The Roles of Nitric Oxide Synthase/Nitric Oxide Pathway in the Pathology of Vascular Dementia and Related Therapeutic Approaches

Abstract

Vascular dementia (VaD) is the second most common form of dementia worldwide. It is caused by cerebrovascular disease, and patients often show severe impairments of advanced cognitive abilities. Nitric oxide synthase (NOS) and nitric oxide (NO) play vital roles in the pathogenesis of VaD. The functions of NO are determined by its concentration and bioavailability, which are regulated by NOS activity. The activities of different NOS subtypes in the brain are partitioned. Pathologically, endothelial NOS is inactivated, which causes insufficient NO production and aggravates oxidative stress before inducing cerebrovascular endothelial dysfunction, while neuronal NOS is overactive and can produce excessive NO to cause neurotoxicity. Meanwhile, inflammation stimulates the massive expression of inducible NOS, which also produces excessive NO and then induces neuroinflammation. The vicious circle of these kinds of damage having impacts on each other finally leads to VaD. This review summarizes the roles of the NOS/NO pathway in the pathology of VaD and also proposes some potential therapeutic methods that target this pathway in the hope of inspiring novel ideas for VaD therapeutic approaches.

Keywords: nitric oxide; nitric oxide synthase; pathology; therapeutic approaches; vascular dementia.

Figure 1

Overview of the pathological mechanism of VaD.

Figure 2

The active structure of NOS.

Figure 3

Mechanism of eNOS uncoupling.

Figure 4

Alterations in eNOS phosphorylation state are involved in CEC dysfunction. (A). Under normal conditions, the PI3K/Akt pathway can promote the phosphorylation of eNOS at the Ser1177 locus and the dephosphorylation of the Thr495 locus, thereby enhancing the binding of eNOS to CaM. Thus, eNOS can be rapidly activated to produce adequate amounts of NO to protect vascular function. (B). However, during severe cerebral ischemia, the PI3K/Akt pathway is inhibited, leading to the altered phosphorylation of eNOS—i.e., dephosphorylation at the Ser1177 locus but phosphorylation at the Thr495 locus, which prevents eNOS from being activated and producing NO, thereby exacerbating the dysfunction of CECs.

Figure 5

Inflammation leads to VaD pathogenesis by increasing the expression of iNOS.