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

Abstract

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 (AUC0→24) 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 AUC0→24 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.

A multifaceted review on dihydromyricetin resources, extraction, bioavailability, biotransformation, bioactivities, and food applications with future perspectives to maximize its value

“…It was demonstrated that DMY could protect rats against ethanol‐induced acute intoxication by affecting the related targets of γ‐Aminobutyric acid type A (GABAA) receptors (GABAARs) [111]. Furthermore, an investigation on the biotransformation of DMY related to the acute ethanol anti‐intoxication in mice demonstrated that 3 metabolites of DMY influenced the increased expression of GABAARs [99].…”

Phenolics as GABAA Receptor Ligands: An Updated Review

“…Furthermore, dihydromyricetin had no adverse side effects on pregnant rats, which could make it a good candidate for prevention of foetal alcohol spectrum disorders [ 110 ]. More recently, dihydromyricetin was demonstrated to potentiate GABAergic activity, as shown in electrophysiology studies of α 5 β 3 γ 2 GABA A Rs expressed in Xenopus oocytes, although its metabolite 4- O -methyl-dihydromyricetin negatively modulates GABAergic activity [ 130 ]. In the case of the quercetin 5-dehydroxy-derivate fisetine ( Table 1 ), chronic treatment can delay or correct neuropathic hyperalgesia and allodynia in mice with type-1 diabetes; mechanistically, this effect may be associated with its antioxidant activity and spinal GABA A [ 73 ].…”

Improving the solubility of pseudo-hydrophobic Alzheimer’s Disease medicinal chemicals through co-crystal formulation

“…In the present work, we investigated the solubility, activity, and Microcrystal electron diffraction (MicroED) 4,5 structure of salt formulations of the natural product dihydromyricetin (DHM), a brainpermeable flavonoid with high chemical similarity to a known in vitro tau inhibitor, EGCG 6 . DHM is a plant-derived polyphenol with antioxidant 7,8 and anti-inflammatory [9][10][11] activity and potential benefits in ameliorating dyslipidemia 7,9,12,13 and alcohol intoxication 14,15 . The CNS effects of DHM are attributed to increased GABAergic transmission and synaptic functioning, reduced neuroinflammation, and restoration of redox imbalances in neurons through improved mitochondrial function.…”

“…While hydrophobic character of DHM allows for permeability to the CNS, poor water solubility impedes dosing and intestinal absorption. [19][20][21][22] Water-soluble formulations of DHM could overcome dosing issues by enabling delivery of higher dosage concentrations to enable increased absorption.…”