Dietary targeting of dihydrolipoamide dehydrogenase for stroke tolerance

二氢硫辛酰胺脱氢酶的饮食靶向治疗中风耐受性

• 批准号: 8506257
• 负责人: MICHAEL J. FORSTER
• 金额: $ 25.38万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8506257
• 关键词: Address; Adult; Affect; Antioxidants; Attenuated; Binding; Blood - brain barrier anatomy; Blood Glucose; Brain; Brain Infarction; Brain Injuries; Carboxylic Acids; Cause of Death; Cell Nucleus; Cessation of life; Chemical Agents; Chemicals; Chronic; Clinical; Cognitive; Complex; Cytoplasm; Data; Development; Diet; Dietary intake; Eating; Enzymes; Exposure to; Fostering; General Population; Goals; Hippocampus (Brain); Hour; Human; Individual; Infarction; Injury; Investigation; Ischemia; Ischemic Brain Injury; Ischemic Preconditioning; Ischemic Stroke; Knowledge; Lead; Long-Term Potentiation; Measures; Metabolism; Middle Cerebral Artery Occlusion; Mitochondria; Modeling; NAD(P)H dehydrogenase (quinone) 1, human; NQO1 gene; Nuclear; Pathway interactions; Phenotype; Pre-Clinical Model; Prevention strategy; Preventive; Preventive Intervention; Proteins; Rattus; Recovery; Recurrence; Regimen; Reperfusion Therapy; Research; Response Elements; Risk; Signal Pathway; Signal Transduction; Stimulus; Stress; Stroke; Stroke prevention; Supplementation; Synaptic plasticity; Testing; Therapeutic; United States; Weight Gain; Withdrawal; Work; base; cerebral artery; cognitive recovery; dietary supplements; dihydrolipoamide dehydrogenase; disability; expectation; experience; feeding; high risk; inhibitor/antagonist; methoxyindole; neurobehavioral; neuroprotection; new therapeutic target; novel; novel strategies; novel therapeutics; pre-clinical; preconditioning; prevent; prophylactic; public health relevance; respiratory; transcription factor

DESCRIPTION (provided by applicant): New and recurrent stroke is the third leading cause of death and the leading cause of long-term disability in the United States, yet no effective endogenous targets have been defined to prevent or attenuate stroke-induced brain injury. We have discovered that mitochondrial dihydrolipoamide dehydrogenase (DLDH) could be a target for chemical preconditioning against stroke injury. The objective of this application is thus to evaluate the neuroprotective efficacy of DLDH chemical preconditioning and delineate its underlying mechanisms. Our preliminary studies show that when rats were fed a 4-week diet supplemented with 5-methoxyindole-2- carboxylic acid (MICA), a specific and competitive DLDH inhibitor, brain infarction volume decreased by c. 60% after transient middle cerebral artery occlusion (tMCAO, 1 hr ischemia and 24 hr reperfusion). This result indicates that chronic DLDH inhibition by MICA affords robust cerebroprotection against stroke. Further studies of MICA-treated rats in the absence of stroke indicate that DLDH activity was lower than in control rats whilst NAD(P)H: quinone oxidoreductase-1 (NQO1) activity increased significantly in the MICA-treated rats. NQO1 is an inducible enzyme and its expression is activated by binding of the nuclear transcription factor E2-related factor 2 (Nrf2) to the antioxidant response element (ARE). Our preliminary studies also indicate that 4 weeks' MICA dietary administration did not affect food intake, body weight gain, blood glucose concentration, or mitochondrial respiratory complexes. These preliminary results support our central hypothesis that dietary inhibition of DLDH induces persistent cerebroprotection, affording enhanced recovery of cognitive and locomotor function after ischemic stroke, via activation of the Nrf2-ARE signaling cascade. The rationale for the proposed investigation is that identifying nontoxic, blood brain barrier-permeable chemical agents that afford brain protection from stroke, and defining the protective mechanisms, will foster development and clinical implementation of such agents to minimize death and disability in human victims of stroke. We plan to test our central hypothesis and, thereby, accomplish the objective of this application by addressing the following three Specific Aims: (1) To define the extent to which Nrf2 nuclear localization and NQO1 expression increase following MICA administration and tMCAO, (2) To measure the extent to which dietary preconditioning can produce persistent neuroprotection from stroke, and (3) To evaluate the effects of MICA diet and experimental stroke on neurobehavioral function and hippocampal synaptic plasticity measured as CA1 long-term potentiation (LTP). It is expected that the successfully completed study will provide novel strategies using DLDH as a target for stroke therapeutics.

描述（由申请人提供）：在美国，新发和复发性卒中是第三大死亡原因和长期残疾的主要原因，但没有有效的内源性靶点来预防或减轻卒中引起的脑损伤。我们发现线粒体二氢脂酰胺脱氢酶（DLDH）可能是脑卒中损伤化学预处理的靶标。因此，本应用的目的是评估DLDH化学预处理的神经保护功效并描述其潜在机制。我们的初步研究表明，给大鼠喂食添加5-甲氧基吲哚-2-羧酸（MICA）的4周饮食，MICA是一种特异性和竞争性的DLDH抑制剂，在短暂性大脑中动脉闭塞（tMCAO，缺血1小时，再灌注24小时）后，脑梗死体积减少了60%。这一结果表明，MICA慢性抑制DLDH对脑卒中具有强大的脑保护作用。对未发生脑卒中的mica处理大鼠的进一步研究表明，DLDH活性低于对照组大鼠，而NAD(P)H：醌氧化还原酶-1 （NQO1）活性显著升高。NQO1是一种诱导型酶，其表达是通过核转录因子e2相关因子2 （Nrf2）与抗氧化反应元件（ARE）结合而激活的。我们的初步研究还表明，4周的MICA饮食管理不会影响食物摄入量、体重增加、血糖浓度或线粒体呼吸复合物。这些初步结果支持了我们的中心假设，即饮食抑制DLDH可诱导持续的脑保护，通过激活Nrf2-ARE信号级联，增强缺血性卒中后认知和运动功能的恢复。这项拟议研究的基本原理是，确定无毒的、可通过血脑屏障的化学制剂，这些化学制剂可以保护大脑免受中风的伤害，并确定保护机制，将促进这些药物的开发和临床应用，以最大限度地减少中风患者的死亡和残疾。我们计划测试我们的中心假设，从而通过解决以下三个具体目标来实现本应用程序的目标：(1)确定MICA给药和tMCAO后Nrf2核定位和NQO1表达增加的程度；(2)测量饮食预处理对脑卒中后持续神经保护的程度；(3)评估MICA饮食和实验性脑卒中对神经行为功能和海马突触可塑性（以CA1长期增强（LTP）测量）的影响。预计成功完成的研究将为使用DLDH作为中风治疗靶点提供新的策略。