Abstract
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.
Highlights
Vascular dementia (VaD) is the second most common form of dementia, accounting globally for approximately 20% of dementia cases
It can be inferred that calmodulin-dependent protein kinase II (CaMKII) performs a pivotal role in many aspects of VaD involving the control of cognitive deficit and the evocation of oxidative stress, inflammatory reactions, and cell apoptosis
Subsequent comparisons demonstrated that rats with 2-vessel occlusion (2VO) displayed longer escape latency compared with sham rats (Figure 4(a), P < 0:05), and dosages of both 20 mg/kg and 40 mg/kg tilianin significantly reduced escape latency on days 2 to 5 compared with rats with 2VO (Figure 4(a), P < 0:05 and 0.01)
Summary
Vascular dementia (VaD) is the second most common form of dementia, accounting globally for approximately 20% of dementia cases It is caused by insufficient oxygen and nutrients due to a restricted blood supply to parts of the brain, leading to gradual cognitive decline. Intracellular calcium ions activate autophosphorylation of CaMKII, which plays a role in the induction and maintenance of long-term potentiation (LTP), referred to as a “molecular memory switch” [5]. Oxidative stress induced by intracellular calcium overload leads to the production of large quantities of reactive oxygen species (ROS), which activates oxCaMKII and triggers subsequent mitogen-activated protein kinase (MAPK)/nuclear factor kappa-B (NF-κB) pathways, leading to inflammatory response, cell apoptosis, and neuronal damage [7]. It can be inferred that CaMKII performs a pivotal role in many aspects of VaD involving the control of cognitive deficit and the evocation of oxidative stress, inflammatory reactions, and cell apoptosis. The mechanisms underlying the neuroprotective action and antioxidant, anti-inflammatory, and antiapoptotic properties were elucidated
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