Pharmacological Treatment of Vascular Dementia: A Molecular Mechanism Perspective

Abstract

Vascular dementia (VaD) is a neurodegenerative disease, with cognitive dysfunction attributable to cerebrovascular factors. At present, it is the second most frequently occurring type of dementia in older adults (after Alzheimer's disease). The underlying etiology of VaD has not been completely elucidated, which limits its management. Currently, there are no approved standard treatments for VaD. The drugs used in VaD are only suitable for symptomatic treatment and cannot prevent or reduce the occurrence and progression of VaD. This review summarizes the current status of pharmacological treatment for VaD, from the perspective of the molecular mechanisms specified in various pathogenic hypotheses, including oxidative stress, the central cholinergic system, neuroinflammation, neuronal apoptosis, and synaptic plasticity. As VaD is a chronic cerebrovascular disease with multifactorial etiology, combined therapy, targeting multiple pathophysiological factors, may be the future trend in VaD.

Keywords: Vascular dementia; central cholinergic system; neuroinflammation; neuronal apoptosis; oxidative stress; pharmacological treatment; synaptic plasticity.

Figure 1.

Drugs treat VaD through regulating the Nrf2/HO-1 signaling pathway. The Nrf2/HO-1 pathway plays an essential role in inhibiting the oxidative stress in the targets of treatment of VaD. In the case of oxidative stress, Nrf2 is released from the Keap1-Nrf2 complex, transferred from the cytoplasm to the nucleus, and binds to the AREs, promoting the expression of HO-1 and other antioxidant enzymes such as SOD, GSH, and CAT. These antioxidant substances could promote free radical scavenging and exert antioxidant and neuroprotective effects on VaD. Resveratrol, chitosan, DM and PNC could up-regulate the expression of Nrf2, initiating the Nrf2/HO-1 pathway, thus inhibiting the oxidative damage and alleviating the cognitive deficits of VaD. ERK phosphorylation is the core pathway implicated in the activation of Nrf2. Edaravone could enhance the expression of ERK1/2 and then activate the Nrf2/HO-1 pathway, exerting neuroprotective effects on VaD.

Figure 2.

Drugs treat VaD through regulating inflammation-related signaling pathways. There are several inflammation-related pathways involved in neuroinflammation of VaD, which can be used as pharmacological targets. The NF-κB signaling is a core pathway among these inflammation-related pathways. Some drugs such as ReA, PF, Fructus mume, Salvia miltiorrhiza, and RAD001 can act directly on NF-κB or its upstream molecules, thereby inhibiting the pro-inflammatory pathways, reducing expression of inflammatory cytokines, suppressing the activation of glia and promoting the polarization of M1/M2. These effects are beneficial to the cognitive improvement of VaD. Other inflammation-related signaling pathways, such as NLRP3/caspase-1/IL-1β and MAPK signaling could be inhibited by DY-9836 and HRT respectively. Hence, these drugs can exert a neuroprotective effect on VaD.

Figure 3.

Drugs treat VaD through regulating apoptosis-related pathways. The mechanisms of neuronal apoptosis are of great significance for understanding the pathogenesis of VaD. Similar to inflammation-related pathways, neuronal apoptosis also involved in several pathways. Administration of WIN can inhibit apoptosis through activating the PI3K/AKT pathway and blocking the ASK1/p38 pathway. Besides, the L-BNP can also inhibit apoptosis through GDNF/GFRα1/Ret and AKT/ERK1/2 pathways. The BDNF serves as an anti-apoptotic factor by down-regulating the pro-apoptotic factors MCP-1 and Hcy. Drugs, such as ligustrazine and PF, can suppress neuronal apoptosis by increasing BNDF levels. ORC also could inhibit neuronal apoptosis by up-regulating the AKT/mTOR pathway. The results of the aforementioned drugs will lead to a decrease in the Bax/Bcl-2 ratio and the expression of caspase-3. These effects are likely to improve cognitive deficits in VaD.