Tobacco smoking is considered a major public health challenge, responsible for more than 400,000 deaths each year in the United States alone. To reduce the risk of health damage caused by tobacco smoke (TS) the tobacco industry is marketing and advertising a line of """"""""reduced-exposure"""""""" tobacco products (such as """"""""Advance"""""""" manufactured by Brown &Williamson Tobacco Corporation, """"""""Omni"""""""" and Quest 3 manufactured by Vector Group Ltd), which claim to be less harmful than the leading """"""""light"""""""" cigarette brands. However, the scientific evidence provided is insufficient to evaluate whether these products actually reduce the users'risk for tobacco-related diseases including those associated to vascular impairments. Despite the strong evidence for an association between tobacco smoke and vascular impairment, the impact of TS exposure on the blood-brain barrier (BBB) has been only marginally addressed and studies were limited to only few selective substances among the thousands contained in TS thus, leaving BBB research a substantial understudied area. To address these relevant health public concerns we propose a multimodal approach that involve the parallel use of 1) a novel humanized dynamic in vitro BBB model;2) freshly isolated peripheral blood immune cells (PBMC) and platelets from smoker and non-smoker volunteers;3) 3 vessel occlusion rat models of focal ischemia that will be used to complement the results in vitro and assess the likelihood and magnitude of secondary brain injury (brain edema) caused by TS exposure (from regular and """"""""reduced-exposure"""""""") in synergism with temporary loss of blood flow. Based on these premises we propose to: 1. Evaluate the effect of tobacco smoke from reduced-exposure and regular tobacco products on BBB integrity and function and assess the immunoactivity of each tobacco product. 2. Investigate the effect of TS exposure on BBB function and viability in synergism with rheological changes and how this may impact the pathogenesis of secondary brain injury.

Public Health Relevance

Active and passive tobacco smoking are associated with dysfunction of vascular endothelial physiology in a causative and dose dependent way. Despite the strong evidence for an association between tobacco smoke and vascular impairment, the impact of TS exposure on the blood-brain barrier (BBB) has been only marginally addressed and studies were limited to only few selective substances among the thousands contained in TS thus, leaving BBB research a substantial understudied area. To address these critical issues, we propose to evaluate the effect of tobacco smoke from reduced-exposure and regular tobacco products on BBB integrity and function. We also propose to investigate the effect of TS exposure on BBB function and viability in synergism with rheological changes and how this may impact the pathogenesis of secondary brain injury. This proposal is in response to the PA-09-046. This program announcement specifically asks to explore the differential toxicity of various tobacco and nicotine products. In this respect, we believe that our study will produce a remarkable impact on the awareness of tobacco smoke toxicity in an under considered health area and will provide the foundations for additional studies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA029121-04
Application #
8434944
Study Section
Special Emphasis Panel (ZRG1-BDCN-T (02))
Program Officer
Purohit, Vishnudutt
Project Start
2011-03-01
Project End
2016-02-29
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
4
Fiscal Year
2013
Total Cost
$285,120
Indirect Cost
$93,120
Name
Texas Tech University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
609980727
City
Lubbock
State
TX
Country
United States
Zip Code
79430
Sifat, Ali E; Vaidya, Bhuvaneshwar; Kaisar, Mohammad A et al. (2018) Nicotine and electronic cigarette (E-Cig) exposure decreases brain glucose utilization in ischemic stroke. J Neurochem 147:204-221
Sivandzade, Farzane; Prasad, Shikha; Bhalerao, Aditya et al. (2018) NRF2 and NF-?B interplay in cerebrovascular and neurodegenerative disorders: Molecular mechanisms and possible therapeutic approaches. Redox Biol 21:101059
Sivandzade, Farzane; Cucullo, Luca (2018) In-vitro blood-brain barrier modeling: A review of modern and fast-advancing technologies. J Cereb Blood Flow Metab 38:1667-1681
Ashraf-Uz-Zaman, Md; Sajib, Md Sanaullah; Cucullo, Luca et al. (2018) Analogs of penfluridol as chemotherapeutic agents with reduced central nervous system activity. Bioorg Med Chem Lett 28:3652-3657
Kaisar, Mohammad A; Sivandzade, Farzane; Bhalerao, Aditya et al. (2018) Conventional and electronic cigarettes dysregulate the expression of iron transporters and detoxifying enzymes at the brain vascular endothelium: In vivo evidence of a gender-specific cellular response to chronic cigarette smoke exposure. Neurosci Lett 682:1-9
Sajja, Ravi K; Kaisar, Mohammad A; Vijay, Vikrant et al. (2018) In Vitro Modulation of Redox and Metabolism Interplay at the Brain Vascular Endothelium: Genomic and Proteomic Profiles of Sulforaphane Activity. Sci Rep 8:12708
Festoff, Barry W; Sajja, Ravi K; Cucullo, Luca (2017) Proximate Mediators of Microvascular Dysfunction at the Blood-Brain Barrier: Neuroinflammatory Pathways to Neurodegeneration. Biomed Res Int 2017:1549194
Kaisar, Mohammad A; Villalba, Heidi; Prasad, Shikha et al. (2017) Offsetting the impact of smoking and e-cigarette vaping on the cerebrovascular system and stroke injury: Is Metformin a viable countermeasure? Redox Biol 13:353-362
Kaisar, Mohammad A; Sajja, Ravi K; Prasad, Shikha et al. (2017) New experimental models of the blood-brain barrier for CNS drug discovery. Expert Opin Drug Discov 12:89-103
Prasad, Shikha; Sajja, Ravi K; Kaisar, Mohammad Abul et al. (2017) Role of Nrf2 and protective effects of Metformin against tobacco smoke-induced cerebrovascular toxicity. Redox Biol 12:58-69

Showing the most recent 10 out of 37 publications