Brain, Nrf2, and Tobacco: Mechanisms and Countermechanisms Underlying Oxidative-Stress-Mediated Cerebrovascular Effects of Cigarette Smoking

Abstract It is well established that tobacco smoking (TS) has been associated with vascular endothelial dysfunction in a causative and dose-dependent manner. This is primarily related to the TS content of reactive oxygen species (ROS), nicotine, and oxidative stress (OS)-driven inflammation. Current scientific opinion considers OS to play a major role in the pathogenesis of major cerebrovascular and neuroinflammatory disorders associated with TS including stroke, vascular dementia, small vessel ischemic disease, and Alzheimer's disease (AD). Preclinical studies have also shown that nicotine (the principal e-liquid's ingredient used in e-cigarettes—e-cigs) can also cause OS and inflammation and exacerbation of cerebral ischemia. Recently published in vitro and in vivo findings strongly suggest the onset and/or progression of these cerebrovascular/neuroinflammatory disorders associated with OS is largely modulated by common key factors. These include alterations of the endogenous antioxidant response element (ARE) regulated by the nuclear factor erythroid 2-related factor (Nrf2). In fact, the activity of the Nrf2-ARE pathway not only supports BBB viability and integrity as recently demonstrated but also plays a major role in protecting cells and tissue from excessive OS such that associated with TS.