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Featured ArticleArticles, Neurobiology of Disease

Dihydromyricetin As a Novel Anti-Alcohol Intoxication Medication

Yi Shen, A. Kerstin Lindemeyer, Claudia Gonzalez, Xuesi M. Shao, Igor Spigelman, Richard W. Olsen and Jing Liang
Journal of Neuroscience 4 January 2012, 32 (1) 390-401; DOI: https://doi.org/10.1523/JNEUROSCI.4639-11.2012
Yi Shen
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A. Kerstin Lindemeyer
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Claudia Gonzalez
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Xuesi M. Shao
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Igor Spigelman
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Richard W. Olsen
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Jing Liang
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Abstract

Alcohol use disorders (AUDs) constitute the most common form of substance abuse. The development of AUDs involves repeated alcohol use leading to tolerance, alcohol withdrawal syndrome, and physical and psychological dependence, with loss of ability to control excessive drinking. Currently there is no effective therapeutic agent for AUDs without major side effects. Dihydromyricetin (DHM; 1 mg/kg, i.p. injection), a flavonoid component of herbal medicines, counteracted acute alcohol (EtOH) intoxication, and also withdrawal signs in rats including tolerance, increased anxiety, and seizure susceptibility; DHM greatly reduced EtOH consumption in an intermittent voluntary EtOH intake paradigm in rats. GABAA receptors (GABAARs) are major targets of acute and chronic EtOH actions on the brain. At the cellular levels, DHM (1 μm) antagonized both acute EtOH-induced potentiation of GABAARs and EtOH exposure/withdrawal-induced GABAAR plasticity, including alterations in responsiveness of extrasynaptic and postsynaptic GABAARs to acute EtOH and, most importantly, increases in GABAAR α4 subunit expression in hippocampus and cultured neurons. DHM anti-alcohol effects on both behavior and CNS neurons were antagonized by flumazenil (10 mg/kg in vivo; 10 μm in vitro), the benzodiazepine (BZ) antagonist. DHM competitively inhibited BZ-site [3H]flunitrazepam binding (IC50, 4.36 μm), suggesting DHM interaction with EtOH involves the BZ sites on GABAARs. In summary, we determined DHM anti-alcoholic effects on animal models and determined a major molecular target and cellular mechanism of DHM for counteracting alcohol intoxication and dependence. We demonstrated pharmacological properties of DHM consistent with those expected to underlie successful medical treatment of AUDs; therefore DHM is a therapeutic candidate.

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The Journal of Neuroscience: 32 (1)
Journal of Neuroscience
Vol. 32, Issue 1
4 Jan 2012
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Dihydromyricetin As a Novel Anti-Alcohol Intoxication Medication
Yi Shen, A. Kerstin Lindemeyer, Claudia Gonzalez, Xuesi M. Shao, Igor Spigelman, Richard W. Olsen, Jing Liang
Journal of Neuroscience 4 January 2012, 32 (1) 390-401; DOI: 10.1523/JNEUROSCI.4639-11.2012

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Dihydromyricetin As a Novel Anti-Alcohol Intoxication Medication
Yi Shen, A. Kerstin Lindemeyer, Claudia Gonzalez, Xuesi M. Shao, Igor Spigelman, Richard W. Olsen, Jing Liang
Journal of Neuroscience 4 January 2012, 32 (1) 390-401; DOI: 10.1523/JNEUROSCI.4639-11.2012
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  • medical Benefits
    Katherine Boucher
    Published on: 13 January 2012
  • Possible Mechanism
    W. R. Klemm
    Published on: 13 January 2012
  • Published on: (13 January 2012)
    Page navigation anchor for medical Benefits
    medical Benefits
    • Katherine Boucher, retired

    I would forsee that the first most valuable utilization of this would be in tne medical care of the alcholic who presented for emergency medical treatment. Persons who require emergency surgery, for medical or trauma may encounter life threatening complications if they are undiagnosed alcoholics. In the case of the diagnosed alcholic, precautions can be taken to try to limit the impact of DTs. However, often there is a...

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    I would forsee that the first most valuable utilization of this would be in tne medical care of the alcholic who presented for emergency medical treatment. Persons who require emergency surgery, for medical or trauma may encounter life threatening complications if they are undiagnosed alcoholics. In the case of the diagnosed alcholic, precautions can be taken to try to limit the impact of DTs. However, often there is a lack of knowledge of the extent of a person's alcholal involvment. patients may have denied, or famlies may have denied. To have a tool to quickly interveen in the onset of alcholol related symptoms for such a patient could be a life saver

    Conflict of Interest:

    None declared

    Show Less
    Competing Interests: None declared.
  • Published on: (13 January 2012)
    Page navigation anchor for Possible Mechanism
    Possible Mechanism
    • W. R. Klemm, Professor

    Some years back my lab published research suggesting that alcohol dehydrates membranes by displacing hydrogen-bonded water in lipid membrane domains in or near particular receptor proteins (Klemm, 1990). The mechanism for dihydromyricetin might be to reduce this membrane dehydration, either by competitive binding to hydrogen-bonding sites on membrane lipid or by sequestering alcohol molecules and reducing the population of alco...

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    Some years back my lab published research suggesting that alcohol dehydrates membranes by displacing hydrogen-bonded water in lipid membrane domains in or near particular receptor proteins (Klemm, 1990). The mechanism for dihydromyricetin might be to reduce this membrane dehydration, either by competitive binding to hydrogen-bonding sites on membrane lipid or by sequestering alcohol molecules and reducing the population of alcohol molecules available for action on such binding sites.

    Reference

    Klemm WR. Dehydration: a new alcohol theory. Alcohol. 1990 Jan-Feb;7(1):49-59.

    Conflict of Interest:

    None declared

    Show Less
    Competing Interests: None declared.

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