Amid accelerating population aging in both developed and developing countries, the incidence of Vascular dementia (VaD) has surged. Accounting for up to 20% of dementia cases, VaD is the second most common cause after Alzheimer's disease (AD), representing 15% of global dementia prevalence (Chang Wong and Chang Chui, 2022; O'Brien and Thomas, 2015). VaD is a common neurodegenerative disorder induced by chronic cerebral hypoperfusion, most frequently resulting from an ischemic stroke. The pathological mechanisms underlying VaD remain incompletely elucidated. Emerging evidence has identified several molecular biomarkers associated with vascular cognitive impairment and dementia, including: endothelial dysfunction, blood-brain barrier disruption, chronic neuroinflammation, glial activation, mitochondrial dynamics and oxidative stress, etc (Du et al., 2024; Hosoki and Sachdev, 2024; Yang et al., 2024). Contributing factors include advanced age, family history, genetic variations, low education, endocarditis, and cerebral amyloid angiopathy, with frequent co-occurrence with AD (Iadecola, 2013). Characterized by high prevalence, disability, and mortality, VaD imposes substantial burdens on families and society, emerging as a major public health challenge in China. Currently, there are no effective treatments or specific drugs for VaD. Hence, discovering novel anti-VaD drugs is critical to human health.

Traditional Chinese medicine (TCM) emphasizes the combination of “symptomatic treatment” and “root-cause treatment” for disease management (Velmurugan et al., 2018). TCM/natural products (NPs) offer holistic therapeutic solutions for chronic diseases through their polypharmacological properties. Their multi-target mechanisms align with systemic medicine principles, simultaneously addressing disease manifestations and root causes (Barabási et al., 2011; Gan et al., 2023; Li et al., 2010). For example, through activity-based protein profiling technology, Wei Wei and colleagues revealed that berberine produces anti-inflammatory effects by specifically preventing interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2) dimer formation without directly blocking its enzymatic activity. This selective inhibition leads to coordinated suppression of key inflammatory signaling pathways including stress-activated protein kinase (JNK), nuclear factor NF-kappa-B (NF-κB) and RAC serine/threonine-protein kinase (AKT) (Wei et al., 2023). Systematic reviews and meta-analyses have demonstrated that the combination of TCM with donepezil is significantly prevalent in the treatment of VaD, with no associated increase in adverse events. Examples of such combinations include Gunao-Yizhi decoction with donepezil and Ginkgo biloba extract with donepezil hydrochloride (Hu et al., 2022; Xiao et al., 2024). This study investigates whether the combined use of multi-target small-molecule drug DL0410 (for symptomatic relief) and natural product LG0367 (for root-cause therapy) can achieve superior therapeutic outcomes for VaD. DL0410 is a novel small-molecule anti-AD drug independently discovered and synthesized by our research team. It was first identified as a potent acetylcholinesterase (AChE) inhibitor (IC50 = 0.29 μM), with an inhibitory activity approximately half that of donepezil (IC50 = 0.085 μM) (Zhou et al., 2016). The therapeutic efficacy of DL0410 in AD has been validated in a series of AD-related animal models, including Aβ1-42, D-galactose and scopolamine-induced ICR mice, D-galactose-induced SD rats, SAMP8 mice, and APP/PS1 transgenic mice (Lian et al., 2017a, 2017b, 2021; Yang et al., 2015; Zhou et al., 2016). DL0410 demonstrated beneficial effects on cognitive impairment, performing equivalently or even better than donepezil. Beyond its role as a cholinesterase inhibitor, DL0410 exerts anti-AD effects through multiple mechanisms, including reducing Aβ generation, protecting mitochondrial respiration, promoting synaptic transmission, reducing neuronal loss, maintaining blood-brain barrier integrity, and inhibiting oxidative stress and neuroinflammation, etc (Appendix 1). LG0367, a metabolite of curcumin, has been demonstrated to effectively treat various neurodegenerative diseases, including AD, cerebral ischemia/reperfusion injury, and Parkinson's disease. Its primary mechanisms of action are attributed not only to its strong antioxidant properties and ability to reduce amyloid β aggregates, but also to its pleiotropic pharmacological effects, such as anti-neuronal apoptosis and improvement of mitochondrial structure (Greeshma et al., 2015; Josifovska et al., 2023; Park et al., 2019; Wei et al., 2017).

In this study, we compared the therapeutic efficacy and mechanisms of DL0410 and LG0367 combination therapy versus monotherapy in treating VaD, based on their multiple pharmacological mechanisms. Our results show that combination treatment with DL0410 and LG0367 has significant advantages over single treatment in repressing neuroinflammation, reducing oxidative stress and protect neurons from damage. etc. Our findings provide new insights into exploring therapies for VaD.