Vascular dementia (VaD) is a common cause of
cognitive decline and
dementia of vascular origin, but the precise pathological mechanisms are unknown, and so effective clinical treatments have not been established.
Tilianin, the principal active compound of total
flavonoid extract from Dracocephalum moldavica L., is a candidate
therapy for cardio-
cerebrovascular diseases in China. However, its potential in the treatment of VaD is unclear. The present study is aimed at investigating the protective effects of
tilianin on VaD and exploring the underlying mechanism of the action. A model of VaD was established by permanent 2-vessel occlusion (2VO) in rats. Human neurons (hNCs) differentiated from human-induced pluripotent stem cells were used to establish an
oxygen-
glucose deprivation (OGD) model. The
therapeutic effects and potential mechanisms of
tilianin were identified using behavioral tests, histochemistry, and multiple molecular biology techniques such as Western blot analysis and gene silencing. The results demonstrated that
tilianin modified spatial
cognitive impairment, neurodegeneration, oxidation, and apoptosis in rats with VaD and protected hNCs against OGD by increasing cell viability and decreasing apoptosis rates. A study of the mechanism indicated that
tilianin restored p-
CaMKII/ERK1/2/CREB signaling in the hippocampus, maintaining hippocampus-independent memory. In addition,
tilianin inhibited an ox-
CaMKII/
p38 MAPK/JNK/NF-κB associated inflammatory response caused by cerebral oxidative stress imbalance in rats with VaD. Furthermore, specific CaMKIIα
siRNA action revealed that
tilianin-exerted neuroprotection involved increase of neuronal viability, inhibition of apoptosis, and suppression of
inflammation, which was dependent on CaMKIIα. In conclusion, the results suggested the
neuroprotective effect of
tilianin in VaD and the potential mechanism associated with dysfunction in the regulation of p-
CaMKII-mediated long-term memory and oxidation and
inflammation involved with ox-
CaMKII, which may lay the foundation for clinical trials of
tilianin for the treatment of VaD in the future.