Vascular dementia (VaD) is one of the most common neurodegenerative diseases, and there is no effective therapy to prevent or cure VaD to date. 1,1'-(1,1'-Biphenyl-4,4'-diyl)bis(3-piperidino-1-propanone) dihydrochloride (DL0410) is a novel multi-target small-molecule drug against Alzheimer's disease (AD), with particularly outstanding acetylcholinesterase (AChE) inhibitory activity and Histamine H3 receptor (H3R) inhibitory activity. Natural derivative 1,7-bis(4-hydroxy-3-methoxyphenyl)heptane-3,5-dione (LG0367) is a metabolite of curcumin. Previous studies have demonstrated that LG0367 exhibited better pharmacokinetic properties and therefore displayed better pharmacological activity than curcumin. Here, using bilateral common carotid artery occlusion (2VO) rat model, we found that the combined treatment of DL0410 and LG0367 had a much better effect on improving cognitive function in rats than single-drug treatment or donepezil, suggesting a synergistic effect between the small-molecule drug DL0410 and the natural derivertive LG0367. In addition, we found that the combined DL0410 and LG0367 treatment had significant synergic effects on inhibiting AChE production in cortex of 2VO rats. Furthermore, compound-target network and enrichment analyses revealed that DL0410 and LG0367 exhibit synergistic potential against VaD based on multiple mechanisms. In addition, the study also showed that the combination treatment had remarkable synergic effects on decreasing inflammatory responses and oxidative stress, protecting mitochondrial structure, reducing the release of astrocytes, and decreasing neuronal damage and activating the expression of SHH protein in the cortex and hippocampus of 2VO rats. Our findings not only demonstrated a potent synergistic effect between the synthetic small-molecule DL0410 and the natural derivative LG0367, but also illuminate a promising "symptom-to-root" therapeutic strategy for VaD, providing a systematic and evidence-based model for modernizing phytotherapy. Ultimately, this study will provide important information for future clinical trials aimed at translating this synergistic combination into a tangible "multi-target, multi-mechanism" treatment option for VaD patients.
