmark of neurodegenerative diseases such as Alzheimer’s disease (AD), poses a major global health challenge. Current treatments like donepezil provide symptomatic relief but are limited by side effects and do not halt disease progression. This study aimed to investigate the synergistic effects of low-dose donepezil combined with sinomenine hydrochloride, a natural alkaloid with anti-inflammatory and neuroprotective properties, on cognitive deficits. Materials and Methods: An in vivo model of cognitive impairment was used to assess the effects of combination therapy on cholinergic function, oxidative stress, and the Nrf2-dependent anti-oxidative pathway. Behavioral tests evaluated spatial and recognition memory, while biochemical assays measured acetylcholine esterase (AChE), choline acetyltransferase (ChAT), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH). Expression of Nrf2 and its downstream targets, heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1), was analyzed. All data were analyzed using GraphPad Prism 9.0 and expressed as Mean±SEM, with significance determined at p<0.05 using one-way ANOVA (Tukey’s post hoc test) and repeated-measures ANOVA for MWM escape latency. Results: Combined low-dose donepezil and sinomenine hydrochloride significantly improved spatial and recognition memory, restored AChE/ChAT balance, and reduced oxidative stress (MDA). The treatment robustly activated the Nrf2 pathway, increasing HO-1 and NQO1 expression and enhancing antioxidant capacity (SOD, GSH). These effects were superior to those observed with either agent alone, indicating a potent synergistic effect. Conclusion: The combination of low-dose donepezil and sinomenine hydrochloride synergistically improves cognitive function by modulating cholinergic neurotransmission and enhancing Nrf2-dependent antioxidant defenses. This strategy offers a promising approach to managing cognitive decline with potentially reduced side effects, warranting further investigation in clinical settings.