Mechanisms underlying effects of Hovenia-dihydromyricetin on alcohol intoxication

枳椇二氢杨梅素治疗酒精中毒的潜在机制

• 批准号: 7934541
• 负责人: Jing Liang
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-20 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7934541
• 关键词: Accounting; Acute; Adverse effects; Agonist; Alcohol consumption; Alcohol dependence; Alcoholic Intoxication; Alcohols; Anesthetics; Anti-Anxiety Agents; Anxiety; Asia; Automobile Driving; Behavioral; Benzodiazepines; Biological Assay; Blood alcohol level measurement; Brain; Cells; Central Nervous System Depressants; Cessation of life; Chemical Structure; Chemosensitization; Dose; Drug Kinetics; Ethanol; Flavonoids; Future; Goals; Grant; Herbal Medicine; Hippocampus (Brain); Impairment; In Vitro; Individual; Intoxication; Lead; Literature; Measurement; Mediating; Medicine; Metabolism; Movement; Neurons; Patients; Peptides; Performance; Pharmaceutical Preparations; Pilot Projects; Public Health; Rattus; Reporting; Research; Research Personnel; Slice; Synapses; Techniques; Testing; Therapeutic Effect; Therapeutic Intervention; Transportation; United States; Vehicle crash; absorption; base; behavior measurement; clinical application; improved; in vivo; injured; killings; novel; prevent; problem drinker; public health relevance; receptor; receptor function; response; sedative; trafficking

DESCRIPTION (provided by applicant): Alcohol intoxication is the greatest contributing factor to transportation fatalities in the United States. Alcohol's (EtOH) major pharmacological target is GABAA receptors (GABAAR). The goal of our research is to develop novel anti-alcohol drugs, which may reduce alcohol-related transportation fatalities. Alcohol consumption enhances GABAAR function and induces GABAAR plasticity. Hovenia, an herbal medicine, has been used in Asia to treat alcohol dependence safely and effectively for more than a millennium. We have demonstrated in pilot studies that Hovenia can reduce EtOH intoxication and block the changes in GABAAR subunit 14 and 11 peptide levels after EtOH intoxication in rats. We showed that Hovenia enhances GABAAR-mediated inhibitory synaptic and extrasynaptic currents in hippocampal neurons in brain slices in vitro. We have identified the active constituents in Hovenia and their chemical structures. Hovenia-dihydromyricetin (H-DHM) is the major component (pilot studies) of the active constituents. The purpose of this application is to study the cellular mechanisms of H-DHM interactions with EtOH and GABAARs. We will pursue these specific aims: Specific aim 1) To determine H-DHM effects on synaptic and extrasynaptic GABAAR function, whole cell-patch recording of hippocampal neurons in brain slices will be performed in vitro. Dose-response studies of H-DHM interactions with GABAARs and EtOH will be conducted using our standard electrophysiological and pharmacological techniques. Specific aim 2) To determine H-DHM effects on acute EtOH intoxication, selected behavioral measurements will be performed in vivo. Rotarod performance will provide a measurement of coordinated movement. Elevate plus maze will be used to evaluate anxiolytic effects. The LORR assay will be able to evaluate sedative/anesthetic effects. Specific aim 3) To determine H-DHM effects on EtOH pharmacokinetics. These studies are necessary because literature suggests that herbal medicines for alcohol intoxication act to reduce alcohol absorption on the gut, or increase metabolism, thus lowering blood alcohol levels. The novelty of this application is testing H-DHM from Hovenia as a potential treatment for alcohol intoxication and alcohol dependence as well as to elucidate the cellular mechanisms underlying the therapeutic effects of H-DHM. By the end of this grant period, we will understand how H-DHM interacts with GABAARs and EtOH to block EtOH intoxication-induced plasticity, and the resultant EtOH-induced behavioral changes. Understanding the effects of H-DHM in acute alcohol intoxication will provide a pharmacological basis for developing a novel anti-alcoholic therapy that might decrease alcohol-related transportation fatalities. PUBLIC HEALTH RELEVANCE: Motor vehicle collisions are the leading cause of transportation fatalities in the nation and alcohol is the primary factor contributing to the fatalities. The goal of our project is to understand the cellular mechanisms underlying the therapeutic effects of the active in gradient H-DHM on acute alcohol intoxication and alcohol dependence so as to develop a novel anti- alcohol intoxication drug that can prevent alcohol-related transportation fatalities.

