GSK3beta, a mediator of ethanol neurotoxicity

GSK3beta，乙醇神经毒性介质

• 批准号: 8086466
• 负责人: JIA LUO
• 金额: $ 37.15万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8086466
• 关键词: Acids; Acute; Adverse effects; Alcohol-Induced Disorders; Alcohol-Induced Neurotoxicity; Alcohols; Animals; Anthocyanins; Antioxidants; Apoptotic; Behavior; Behavioral; Blood - brain barrier anatomy; Brain; C57BL/6 Mouse; Cell Death; Cells; Cerebellum; Cerebral cortex; Cessation of life; Clinical Trials; Drug Kinetics; Electron Spin Resonance Spectroscopy; Episodic memory; Equilibrium; Ethanol; Ethanol toxicity; Exposure to; Family; Fetal Alcohol Spectrum Disorder; Fetal Alcohol Syndrome; Funding; Future; Generations; Glucosides; Glycogen Synthase Kinases; Health; Hippocampus (Brain); Human; Hydrogen Peroxide; Hydroxyl Radical; Hyperactive behavior; In Vitro; Learning; Life; Mediating; Mediator of activation protein; Memory; Mental Retardation; Microglia; Modeling; Motor; Mus; Neonatal Alcohol Exposure; Nerve Degeneration; Neuraxis; Neurons; Neuroprotective Agents; North America; Oral; Oral Administration; Oxidative Stress; Pathway interactions; Production; Property; Protein Kinase; Protein-Serine-Threonine Kinases; RAPGEF1 gene; Role; Signal Transduction; Superoxides; Testing; Therapeutic; Third Pregnancy Trimester; alcohol behavior; alcohol consumption during pregnancy; alcohol effect; alcohol exposure; base; caspase-3; free radical oxygen; in vivo; in vivo Model; inhibitor/antagonist; intravenous administration; intravenous injection; member; neuroblastoma cell; neuron apoptosis; neuron loss; neuroprotection; neurotoxicity; novel; novel therapeutics; postnatal; prenatal; prevent; research study

DESCRIPTION (provided by applicant): Alcohol is a neuroteratogen; alcohol consumption during pregnancy may cause Fetal Alcohol Spectrum Disorders (FASD), among which, fetal alcohol syndrome (FAS) is the most severe form. The depletion of neurons in the developing CNS is the most deteriorating effect of ethanol. The loss of CNS neurons may underlie many of the behavioral deficits observed in FASD. Glycogen synthase kinase 3¿ (GSK3¿), a serine/threonine kinase, is an important mediator of neuron degeneration. We have demonstrated that ethanol activates GSK3¿, and the activation of GSK3¿ leads to neuronal death. Oxidative stress is also considered an important contributor to ethanol-induced neurotoxicity. We have purified a potent antioxidant from blackberries, cyanidin-3-glucoside (C3G). Our study indicates that C3G inhibits GSK3¿ activity and alleviates oxidative stress in cultured neuronal cells. In addition, C3G protects neuronal cells against ethanol-induced cell death. C3G-mediated neuroprotection is much more potent than other antioxidants and GSK3¿ inhibitors. C3G can cross the blood brain barrier (BBB) and distribute in the brain. C3G diminishes ethanol-induced activation of caspase-3 and Bax in the developing brain. Pharmacologically relevant concentrations of C3G are achievable through oral administration or intravenous (iv) injection in animals, and no adverse effect is observed. These findings suggest that C3G is a promising neuroprotective agent that may ameliorate/prevent ethanol-induced neuronal damage. We hypothesize that C3G's potent protection against ethanol-induced neuronal loss is mediated by the combined action of its antioxidant property and inhibition of pro-apoptotic signaling, GSK3¿/Bax pathways. To test the hypothesis, we will (1) investigate the antioxidant property of C3G and its metabolites, and their effects on GSK3¿ activity; (2) determine whether C3G protection against ethanol- induced neuronal loss is mediated by the combined action of its antioxidant property and the inhibition of GSK3¿; (3) determine whether C3G ameliorates ethanol-induced behavioral deficits. C3G is a potent natural antioxidant and has diverse potential benefits for human health. It is a promising neuroprotective agent against ethanol toxicity due to its dual functions as an antioxidant and a GSK3¿ inhibitor. As a unit, the proposed experiments will elucidate the novel role of C3G, and provide an important basis for future clinical trials to evaluate the feasibility of C3G to treat ethanol neurotoxicity. Our study will potentially offer a new therapeutic strategy. PUBLIC HEALTH RELEVANCE: Alcohol consumption during pregnancy may cause Fetal Alcohol Spectrum Disorders (FASD), among which, fetal alcohol syndrome (FAS) is the most severe form. The developing central nervous system (CNS) is particularly sensitive to ethanol. The loss of CNS neurons may underlie many of the behavioral deficits observed in FASD. Both glycogen synthase kinase 3¿ (GSK3¿) and oxidative stress contributes to ethanol neurotoxicity. We have purified a potent antioxidant from blackberries, cyanidin-3-glucoside (C3G) which can also inhibit GSK3¿ and reduce oxidative stress. The current study is to determine whether C3G ameliorates ethanol-induced neuronal loss as well as behavioral deficits. The proposal will potentially develop a new therapeutic strategy.

