Intermittent Hypoxia-Induced Cognitive Deficits Are Mediated by NADPH Oxidase Activity in a Murine Model of Sleep Apnea

Background: In rodents, exposure to intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), is associated with neurobehavioral impairments, increased apoptosis in the hippocampus and cortex, as well as increased oxidant stress and inflammation. Excessive NADPH oxidase activity may play a role in IH-induced CNS dysfunction. Methods and Findings: The effect of IH during light period on two forms of spatial learning in the water maze and well as markers of oxidative stress was assessed in mice lacking NADPH oxidase activity (gp91phox _/Y) and wild-type littermates. On a standard place training task, gp91phox _/Y displayed normal learning, and were protected from the spatial learning deficits observed in wild-type littermates exposed to IH. Moreover, anxiety levels were increased in wild-type mice exposed to IH as compared to room air (RA) controls, while no changes emerged in gp91phox _/Y mice. Additionally, wild-type mice, but not gp91phox _/Y mice had significantly elevated levels of NADPH oxidase expression and activity, as well as MDA and 8-OHDG in cortical and hippocampal lysates following IH exposures. Conclusions: The oxidative stress responses and neurobehavioral impairments induced by IH during sleep are mediated, at least in part, by excessive NADPH oxidase activity, and thus pharmacological agents targeting NADPH oxidase may provid

Reactive oxygen species and cerebrovascular diseases

In the normal physiologic state, reactive oxygen species (ROS) generation is intentional and important for the functioning of cerebral and systemic circulations. Furthermore, emerging evidence indicates that cerebral arteries generate higher levels of ROS than arteries outside of the brain in the normal physiologic state. As such, it has been proposed that ROS may play a more prominent role in the physiologic regulation of cerebral arteries. There are numerous potential enzymatic sources of ROS in the cerebral vasculature; however, increasing evidence indicates that the family of NADPH oxidases is a major source. Aberrant redox signaling or oxidative stress in the cerebral circulation, usually as a result of excessive production of ROS and reactive nitrogen species (RNS), is a common feature in diverse models of cardiovascular risk factors (e.g., hypertension, hypercholesterolemia) and cerebrovascular disease. Furthermore, oxidative stress is now believed to be an underlying cause of cerebrovascular dysfunction and damage associated with these disease states. In this chapter, we summarize the effects and potential roles of ROS/RNS in modulating cerebral artery function in the normal physiologic state, with a particular focus on their roles in modulating cerebrovascular tone. Furthermore, we will highlight current evidence for the involvement of ROS/RNS in cerebrovascular dysfunction associated with cardiovascular risk factors, stroke, and Alzheimer's disease