Tobacco Smoke Chemicals and Stroke Alter Brain K+ Efflux

描述（由申请人提供）：就社会成本和患者残疾而言，中风与阿尔茨海默病并列为两种最重要的神经系统疾病。尼古丁是烟草烟雾的主要成分，对脑卒中后神经元损伤和脑水肿的形成有重要影响，并阻碍脑卒中后的恢复。已知由脑内皮形成的血脑屏障（BBB）在调节中枢神经系统（CNS）内的水和电解质平衡中起关键作用。我们实验室中令人兴奋的初步数据表明，尼古丁下调BBB的表达和关键离子转运蛋白Na，K，2Cl-协同转运蛋白的功能，该转运蛋白通常在体外中风条件下介导钾离子的脑-血清除。对于脑缺血，维持低的脑细胞外钾浓度对于中风后适当的神经元传导和恢复是必要的。在体外和体内研究烟雾成分的血脑屏障性质的改变是至关重要的，是本研究应用的重点。本申请的目的是系统地测试尼古丁和烟雾成分在中风条件下对BBB钾转运的影响，并确定nAChR对BBB离子转运的生理作用。我们工作的中心假设是，尼古丁通过血脑屏障上的烟碱乙酰胆碱受体（nAChR）激活降低脑-血钾转运，从而损害中风适应所需的离子转运。我们计划利用复杂的，充分表征的体内模型，旨在模拟尼古丁和烟草烟雾成分暴露耦合到验证模型的中风。这项重点研究计划将确定血脑屏障的可能治疗靶点，以防止在尼古丁或烟雾成分暴露期间脑水肿和中枢神经系统钾稳态的改变，并伴有中风。我们希望新的中风治疗将利用调节多个过程（BBB破坏和缺血性神经元死亡）的药物组合，为吸烟和非吸烟患者提供最有效的中风治疗。这项研究计划还将确定涉及尼古丁和其他烟草烟雾成分在脑卒中期间改变BBB功能的关键生化和分子机制，以便设计个性化的脑卒中治疗来改善吸烟者的健康结果。

DESCRIPTION (provided by applicant): 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.