Cerebral Small Vessel Disease: Targeting Oxidative Stress as a Novel Therapeutic Strategy?

Abstract

Cerebral small vessel disease (SVD) is a major contributor to stroke, and a leading cause of cognitive impairment and dementia. Despite the devastating effects of cerebral SVD, the pathogenesis of cerebral SVD is still not completely understood. Moreover, there are no specific pharmacological strategies for its prevention or treatment. Cerebral SVD is characterized by marked functional and structural abnormalities of the cerebral microcirculation. The clinical manifestations of these pathological changes include lacunar infarcts, white matter hyperintensities, and cerebral microbleeds. The main purpose of this review is to discuss evidence implicating oxidative stress in the arteriopathy of both non-amyloid and amyloid (cerebral amyloid angiopathy) forms of cerebral SVD and its most important risk factors (hypertension and aging), as well as its contribution to cerebral SVD-related brain injury and cognitive impairment. We also highlight current evidence of the involvement of the NADPH oxidases in the development of oxidative stress, enzymes that are a major source of reactive oxygen species in the cerebral vasculature. Lastly, we discuss potential pharmacological strategies for oxidative stress in cerebral SVD, including some of the historical and emerging NADPH oxidase inhibitors.

Keywords: NADPH oxidases (Noxs); brain injury; cerebral small vessel disease; cognitive impairment; oxidative stress and redox regulation; pharmacological strategies.

FIGURE 1

Compelling experimental evidence suggests that oxidative stress underlies some aspects of cerebral vascular dysfunction associated with known risk factors for non-amyloid cerebral small vessel disease (SVD), and contributes to the deleterious actions of soluble and deposited amyloid-beta in the setting of cerebral amyloid angiopathy (CAA). The NADPH oxidases appear to be a major driver of this oxidative stress, however, future research is needed to elucidate the potential contributes of other enzymes. Various experimental models have been employed to study the cerebral vascular lesions and cognitive impairment that typically manifest in cerebral SVD. Oxidative stress and the NADPH oxidases are once again implicated. Despite evidence of its devastating effects on the brain, there are at currently no specific pharmacological strategies to prevent or treat cerebral SVD. Modifying risk factors with drugs already in the clinic (e.g., ACE inhibitors, angiotensin II receptor blockers) seems like a logical approach. Moreover, agents that target the endothelium (i.e., increasing nitric oxide bioavailability) may be useful in rescuing the functioning of the cerebral vasculature. Lastly, strategies to combat oxidative stress (e.g., NADPH oxidase inhibitors) may also be a novel strategy.