title: Role of Nrf2 and protective effects of Metformin against tobacco smoke-induced cerebrovascular toxicity.
abstract: Cigarette smoking (CS) is associated with vascular endothelial dysfunction in a causative way primarily related to the TS content of reactive oxygen species (ROS), nicotine, and inflammation. TS promotes glucose intolerance and increases the risk of developing type-2 diabetes mellitus (2DM) with which it shares other pathogenic traits including the high risk of cerebrovascular and neurological disorders like stroke via ROS generation, inflammation, and blood-brain barrier (BBB) impairment. Herein we provide evidence of the role played by nuclear factor erythroid 2-related factor (Nrf2) in CS-induced cerebrobvascular/BBB impairments and how these cerebrovascular harmful effects can be circumvented by the use of metformin (MF; a widely prescribed, firstline anti-diabetic drug) treatment. Our data in fact revealed that MF activates counteractive mechanisms primarily associated with the Nrf2 pathway which drastically reduce CS toxicity at the cerebrovascular level. These include the suppression of tight junction (TJ) protein downregulation and loss of BBB integrity induced by CS, reduction of inflammation and oxidative stress, renormalization of the expression levels of the major BBB glucose transporter Glut-1 and that of the anticoagulant factor thrombomodulin. Further, we provide additional insights on the controversial interplay between Nrf2 and AMPK.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 S. Coulter Street, Amarillo, TX 79106, USA. Electronic address: prasad.shikha@ttuhsc.edu.
authors.forename: Shikha
authors.initials: S
authors.lastname: Prasad
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 S. Coulter Street, Amarillo, TX 79106, USA. Electronic address: ravi.sajja@ttuhsc.edu.
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Sajja
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 S. Coulter Street, Amarillo, TX 79106, USA. Electronic address: md.a.kaisar@ttuhsc.edu.
authors.forename: Mohammad Abul
authors.initials: MA
authors.lastname: Kaisar
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 S. Coulter Street, Amarillo, TX 79106, USA. Electronic address: JH.park@ttuhsc.edu.
authors.forename: Jee Hyun
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 S. Coulter Street, Amarillo, TX 79106, USA. Electronic address: heidi.villalba@ttuhsc.edu.
authors.forename: Heidi
authors.initials: H
authors.lastname: Villalba
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 S. Coulter Street, Amarillo, TX 79106, USA. Electronic address: taylor.liles@ttuhsc.edu.
authors.forename: Taylor
authors.initials: T
authors.lastname: Liles
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 S. Coulter Street, Amarillo, TX 79106, USA; Center for Blood Brain Barrier Research, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA. Electronic address: Thomas.Abbruscato@ttuhsc.edu.
authors.forename: Thomas
authors.initials: T
authors.lastname: Abbruscato
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 S. Coulter Street, Amarillo, TX 79106, USA; Center for Blood Brain Barrier Research, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA. Electronic address: luca.cucullo@ttuhsc.edu.
authors.forename: Luca
authors.initials: L
authors.lastname: Cucullo
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008687:Metformin / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana
chemical_list: D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D012906:Smoke; D008687:Metformin
keywords: Blood brain barrier; Blood hemostasis; Cigarette smoke; Glucose transporter; Metformin; Nrf2; Oxidative stress; Tight junctions