Identification of Dihydromyricetin and Metabolites in Serum and Brain Associated with Acute Anti-Ethanol Intoxicating Effects in Mice

Int J Mol Sci. 2021 Jul 12;22(14):7460. doi: 10.3390/ijms22147460.


Dihydromyricetin is a natural bioactive flavonoid with unique GABAA receptor activity with a putative mechanism of action to reduce the intoxication effects of ethanol. Although dihydromyricetin's poor oral bioavailability limits clinical utility, the promise of this mechanism for the treatment of alcohol use disorder warrants further investigation into its specificity and druggable potential. These experiments investigated the bioavailability of dihydromyricetin in the brain and serum associated with acute anti-intoxicating effects in C57BL/6J mice. Dihydromyricetin (50 mg/kg IP) administered 0 or 15-min prior to ethanol (PO 5 g/kg) significantly reduced ethanol-induced loss of righting reflex. Total serum exposures (AUC024) of dihydromyricetin (PO 50 mg/kg) via oral (PO) administration were determined to be 2.5 µM × h (male) and 0.7 µM × h (female), while intraperitoneal (IP) administration led to 23.8-fold and 7.2- increases in AUC024 in male and female mice, respectively. Electrophysiology studies in α5β3γ2 GABAA receptors expressed in Xenopus oocytes suggest dihydromyricetin (10 µM) potentiates GABAergic activity (+43.2%), and the metabolite 4-O-methyl-dihydromyricetin (10 µM) negatively modulates GABAergic activity (-12.6%). Our results indicate that administration route and sex significantly impact DHM bioavailability in mice, which is limited by poor absorption and rapid clearance. This correlates with the observed short duration of DHM's anti-intoxicating properties and highlights the need for further investigation into mechanism of DHM's potential anti-intoxicating properties.

Keywords: GABAA receptors; acute alcohol intoxication; alcohol use disorder; bioavailability; dihydromyricetin; loss of righting reflex; metabolism.

MeSH terms

  • Alcoholic Intoxication / etiology
  • Alcoholic Intoxication / metabolism
  • Alcoholic Intoxication / pathology
  • Alcoholic Intoxication / prevention & control*
  • Animals
  • Brain / drug effects
  • Brain / metabolism*
  • Brain / pathology
  • Central Nervous System Depressants / toxicity
  • Ethanol / toxicity*
  • Female
  • Flavonols / blood
  • Flavonols / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL


  • Central Nervous System Depressants
  • Flavonols
  • Ethanol
  • dihydromyricetin