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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

基本信息

批准号：
9240669
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
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2019-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9240669
关键词：
Address Adult 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 Complex Cytoplasm Data Development Diet Dietary intake Eating Enzymes Ethics Exposure to Fostering General Population Goals Hippocampus (Brain)Hour Human Impairment Individual Infarction Injury Investigation Ischemia Ischemic Brain Injury Ischemic Preconditioning Ischemic Stroke Knowledge Lead Locomotor Recovery Long-Term Potentiation Measures Metabolism Middle Cerebral Artery Occlusion Mitochondria Modeling NQO1 gene Nuclear Oxidoreductase Pathway interactions Permeability Pharmacology Phenotype Pre-Clinical Model Prevention strategy Preventive Intervention Preventive measure Proteins Quinones 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 base cerebral artery clinical development cognitive recovery dihydrolipoamide dehydrogenase disability expectation experience 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

项目摘要

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）：新发和复发性卒中是美国第三大死亡原因和长期残疾的主要原因，但尚未确定有效的内源性靶点来预防或减轻卒中诱导的脑损伤。我们发现线粒体二氢硫辛酰胺脱氢酶（DLDH）可能是化学预处理抗脑卒中损伤的靶点。因此，本申请的目的是评估DLDH化学预处理的神经保护作用，并阐明其潜在的机制。我们的初步研究表明，当大鼠喂养4周的饮食补充5-甲氧基吲哚-2-羧酸（云母），特异性和竞争性DLDH抑制剂，脑梗死体积减少c。短暂性大脑中动脉闭塞（tMCAO，1小时缺血和24小时再灌注）后60%。该结果表明，云母的慢性DLDH抑制提供了针对中风的强有力的保护作用。在没有中风的情况下对MICA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：醌氧化还原酶-1（NQO 1）活性在MICA处理的大鼠中显著增加。NQO 1是一种诱导酶，其表达通过核转录因子E2相关因子2（Nrf 2）与抗氧化反应元件（ARE）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、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诱导持久的脑保护，通过激活Nrf 2-ARE信号级联反应，增强缺血性卒中后认知和运动功能的恢复。拟议调查的理由是，确定无毒，血脑屏障渗透化学试剂，提供脑保护中风，并定义保护机制，将促进开发和临床实施这些代理，以尽量减少死亡和残疾的人中风受害者。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申请的目标：（1）确定云母给药和tMCAO后Nrf 2核定位和NQO 1表达增加的程度，（2）测量饮食预处理对中风产生持久神经保护的程度，（3）观察云母饮食和实验性脑卒中对大鼠神经行为功能和海马突触可塑性的影响。预期成功完成的研究将提供使用DLDH作为中风治疗靶点的新策略。