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）：新的和经常性的中风是美国的第三大主要原因，也是美国长期残疾的主要原因，但是尚未定义有效的内源性目标以预防或减弱中风引起的脑损伤。我们已经发现，线粒体二氢氨基酰胺脱氢酶（DLDH）可能是针对中风损伤的化学预处理的靶标。因此，该应用的目的是评估DLDH化学预处理的神经保护功效，并描绘其基本机制。我们的初步研究表明，当大鼠被喂食为4周饮食中补充了5-甲氧基-2-羧酸（MICA）（一种特定且有竞争力的DLDH抑制剂）时，脑梗塞体积减少了。瞬时脑动脉阻塞后60％（TMCAO，1小时缺血和24小时再灌注）。该结果表明，MICA的慢性DLDH抑制作用可对中风进行强大的脑保护。在没有中风的情况下，对云母处理的大鼠的进一步研究表明，DLDH活性低于对照大鼠，而NAD（P）H：米云处理大鼠的NAD（P）H：Quinone氧化还原酶1（NQO1）的活性显着增加。 NQO1是一种可诱导的酶，其表达通过核转录因子E2相关因子2（NRF2）与抗氧化剂反应元件的结合而激活。我们的初步研究还表明，4周的云母饮食给药不影响食物摄入量，体重增加，血糖浓度或线粒体呼吸道复合物。这些初步结果支持了我们的中心假设，即DLDH的饮食抑制会引起持续的脑保护，从而通过激活NRF2-ARE信号级联反应后，可增强缺血性中风后认知和运动功能的恢复。拟议的研究的理由是，确定无毒的，血脑屏障的可渗透化学剂，这些化学剂可提供脑部免受中风的保护，并定义保护机制，将促进这种药物的发展和临床实施，以最大程度地减少中风受害者的死亡和残疾。我们计划通过解决以下三个具体目的来测试我们的中心假设，从而实现此应用的目标：（1）确定NRF2核定位和NQO1表达在MICA给药和TMCAO后的表达增加程度，（2）衡量对饮食中的饮食预处理的程度，以衡量饮食中的持续性神经饮食，以对遇到型号和（3）的效果（3）效果（3）神经行为功能和海马突触可塑性测量为CA1长期增强（LTP）。预计成功完成的研究将使用DLDH作为中风治疗的目标提供新颖的策略。