描述（通过应用程序提供）：酒精是神经孕激素；怀孕期间的饮酒可能会导致胎儿酒精谱系（FASD），其中胎儿酒精综合征（FAS）是最严重的形式。中枢神经系统神经元的丧失可能是许多行为定义在FASD中观察到的。丝氨酸/苏氨酸激酶是糖原合酶激酶3（GSK3¿）是神经元变性的重要介体。我们已经证明乙醇激活GSK3，而GSK3的激活导致神经元死亡。氧化应激也被认为是乙醇引起的神经毒性的重要促进者。我们已经纯化了来自黑莓，氰肽-3-葡萄糖苷（C3G）的潜在抗氧化剂。我们的研究表明，C3G抑制了GSK3的活性，并减轻培养的神经元细胞中的氧化应激。此外，C3G可保护神经元细胞免受乙醇诱导的细胞死亡。 C3G介导的神经保护比其他抗氧化剂和GSK3抑制剂具有更大的潜力。 C3G可以越过血脑屏障（BBB）并分布在大脑中。 C3G减少了发育中的大脑中乙醇诱导的caspase-3和Bax的激活。通过在动物中口服或静脉注射（IV）注射C3G的药理学相关浓度的C3G浓度，并且未观察到不良影响。这些发现表明，C3G是一种承诺的神经保护剂，可能会改善 /预防乙醇诱导的神经元，我们假设C3G对乙醇诱导的神经元损失的有效保护是由其抗氧化属性的综合作用介导的，其抗氧化剂性质的综合作用和抑制亲质信号信号的抑制作用，gsk3 pathorey /bax pathorey /bax pathorey /bax。为了检验假设，我们将（1）研究C3G及其代谢产物的抗氧化特性及其对GSK3活动的影响； （2）确定C3G对乙醇诱导的神经元丧失的保护是否是由其抗氧化特性的综合作用和GSK3？的抑制作用介导的； （3）确定C3G是否可以改善乙醇诱导的行为缺陷。 C3G是一种潜在的天然抗氧化剂，对人类健康具有潜在的潜在利益。由于其双重功能作为抗氧化剂和GSK3抑制剂，它是对乙醇毒性的有前途的神经保护剂。作为一个单位，提出的实验将阐明C3G的新作用，并为将来的临床试验提供了重要的基础，以评估C3G治疗乙醇神经毒性的可行性。我们的研究将有可能提供新的治疗策略。 公共卫生相关性：怀孕期间的饮酒可能导致胎儿酒精谱系（FASD），其中，胎儿酒精综合征（FAS）是最严重的形式。发展中心神经系统（CNS）对乙醇特别敏感。 CNS神经元的丧失可能是FASD中观察到的许多行为缺陷的基础。糖原合酶激酶3？（GSK3？）和氧化应激都有助于乙醇神经毒性。我们已经纯化了来自黑莓，氰肽-3-葡萄糖苷（C3G）的潜在抗氧化剂，这也可以抑制GSK3并减少氧化应激。当前的研究是确定C3G是否可以改善乙醇诱导的神经元丧失以及行为缺陷。该提案将有可能制定新的治疗策略。