Increased sodium dependent glucose transport in the ischemic brain

缺血脑中钠依赖性葡萄糖转运增加

• 批准号: 8323456
• 负责人: Thomas J Abbruscato
• 金额: $ 30.05万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8323456
• 关键词: Acidosis; Acute; Admission activity; Age; Behavioral; Blood; Blood - brain barrier anatomy; Brain; Brain Edema; Brain Injuries; Brain Ischemia; Capillary Endothelial Cell; Carrier Proteins; Cause of Death; Cell model; Cerebral Ischemia; Cerebrum; Cessation of life; Characteristics; Clinical; Complex; Coupled; Data; Deterioration; Development; Diabetes Mellitus; Diabetic mouse; Disease; Drug Delivery Systems; Edema; Endothelial Cells; Foundations; Free Radicals; Functional disorder; Generations; Glucose; Glucose Transporter; Glycolysis; Health; Heart Diseases; Hyperglycemia; In Situ; In Vitro; Infarction; Injury; Insulin; Insulin Resistance; Intervention; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Kinetics; Lead; Mediating; Membrane; Microdialysis; Middle Cerebral Artery Occlusion; Modeling; Morbidity - disease rate; Mus; Necrosis; Nerve Degeneration; Neurons; Outcome; Patients; Perfusion; Phlorhizin; Physiological; Physiology; Play; Positioning Attribute; Process; Proteins; Publishing; Recovery; Regulation; Reperfusion Injury; Reperfusion Therapy; Resistance; Risk; Role; SLC2A1 gene; Severities; Sodium; Streptozocin; Stroke; Swelling; Techniques; Testing; Time; Translational Research; Water; Work; acute stroke; blood glucose regulation; diabetic; diabetic patient; disability; expectation; glucose transport; immunoreactivity; improved; in vivo; in vivo Model; inhibitor/antagonist; innovation; mRNA Expression; mortality; non-diabetic; novel; patient population; pre-clinical; protein function; research study

DESCRIPTION (provided by applicant): Stroke is the third leading cause of death and disability in USA. Given that at least one third of stroke patients are hyperglycemic on admission, with most being diabetic, and 65 percent of diabetic patients die from some form of heart disease or stroke, the diabetic stroke patient provides opportunity for unique pharmacologic interventions to improve stroke outcome. Increased glucose supply post ischemic attack has also been associated with cellular acidosis and free radical generation which can exacerbate edema. Recent published and preliminary data from our lab suggest that blood-to-brain glucose transport in both the ischemic and diabetic brain is partially carried by the sodium dependent glucose cotransporter (SGLT1) in addition to the traditional glucose carrier (GLUT1). Blood-brain barrier activation of SGLT1 protein can have deleterious effects in brain ischemia since SGLT1 is known to transport 2Na+ and 210 water molecules for each glucose molecule transported, thus having the propensity to contribute to both vasogenic and cellular brain edema, a leading cause of stroke death. Our data suggests that SGLT1 inhibition, with phlorizin administration post ischemia, resulted in reduced SGLT1 substrate transport across the ischemic brain and improved neurodegeneration, free radical damage, and infarction and edema ratios. Thus we hypothesize that SGLT1 induction during ischemia/reperfusion (IR) and diabetes mellitus (DM) plays a central role in ischemic damage and edema formation. We will test this hypothesis in three specific aims using both in vitro and in vivo models of IR injury and a model of DM. AIM 1: Elucidate the functional "transport" role of BBB SGLT1 using in vitro and in vivo models of brain ischemia and DM. Working Hypothesis: Brain endothelial cells subjected to high glucose (HG) and/or IR will increase SGLT1 mediated transport. AIM 2: Determine the regulatory mechanisms for SGLT1 activity at the BBB during conditions of both IR and HG. Working Hypothesis: Conditions of HG and IR will regulate SGLT1 activity by availability of Na and PKC control of SGLT1 membrane insertion. AIM 3: Evaluate the effects of SGLT1 inhibition on brain ECF [glucose], edema and infarction ratios, behavioral endpoints, and penumbral injury after in vivo focal ischemia with and without DM. Working Hypothesis: SGLT1 inhibition will decrease brain ECF [glucose] and improve stroke outcome in streptozotocin (STZ) treated mice and age matched controls. An understanding of altered blood-brain barrier SGLT1 function, regulation and neuroprotective effects of inhibition during stroke and DM is vital to provide a foundation for the development of phlorizin and other SGLT1 specific inhibitors as potential neuroprotective strategies to treat brain ischemia in both diabetic and non-diabetic stroke patients.

描述（由申请人提供）：中风是美国第三大死亡和残疾原因。鉴于至少三分之一的中风患者在入院时患有高血糖，其中大多数是糖尿病，并且 65% 的糖尿病患者死于某种形式的心脏病或中风，糖尿病中风患者为改善中风结果的独特药物干预提供了机会。缺血性发作后葡萄糖供应增加也与细胞酸中毒和自由基产生有关，从而加剧水肿。我们实验室最近发表的初步数据表明，除了传统的葡萄糖载体 (GLUT1) 之外，缺血性大脑和糖尿病大脑中的血液到大脑的葡萄糖转运部分由钠依赖性葡萄糖协同转运蛋白 (SGLT1) 携带。 SGLT1 蛋白的血脑屏障激活可能对脑缺血产生有害影响，因为已知 SGLT1 为每个葡萄糖分子转运 2Na+ 和 210 个水分子，因此有可能导致血管性和细胞性脑水肿，这是脑缺血的主要原因。中风死亡。我们的数据表明，缺血后使用根皮苷抑制 SGLT1 会导致 SGLT1 底物在缺血性大脑中的转运减少，并改善神经退行性变、自由基损伤以及梗死和水肿比率。因此，我们假设缺血/再灌注 (IR) 和糖尿病 (DM) 期间 SGLT1 的诱导在缺血性损伤和水肿形成中发挥核心作用。我们将使用 IR 损伤的体外和体内模型以及 DM 模型在三个特定目标上测试这一假设。目标 1：利用脑缺血和 DM 的体外和体内模型阐明 BBB SGLT1 的功能性“运输”作用。工作假设：接受高葡萄糖 (HG) 和/或 IR 的脑内皮细胞会增加 SGLT1 介导的转运。目标 2：确定 IR 和 HG 条件下 BBB SGLT1 活性的调节机制。工作假设：HG 和 IR 条件将通过 Na 的可用性和 PKC 控制 SGLT1 膜插入来调节 SGLT1 活性。目标 3：评估 SGLT1 抑制对患有或不患有 DM 的体内局灶性缺血后脑 ECF [葡萄糖]、水肿和梗塞比率、行为终点和半暗带损伤的影响。工作假设：SGLT1 抑制将降低链脲佐菌素 (STZ) 治疗小鼠和年龄匹配对照小鼠的脑 ECF [葡萄糖] 并改善中风结果。了解血脑屏障 SGLT1 功能的改变、调节以及中风和糖尿病期间抑制的神经保护作用对于开发根皮苷和其他 SGLT1 特异性抑制剂作为治疗糖尿病和非糖尿病患者脑缺血的潜在神经保护策略至关重要。 - 糖尿病中风患者。