PMID- 25925411 OWN - NLM STAT- MEDLINE DCOM- 20160105 LR - 20181113 IS - 2045-8118 (Print) IS - 2045-8118 (Electronic) IS - 2045-8118 (Linking) VI - 12 DP - 2015 Apr 29 TI - Nicotine pre-exposure reduces stroke-induced glucose transporter-1 activity at the blood-brain barrier in mice. PG - 10 LID - 10.1186/s12987-015-0005-y [doi] LID - 10 AB - BACKGROUND: 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. 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. METHODS: Nicotine 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. RESULTS: The nicotine pre-exposure (1, 7 & 14 day) resulted in significant reduction in D-glucose influx rate (K in ) 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. CONCLUSIONS: Nicotine 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. FAU - Shah, Kaushik K AU - Shah KK AD - Texas Tech University Health Sciences Center, 1300S Coulter, School of Pharmacy, Department of Pharmaceutical Sciences, Amarillo, TX, 79106, USA. Kaushik.Shah@ttuhsc.edu. FAU - Boreddy, Purushotham Reddy AU - Boreddy PR AD - Texas Tech University Health Sciences Center, 1300S Coulter, School of Pharmacy, Department of Pharmaceutical Sciences, Amarillo, TX, 79106, USA. poory_boreddy@yahoo.com. AD - National Center for Cell Science (NCCS), Cancer Biology, Laboratory No. 6, Pune, 411007, Maharashtra, India. poory_boreddy@yahoo.com. FAU - Abbruscato, Thomas J AU - Abbruscato TJ AD - Texas Tech University Health Sciences Center, 1300S Coulter, School of Pharmacy, Department of Pharmaceutical Sciences, Amarillo, TX, 79106, USA. Thomas.Abbruscato@ttuhsc.edu. LA - eng GR - R01 NS046526/NS/NINDS NIH HHS/United States GR - R01 NS076012/NS/NINDS NIH HHS/United States GR - NS046526/NS/NINDS NIH HHS/United States GR - NS076012/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20150429 PL - England TA - Fluids Barriers CNS JT - Fluids and barriers of the CNS JID - 101553157 RN - 0 (Blood Glucose) RN - 0 (Glucose Transporter Type 1) RN - 6M3C89ZY6R (Nicotine) SB - IM MH - Animals MH - Biological Transport MH - Blood Glucose/drug effects/*metabolism MH - Blood-Brain Barrier/*drug effects/*metabolism MH - Brain Ischemia/*metabolism MH - Glucose Transporter Type 1/*metabolism MH - Infarction, Middle Cerebral Artery/metabolism MH - Male MH - Mice MH - Nicotine/*administration & dosage/toxicity MH - Reperfusion Injury/metabolism MH - Stroke/*metabolism PMC - PMC4425877 EDAT- 2015/05/01 06:00 MHDA- 2016/01/06 06:00 PMCR- 2015/04/29 CRDT- 2015/05/01 06:00 PHST- 2015/02/04 00:00 [received] PHST- 2015/04/02 00:00 [accepted] PHST- 2015/05/01 06:00 [entrez] PHST- 2015/05/01 06:00 [pubmed] PHST- 2016/01/06 06:00 [medline] PHST- 2015/04/29 00:00 [pmc-release] AID - 10.1186/s12987-015-0005-y [pii] AID - 5 [pii] AID - 10.1186/s12987-015-0005-y [doi] PST - epublish SO - Fluids Barriers CNS. 2015 Apr 29;12:10. doi: 10.1186/s12987-015-0005-y.