Paeonol ameliorates scopolamine- and β-amyloid 1-42 oligomer-induced cognitive impairments through modulation of the TGR5-PKA-cAMP response element-binding-brain-derived neurotrophic factor pathway and inhibition of acetylcholinesterase.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, synaptic dysfunction, and cholinergic signaling deficits. Paeonol (2-hydroxy-4-methoxyacetophenone), a phenolic compound derived from Paeonia suffruticosa, has well-documented neuroprotective activity, but potential cognitive benefits and the underlying mechanisms have not been widely examined. Here, we investigated the potential of paeonol to improve cognitive function in scopolamine- and Aβ1-42 oligomer-induced mouse models of AD. Paeonol significantly improved the performance of both models in the Y-maze, novel object recognition, and passive avoidance tests, particularly at 10 mg/kg. Western blotting of excised brain tissue revealed that paeonol treatment reversed scopolamine- and Aβ1-42 oligomer-induced suppression of hippocampal PKA and cAMP response element-binding (CREB) phosphorylation and concomitantly enhanced brain-derived neurotrophic factor (BDNF) expression. Notably, paeonol also reversed scopolamine- and Aβ1-42-induced downregulation of Takeda G-protein-coupled receptor 5 (TGR5), an upstream regulator of the PKA-CREB-BDNF pathway, and molecular docking simulations predicted a possible paeonol-TGR5 interaction. Moreover, paeonol suppressed scopolamine-induced elevation of acetylcholinesterase activity with efficacy comparable to the clinical inhibitor donepezil. These findings support the potential of paeonol as a naturally sourced multitarget therapeutic agent for AD.