Nicotine and electronic cigarette (E‐Cig) exposure decreases brain glucose utilization in ischemic stroke

• Published in: Journal of neurochemistry Vol. 147; no. 2; pp. 204 - 221
• Main Authors: Sifat, Ali E., Vaidya, Bhuvaneshwar, Kaisar, Mohammad A., Cucullo, Luca, Abbruscato, Thomas J.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.10.2018
• Subjects: Acetylcholine receptors (nicotinic); alpha7 Nicotinic Acetylcholine Receptor - biosynthesis; alpha7 Nicotinic Acetylcholine Receptor - genetics; Animals; Brain; Brain injury; Brain Ischemia - metabolism; Brain slice preparation; Cotinine; Deprivation; Electronic cigarettes; Electronic Nicotine Delivery Systems; Exposure; E‐cigarette; Glucose; Glucose - deficiency; Glucose - metabolism; Glucose transport; Glucose Transport Proteins, Facilitative - metabolism; glucose utilization; Glycolysis; Head injuries; Health risks; Hypoxia, Brain - metabolism; Immunofluorescence; In Vitro Techniques; Ischemia; ischemic stroke; Male; Mecamylamine; Metabolism; Mice; Mice, Inbred C57BL; Model testing; neuron; Neurons - drug effects; Neurons - metabolism; Nicotine; Nicotine - pharmacology; Nicotinic Agonists - pharmacology; Oxygen Consumption - drug effects; Primary Cell Culture; Reperfusion; Stroke; Stroke - metabolism; Utilization; Western blotting; neuron; nicotine; brain; ischemic stroke; E-cigarette; glucose utilization
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.14561

Previous studies in our laboratory have shown that nicotine exposure decreases glucose transport across the blood–brain barrier in ischemia‐reperfusion conditions. We hypothesize that nicotine can also dysregulate brain parenchymal glucose utilization by altering glucose transporters with effects on sensitivity to ischemic stroke. In this study, we investigated the effects of nicotine exposure on neuronal glucose utilization using an in vitro ischemic stroke model. We also tested the effects of e‐Cig vaping on ischemic brain glucose utilization using an acute brain slice technique. Primary cortical neurons and brain slices were subjected to oxygen‐glucose deprivation followed by reoxygenation to mimic ischemia‐reperfusion injury. We estimated brain cell glucose utilization by measuring the uptake of [3H] deoxy‐d‐glucose. Immunofluorescence and western blotting were done to characterize glucose transporters (GLUTs) and α7 nicotinic acetylcholine receptor (nAChR) expression. Furthermore, we used a glycolytic stress test to measure the effects of nicotine exposure on neuronal glucose metabolism. We observed that short‐ and long‐term nicotine/cotinine exposure significantly decreased neuronal glucose utilization in ischemic conditions and the non‐specific nAChR antagonist, mecamylamine reversed this effect. Nicotine/cotinine exposure also decreased neuronal GLUT1 and up‐regulated α7 nAChR expression and decreased glycolysis. Exposure of mice to e‐Cig vapor for 7 days likewise decreases brain glucose uptake under normoxic and ischemic conditions along with down‐regulation of GLUT1 and GLUT3 expressions. These data support, from a cerebrovascular perspective, that nicotine and/or e‐Cig vaping induce a state of glucose deprivation at the neurovascular unit which could lead to enhanced ischemic brain injury and/or stroke risk. Open Practices Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/ We propose that long‐term exposure of nicotine and nicotine containing e‐Cig vapors can decrease brain and neuronal glucose uptake and metabolism in ischemia‐reperfusion conditions primarily via down‐regulation of glucose transporter 1. These effects were, in part, mediated by nicotinic acetylcholine receptors (possibly α7) as the non‐selective receptor antagonist, mecamylamine could reverse those effects. Thus, nicotine or e‐Cig exposure can result in an enhanced glucose‐deprived state at the neurovascular unit after ischemic stroke increasing the risk for ischemic brain injury.