title: 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 response 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 and IL-8, reduced (not Co-Q10) CSE-induced up-regulation of Platelet Cell Adhesion Molecule-1 (PECAM-1), Vascular 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.
authors.affiliation: Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, United States.
authors.forename: Mohammad Abul
authors.initials: MA
authors.lastname: Kaisar
authors.affiliation: Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, United States.
authors.forename: Shikha
authors.initials: S
authors.lastname: Prasad
authors.affiliation: Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, United States; Center for Blood-Brain Barrier Research, Texas Tech University Health Sciences Center, Amarillo, TX 79106, United States. Electronic address: luca.cucullo@ttuhsc.edu.
authors.forename: Luca
authors.initials: L
authors.lastname: Cucullo
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000166:cytology*; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D044842:Cullin Proteins / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004727:Endothelium / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008550:Melatonin / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D010936:Plant Extracts / Q000737:chemistry*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology; D062789:Tobacco Products; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000975:Antioxidants; C496871:CUL5 protein, human; D044842:Cullin Proteins; D016207:Cytokines; D010936:Plant Extracts; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D013267:Stilbenes; D042461:Vascular Endothelial Growth Factor A; D014451:Ubiquinone; D007770:L-Lactate Dehydrogenase; C024989:coenzyme Q10; D005978:Glutathione; D008550:Melatonin; D000077185:Resveratrol
keywords: Alternative; Antioxidant; Blood–Brain Barrier; Countermeasure; Inflammation; Oxidative stress; Smoking