描述（由申请人提供）：酒精中毒是美国运输死亡的最大因素。酒精（ETOH）的主要药理学靶标是GABAA受体（GABAAR）。我们研究的目的是开发新型的抗酒精药物，这可能减少与酒精相关的运输死亡。饮酒增强了Gabaar功能并诱导Gabaar可塑性。 Hovenia是一种草药，在亚洲已被用来安全有效地治疗千年以上的酒精依赖。我们在试点研究中证明，Hovenia可以减少EtOH中毒，并阻止大鼠EtOH中毒后Gabaar亚基14和11肽水平的变化。我们表明，Hovenia在体外脑切片中的海马神经元中增强了GABAAR介导的抑制性突触和突触外电流。我们已经确定了Hovenia及其化学结构的活性成分。 Hovenia-drymyryricetin（H-DHM）是活性成分的主要成分（初步研究）。该应用的目的是研究H-DHM与EtOH和Gabaars相互作用的细胞机制。我们将追求这些特定目的：具体目的1）确定H-DHM对突触和突触外GABAAR功能的影响，将在体外进行脑切片中海马神经元的全细胞斑记录记录。 H-DHM与GABAARS和ETOH相互作用的剂量反应研究将使用我们的标准电生理和药理技术进行。具体目标2）确定H-DHM对急性EtOH中毒的影响，将在体内进行选定的行为测量。 Rotarod的性能将提供协调运动的测量。抬高Plus迷宫将用于评估抗焦虑作用。 LORR分析将能够评估镇静剂/麻醉效应。具体目标3）确定H-DHM对ETOH药代动力学的影响。这些研究是必要的，因为文献表明，饮酒中毒的草药可以减少肠道上的酒精吸收或增加代谢，从而降低血液酒精的水平。该应用的新颖性是测试Hovenia的H-DHM，是对酒精中毒和酒精依赖性的潜在治疗方法，以及阐明H-DHM治疗作用的细胞机制。到本赠款期结束时，我们将了解H-DHM如何与GABAARS和ETOH相互作用，以阻止ETOH中毒诱导的可塑性，以及所得的ETOH诱导的行为变化。了解H-DHM在急性酒精中毒中的作用将为开发一种新型的抗酒精疗法提供药理基础，以减少与酒精相关的运输死亡。 公共卫生相关性：汽车碰撞是全国运输死亡的主要原因，酒精是导致死亡的主要因素。我们项目的目的是了解活性在梯度H-DHM中对急性酒精中毒和酒精依赖性的治疗作用的细胞机制，从而开发出一种新型的抗酒精中毒药物，以防止酒精相关的运输死亡。

项目成果

Social isolation induces succinate dehydrogenase dysfunction in anxious mice.

• DOI: 10.1016/j.neuint.2022.105434
• 发表时间: 2022-12
• 期刊: NEUROCHEMISTRY INTERNATIONAL
• 影响因子: 4.2
• 作者: Watanabe, Saki;Al Omran, Alzahra J.;Shao, Amy S.;Zhang, Zeyu;Xue, Chen;Zhang, Jifeng;Watanabe, Junji;Liang, Jing
• 通讯作者: Liang, Jing

Social Isolation Induces Neuroinflammation And Microglia Overactivation, While Dihydromyricetin Prevents And Improves Them.

社会隔离会导致神经炎症和小胶质细胞过度激活，而二氢杨梅素则可以预防和改善它们。

• DOI: 10.21203/rs.3.rs-923871/v1
• 发表时间: 2021
• 期刊: Research square
• 作者: AlOmran,AlzahraJ;Shao,AmyS;Watanabe,Saki;Zhang,Zeyu;Zhang,Jifeng;Xue,Chen;Watanabe,Junji;Davies,DarylL;Shao,XuesiM;Liang,Jing
• 通讯作者: Liang,Jing

Dihydromyricetin improves social isolation-induced cognitive impairments and astrocytic changes in mice.

• DOI: 10.1038/s41598-022-09814-5
• 发表时间: 2022-04-07
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Watanabe S;Omran AA;Shao AS;Xue C;Zhang Z;Zhang J;Davies DL;Shao XM;Watanabe J;Liang J
• 通讯作者: Liang J