Protecting the BBB endothelium against cigarette smoke-induced oxidative stress using popular antioxidants: Are they really beneficial?

Abstract

Blood Brain Barrier (BBB) exposed to realistic concentrations (comparable to a chronic heavy smoker) of Cigarette Smoke Extract (CSE) triggers a strong endothelial inflammatory which can lead to the onset of neurological disorders. The involvement of Reactive Oxygen Species (ROS) in this inflammatory cascade is evident from the up-regulation of nuclear factor erythroid 2 related factor 2 (Nrf-2), a transcription factor involved in anti-oxidant response signaling in CSE exposed endothelial cells. We have shown that pre-treatment with α-tocopherol and/or ascorbic acid is highly protective for the BBB, thus suggesting that, prophylactic administration of antioxidants can reduce CSE and/or inflammatory-dependent BBB damage. We have assessed and ranked the protective effects of 5 popular OTC antioxidants (Coenzyme Q10, Melatonin, Glutathione, Lipoic acid and Resveratrol) against CSE-induced BBB endothelial damage using hCMEC/D3 cells. The analysis of pro-inflammatory cytokines release by ELISA revealed that, resveratrol, lipoic acid melatonin and Co-Q10 inhibited the BBB endothelial release of pro-inflammatory cytokines IL-6 & IL-8, reduced (not Co-Q10) CSE-induced up-regulation of Platelet Endothelial Cell Adhesion Molecule -1 (PECAM-1), Vascular Endothelial Cell Adhesion Molecule-1 (VCAM-1) & E-selectin and inhibited monocytes-endothelial cell adhesion. The anti-inflammatory effects correlated with the anti-oxidative protection endowed by these compounds as evidenced by upregulation of NADPH: Quinone Oxidoreductase 1 (NQO1) and reduced cellular oxidative stress. CSE-induced release of Vascular Endothelial Growth Factor (VEGF) was inhibited by all tested compounds although the effect was not strictly dose-dependent. Further in vivo studies are required to validate our results and expand our current study to include combinatorial treatments.

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

“…Indeed, the existing scientific observation believes that ROS-mediated pathways contribute significantly to the pathogenesis of numerous NDs. This proposition is powerfully supported by in vivo and in vitro experiments in which oxidative damage/injury and inflammation induced by cigarette smoke were significantly attenuated by antioxidant supplementation [84,48]. In support of this hypothesis and scientific report, the Food and Nutrition Board of the National Academy of Sciences recommends greater intake of high dietary vitamin C for smokers than for nonsmokers.…”

“…Relation between cigarette smoke and BBB has been limited to a handful of substances among the massive number of substances found in cigarette smoke. Circulation of endothelial cells is an indicator of vascular damage by various stressors [48]. The scientific research by Huang et al [49] exhibited an increase in blood circulation in a specific BBB (brain microvascular endothelial cell) after nicotine treatment.…”

The Potential for Natural Antioxidant Supplementation in the Early Stages of Neurodegenerative Disorders

“…More recently, experimental evidence has proved the direct involvement of Co-Q10 in the expression of a hundred genes responsible for cellular metabolism, the transport of nutrients and signalling. In cases of ataxia, long-term Co-Q10 oral supplementation (30 mg/kg per day) can improve the gait and posture of the patients affected [11].…”

“…On the other hand, the use of relatively safe antioxidant compounds found in the diet as a form of treatment in these disorders is attractive but limited by the difficulty in reaching an active concentration in the brain [11]. Thus, the assessment of the emerging pathophysiological mechanisms occurring in the early stages of neurodegenerative diseases could better address pharmacological and nutraceutical interventions to arrange successful strategies against neuronal loss.…”

Antioxydant and Endotheliotropic Properties 4-Hydroxy-3,5-Di-Tret-Butyl Cinnamic Acid under Conditions of Experimental Brain Ischemia

“…Among potential endothelioprotectors, as the most promising objects for study, it is possible to identify compounds that have antioxidant properties. 5 Elimination of one of the leading factors of cell damage, including endothelial cells, oxidative stress, helps to normalize their functional activity, restore the production of vasoactive and antiplatelet / anticoagulant factors, and also reduces the biodegradation of the formed nitric oxide into peroxonitrite, thereby reducing the secondary a wave of oxidative damage to cellular structures -"nitrite stress, " which also has a beneficial effect on endothelial function. 6 In this connection, the search for substances capable of preserving the structural and functional integrity of endotheliocytes and possessing antioxidant properties is of indisputable scientific and practical interest, thus providing a much milder course of ischemic stroke, and also increasing the chances of a favorable outcome of the disease.…”