In terms of cost to society and disability to patients, stroke ranks with Alzheimer's disease as the two most important neurological disorders. Nicotine, a major constituent of tobacco smoke has been shown to have important effects on neuronal injury and brain edema formation in stroke and hampers brain recovery after stroke. It is known that the blood-brain barrier (BBB), which is formed by the cerebral endothelium, plays a critical role in the regulation of water and electrolyte balance within the central nervous system (CNS). Exciting preliminary data in our laboratory suggests that nicotine down regulates the BBB expression and function of a key ion transporter, Na, K,2Cl-cotransporter, which normally mediates brain-to-blood removal of potassium ions during in vitro stroke conditions. With respect to brain ischemia, maintenance of low brain extracellular potassium concentration is necessary for proper neuronal conduction and recovery after stroke. In vitro and in vivo investigations into smoke constituent alteration of BBB properties is critically important and is the focus of this research application. The objective of this application is to systematically test the effects of nicotine and smoke constituents on BBB potassium transport during stroke conditions and determine the physiological role of nAChRs on BBB ion transport. The central hypothesis of our work is that nicotine decreases brain-to-blood potassium transport through nicotinic acetylcholine receptor (nAChR) activation at the blood-brain barrier that impairs ion transport necessary for stroke adaption. We plan to utilize sophisticated, well characterized in vivo models designed to mimic nicotine and tobacco smoke constituent exposure coupled to validated models of stroke. This focused research plan will identify possible therapeutic targets at the blood-brain barrier to prevent brain edema and altered CNS potassium homeostasis during nicotine or smoke constituent exposure coupled to stroke conditions. We hope that new stroke treatments will utilize a combination of agents that modulate multiple processes (both BBB breakdown and ischemic neuronal death) providing the most efficacious treatment of stroke for both smoking and non-smoking patients. This research plan will also identify key biochemical and molecular mechanisms involved in nicotine and other tobacco smoke constituent alteration in BBB function during stroke so that individualized stroke therapies could be designed to improve health outcomes for smokers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS046526-03
Application #
7039097
Study Section
Special Emphasis Panel (ZRG1-CDIN (01))
Program Officer
Jacobs, Tom P
Project Start
2004-07-01
Project End
2009-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
3
Fiscal Year
2006
Total Cost
$301,802
Indirect Cost
Name
Texas Tech University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
609980727
City
Lubbock
State
TX
Country
United States
Zip Code
79430
Shah, Kaushik K; Boreddy, Purushotham Reddy; Abbruscato, Thomas J (2015) Nicotine pre-exposure reduces stroke-induced glucose transporter-1 activity at the blood-brain barrier in mice. Fluids Barriers CNS 12:10
Yang, Li; Islam, Mohammad R; Karamyan, Vardan T et al. (2015) In vitro and in vivo efficacy of a potent opioid receptor agonist, biphalin, compared to subtype-selective opioid receptor agonists for stroke treatment. Brain Res 1609:1-11
Shah, Kaushik K; Yang, Li; Abbruscato, Thomas J (2012) In vitro models of the blood-brain barrier. Methods Mol Biol 814:431-49
Yang, Li; Shah, Kaushik K; Abbruscato, Thomas J (2012) An in vitro model of ischemic stroke. Methods Mol Biol 814:451-66
Paulson, Jennifer R; Yang, Tianzhi; Selvaraj, Pradeep K et al. (2010) Nicotine exacerbates brain edema during in vitro and in vivo focal ischemic conditions. J Pharmacol Exp Ther 332:371-9
Vemula, Sharanya; Roder, Karen E; Yang, Tianzhi et al. (2009) A functional role for sodium-dependent glucose transport across the blood-brain barrier during oxygen glucose deprivation. J Pharmacol Exp Ther 328:487-95
Yang, Tianzhi; Roder, Karen E; Abbruscato, Thomas J (2007) Evaluation of bEnd5 cell line as an in vitro model for the blood-brain barrier under normal and hypoxic/aglycemic conditions. J Pharm Sci 96:3196-213
Paulson, Jennifer R; Roder, Karen E; McAfee, Ghia et al. (2006) Tobacco smoke chemicals attenuate brain-to-blood potassium transport mediated by the Na,K,2Cl-cotransporter during hypoxia-reoxygenation. J Pharmacol Exp Ther 316:248-54
Yang, Tianzhi; Roder, Karen E; Bhat, G Jayarama et al. (2006) Protein kinase C family members as a target for regulation of blood-brain barrier Na,K,2Cl-cotransporter during in vitro stroke conditions and nicotine exposure. Pharm Res 23:291-302
Lockman, P R; McAfee, G; Geldenhuys, W J et al. (2005) Brain uptake kinetics of nicotine and cotinine after chronic nicotine exposure. J Pharmacol Exp Ther 314:636-42

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