Tobacco Smoke Chemicals and Stroke Alter Brain K+ Efflux

描述(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最重要的两种神经疾病。尼古丁是烟草烟雾中的主要成分，已被证明对中风后神经元损伤和脑水肿形成有重要影响，并阻碍中风后大脑的恢复。众所周知，血脑屏障(BBB)是由脑内皮细胞形成的，在调节中枢神经系统(CNS)水和电解质平衡中起着关键作用。我们实验室令人兴奋的初步数据表明，尼古丁下调了关键离子转运体Na，K，2Cl-转运体的BBB表达和功能，在体外中风条件下，该转运体通常介导脑到血中钾离子的清除。对于脑缺血，维持较低的脑细胞外钾浓度对于卒中后正常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对血脑屏障性质的影响是至关重要的，也是这一研究应用的重点。本应用的目的是系统地测试尼古丁和烟雾成分对中风时血脑屏障钾转运的影响，并确定nAChRs在血脑屏障离子转运中的生理作用。我们工作的中心假设是尼古丁通过激活血脑屏障上的烟碱型乙酰胆碱受体(NAChR)减少了脑到血钾的转运，从而损害了中风适应所需的离子转运。我们计划利用复杂的、具有良好特性的体内模型来模拟尼古丁和烟草烟雾成分的暴露，并将其与经验证的中风模型相结合。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发生脑水肿和改变中枢神经系统钾稳态，并与中风情况相关联。我们希望，新的中风治疗方法将利用多种药物的组合来调节多种过程(包括血脑屏障破坏和缺血性神经元死亡)，为吸烟和不吸烟的患者提供最有效的中风治疗。这项研究计划还将确定中风期间尼古丁和其他烟草烟雾成分改变血脑屏障功能的关键生化和分子机制，以便设计个性化的中风治疗方法，以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.