Reactive Oxygen Species, a Potential Therapeutic Target for Vascular Dementia

Abstract

Vascular dementia (VaD) is a progressive neurodegenerative condition prevalent among elderly adults marked by cognitive decline resulting from injured and/or improperly functioning cerebrovasculature with resultant disruptions in cerebral blood flow. Currently, VaD has no specific therapeutics and the exact pathobiology is still being investigated. VaD has been shown to develop when reactive oxygen species (ROS) form from damaged targets at different levels of organization-mitochondria, endothelial cells, or cerebrovasculature. In this review, we highlight how specific ROS molecules may be important in the development of VaD and how they can be targeted as a potential therapeutic for VaD.

Keywords: Alzheimer’s disease; antioxidants; reactive oxygen species; therapeutic; vascular dementia.

Figure 1

Overview of the possible mechanistic link of primary reactive oxygen species in the development of vascular dementia adverse events in the brain (stroke, eNOS uncoupling, and electron leak from the ETC) which lead to the production of ROS that contribute to much of the common pathological damage seen in vascular dementia. eNOS; endothelial nitric oxide synthase. ETC; electron transport chain. H₂O₂; hydrogen peroxide. ONOO−; peroxynitrite. O₂−; superoxide. VaD; vascular dementia.

Figure 2

Summary of how brain-mitochondrial-sourced hydrogen peroxide contributions to vascular dementia electron leakage from the electron transport chain (ETC) in the presence of superoxide (O₂−) lead to the production of hydrogen peroxide (H₂O₂). H₂O₂ can then modify protein and nucleotide structures, leading to various damages. H₂O₂ can also oxidize LDL, leading to increases in inflammation. The combined effects of high levels of H₂O₂ promote mitochondrial dysfunction and ultimately result in VaD.

Figure 3

Summary of peroxynitrite contributions to vascular dementia in abnormal brain endothelial cells. The reaction between nitric oxide (NO) and superoxide (O₂−) from eNOS uncoupling leads to the production of peroxynitrite (ONOO−). ONOO− is then able to modify neighboring structures, promote eNOS uncoupling, and inhibit glutathione, preventing its antioxidant activity. Various ONOO− induced damage causes endothelial dysfunction and increases in NOX, and ultimately leads to VaD.

Figure 4

Summary of superoxide contributions to vascular dementia in abnormal cerebrovasculature. An ischemic event can lead to the upregulation of NOX enzymes and the production of superoxide (O₂−) and hydrogen peroxide (H₂O₂). O₂− can promote inflammation and BBB damage. H₂O₂ can prolong the ischemic state, leading to further injury. Ultimately, the damage induced by O₂− and H₂O₂ leads to VaD.