Pathobiology of tobacco smoking and neurovascular disorders: untied strings and alternative products

Tobacco smoke (TS) is the leading cause of preventable deaths worldwide. In addition to a host of well characterized diseases including chronic obstructive pulmonary disease, oral and peripheral cancers and cardiovascular complications, epidemiological evidence suggests that chronic smokers are at equal risk to develop neurological and neurovascular complications such as multiple sclerosis, Alzheimer's disease, stroke, vascular dementia and small vessel ischemic disease (SVID). Unfortunately, few direct neurotoxicology studies of tobacco smoking and its pathogenic pathways have been produced so far. A major link between TS and CNS disorders is the blood-brain barrier (BBB). In this review article, we summarize the current understanding of the toxicological impact of TS on BBB physiology and function and major compensatory mechanisms such as nrf2- ARE signaling and anti-inflammatory pathways activated by TS. In the same context, we discuss the controversial role of antioxidant supplementation as a prophylactic and/or therapeutic approach in delaying or decreasing the disease complications in smokers. Further, we cover a number of toxicological studies associated with "reduced exposure" cigarette products including electronic cigarettes. Finally, we provide insights on possible avenues for future research including mechanistic studies using direct inhalation rodent models.