Abstract
BackgroundWith growing electronic cigarette usage in both the smoking and nonsmoking population, rigorous studies are needed to investigate the effects of nicotine on biological systems to determine long-term health consequences. We have previously shown that nicotine exerts specific neurovascular effects that influence blood brain barrier (BBB) function in response to stroke. In this study, we investigated the effects of nicotine on carrier-mediated glucose transport into ischemic brain. Specifically, the present study investigates glucose transporter-1 (GLUT1) function and expression at the BBB in a focal brain ischemia model of mice pre-exposed to nicotine.MethodsNicotine was administrated subcutaneously by osmotic pump at the dose of 4.5 mg/kg/day for 1, 7, or 14 days to reflect the plasma levels seen in smokers. Ischemic-reperfusion (IR) injury was induced by 1 h transient middle cerebral artery occlusion (tMCAO) and 24 h reperfusion. Glucose transport was estimated using an in situ brain perfusion technique with radiolabeled glucose and brain vascular GLUT1 expression was detected with immunofluorescence.ResultsThe nicotine pre-exposure (1, 7 & 14 day) resulted in significant reduction in D-glucose influx rate (Kin) across the BBB, with a 49% reduction in 14 day nicotine-infused animals. We observed a 41% increase in carrier-mediated glucose transport across the BBB in saline-infused tMCAO animals compared to saline-infused sham animals. Interestingly, in the tMCAO group of animals pre-exposed to nicotine for 14 days had significantly attenuated increased glucose transport by 80% and 38% compared to saline-infused tMCAO and sham animals respectively. Furthermore, immunofluorescence studies of GLUT1 protein expression in the brain microvascular endothelium confirmed that GLUT1 was also induced in saline-infused tMCAO animals and this protein expression induction was reduced significantly (P < 0.01) with 14 day nicotine pre-exposure in tMCAO animals.ConclusionsNicotine pre-exposure reduced the IR-enhanced GLUT1 transporter function and expression at the BBB in a focal brain ischemia mouse model. These studies suggest that nicotine exposure prior to stroke could create an enhanced glucose deprived state at the neurovascular unit (NVU) and could provide an additional vulnerability to enhanced stroke injury.
Highlights
With growing electronic cigarette usage in both the smoking and nonsmoking population, rigorous studies are needed to investigate the effects of nicotine on biological systems to determine long-term health consequences
The endothelial cells of the blood brain barrier (BBB) provide a dynamic interface between the blood and central nervous system (CNS), maintaining brain homeostasis by selectively limiting the passage of solutes/nutrient/ions from the circulating blood into and out of the brain and it plays an important role in determining the fate of brain tissue after stroke
Nicotine reduces glucose transport across the BBB We initially evaluated the glucose transport influx rate at different time intervals after nicotine exposure in normal animals
Summary
With growing electronic cigarette usage in both the smoking and nonsmoking population, rigorous studies are needed to investigate the effects of nicotine on biological systems to determine long-term health consequences. Subsequent deficiency in the major obligatory brain fuels, glucose and oxygen, elicits a number of important neurochemical mechanisms (e.g. excitotoxicity, oxidative stress and inflammation) which can lead to irreversible brain damage. This changing brain microenvironment is tightly regulated by the brain microvasculature which functions to segregate the blood from brain interstitial fluid. Brain microvascular endothelial cells working in concert with astrocytes, pericytes and neurons form a neurovascular unit (NVU) Many of these key solutes and nutrients enter the brain by transcellular diffusion and others through passive or active carriers that may utilize receptormediated endocytosis [3]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
