Abstract
Several experimental studies have indicated that nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox) exert detrimental effects on ischemic brain tissue; Nox-knockout mice generally exhibit resistance to damage due to experimental stroke following middle cerebral artery occlusion (MCAO). Furthermore, our previous MCAO study indicated that infarct size and blood-brain barrier breakdown are enhanced in mice with pericyte-specific overexpression of Nox4, relative to levels observed in controls. However, it remains unclear whether Nox affects the stroke outcome directly by increasing oxidative stress at the site of ischemia, or indirectly by modifying physiological variables such as blood pressure or cerebral blood flow (CBF). Because of technical problems in the measurement of physiological variables and CBF, it is often difficult to address this issue in mouse models due to their small body size; in our previous study, we examined the effects of Nox activity on focal ischemic injury in a novel congenic rat strain: stroke-prone spontaneously hypertensive rats with loss-of-function in Nox. In this review, we summarize the current literature regarding the role of Nox in focal ischemic injury and discuss critical issues that should be considered when investigating Nox-related pathophysiology in animal models of stroke.
Highlights
The nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox)—which function solely to generate superoxide—are the predominant source of reactive oxygen species [1,2]
This study reported that the activation of NFκB in the ischemic hemisphere following permanent middle cerebral artery occlusion (MCAO) was significantly greater in Tg-Nox4 mice than in wild-type controls, as predicted by in vitro experiments, and enzymatic activity of matrix metalloproteinase-9 (MMP-9)—known to be involved in the breakdown of the blood-brain barrier (BBB)—was significantly greater and prolonged in Tg-Nox4 [59]
Distal MCAO in SHR is considered to be the best choice for an experimental model of human stroke, the suture model using knockout mice are widely utilized to assess the effects of Nox on stroke pathophysiology
Summary
The nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox)—which function solely to generate superoxide—are the predominant source of reactive oxygen species [1,2]. Several studies have indicated that Nox activity is increased in cerebral arteries during chronic hypertension, and that this increase in expression is associated with greater production of superoxide and vasodilatation in spontaneously hypertensive rats [8]. Whether the effects of Nox on stroke outcomes are due to direct increases in oxidative stress at the site of ischemia or indirect increases due to the modification of physiological variables (e.g., blood pressure or cerebral blood flow (CBF)) remains unknown. We highlight findings obtained in Nox knockout mouse models of experimental stroke, as well as the effects of Nox on cerebral blood vessels and the BBB, focusing on the role of pericytes. We discuss several confounding factors associated with experimental models of stroke based on our recent findings in stroke-prone spontaneously hypertensive rats (SHRSP), which exhibit Nox dysfunction. MCAO, middle cerebral artery occlusion; MCA, middle cerebral artery; ACA, anterior cerebral artery; P, permanent occlusion; T, transient occlusion; SHRSP, stroke-prone spontaneously hypertensive rats
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