In Vitro Assessment of Tobacco Smoke Toxicity at the BBB: Do Antioxidant Supplements Have a Protective Role?

Abstract

BackgroundTobacco smoke (TS) contains highly reactive oxygen species (such as hydrogen peroxide, peroxynitrite, etc), which cause oxidative damage in vascular tissue and may exacerbate inflammatory events leading to the blood-brain barrier damage (BBBD) which accompanies the development of a variety of neurological disorders. Smokers often have elevated leukocyte counts (primarily neutrophils and monocytes), and significant decreases in plasma alpha-tocopherol (vitamin E) and ascorbic acid (vitamin C) levels due to increased anti-oxidative mobilization in response to oxidative stress evoked by TS. For this purpose, using static culture systems and a well-established dynamic in vitro BBB model (DIV-BBB) we tested the hypothesis that antioxidant vitamin supplementation (E and/or C) can protect the BBB during exposure to whole soluble TS.ResultsTS exacerbates inflammatory events and leads to endothelial overexpression of vascular adhesion molecules (VCAM-1, P-selectin and E-selectin), release of pro-inflammatory cytokines (TNF-α and IL-6) and nitric oxide (NO), release and activation of matrix metalloproteinases (MMP-2 and MMP-9), monocytic maturation into macrophages, and adhesion to the vascular endothelium. Furthermore, TS altered the normal glucose metabolic behaviour of in vitro BBB capillaries and caused a period of transient anaerobic respiration to meet the cellular bioenergetic demand. Pre-treatment with antioxidant vitamins (C and/or E) effectively reduced the pro-inflammatory activity associated with TS, protecting the viability and functions of the BBB.ConclusionOur results have shown that loss of endothelial viability as well as BBB function and integrity caused by TS exposure can be prevented or at least reduced by normal physiologic concentrations of antioxidant vitamins in vitro.

Cigarette smoke and related risk factors in neurological disorders: An update

“…Nevertheless, many experimental studies have been conducted and revealed a number of contrasting results from in vitro and/or in vivo studies regarding the therapeutic effect of antioxidants in a number of neurodegenerative disorders [85][86][87]. In the studies of Hossain et al [88] and Cherubini et al [89], the authors proved that supplementation of antioxidant-rich compounds exhibited a beneficial effect on ischemic stroke, loss of BBB integrity, and inflammatory response in smoke-exposed BBB culture.…”

Oxidative and pro-inflammatory impact of regular and denicotinized cigarettes on blood brain barrier endothelial cells: is smoking reduced or nicotine-free products really safe?

“…This provides a solid link to TS-dependent impairment of BBB function whereas cigarette smoke extracts have been shown to act as a powerful activator of immune/inflammatory response pathways altering the integrity/function of the BBB [13,14]. …”

Drugs of abuse and blood-brain barrier endothelial dysfunction: A focus on the role of oxidative stress

“…21 For example, using static or flow-based in vitro BBB models, we previously demonstrated a marked increase in intracellular ROS/RNS and secretory profile of various pro-inflammatory markers accompanied by alterations in BBB TJ protein expression and re-distribution following TS exposure. 43,114 In addition, DNA microarray-based global transcriptome profiling indicated a rapid and transient up-regulation of Nrf2 and its downstream anti-oxidant molecular networks in response to prolonged TS exposure in brain microvascular endothelial cultures. 115 Interestingly, anti-oxidant supplementation toned down TS-induced oxidative stress thus preventing BBB damage.…”

“…115 Interestingly, anti-oxidant supplementation toned down TS-induced oxidative stress thus preventing BBB damage. 114 An interesting argument posed by multiple studies is the extent to which nicotine contributes to the pathogenesis of smoking-related cerebrovascular complications and BBB dysfunction. This is not an easy conundrum to solve given the many discrepancies in the published literature (Hawkins et al, 2002).…”