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

被引:14
作者
Carry, Eileen [1 ,2 ,3 ]
Kshatriya, Dushyant [4 ]
Silva, Joshua [5 ]
Davies, Daryl L. [5 ]
Yuan, Bo [2 ,4 ]
Wu, Qingli [1 ,2 ,4 ]
Patel, Harna [2 ]
Park, Elizabeth R. [3 ]
Gilleran, John [3 ]
Hao, Lihong [4 ]
Roberge, Jacques [3 ]
Bello, Nicholas T. [4 ]
Simon, James E. [1 ,2 ]
机构
[1] Rutgers State Univ, Ernest Mario Sch Pharm, Dept Med Chem, Piscataway, NJ 08854 USA
[2] Rutgers State Univ, Sch Environm & Biol Sci, Dept Plant Biol, New Use Agr & Nat Plant Prod Program, New Brunswick, NJ 08901 USA
[3] Rutgers State Univ, Dept Mol Design & Synth, Off Res & Econ Dev, Piscataway, NJ 08854 USA
[4] Rutgers State Univ, Sch Environm & Biol Sci, Dept Anim Sci, New Brunswick, NJ 08901 USA
[5] Univ Southern Calif, Sch Pharm, Titus Family Dept Clin Pharm, Los Angeles, CA 90089 USA
关键词
dihydromyricetin; metabolism; bioavailability; GABA(A) receptors; acute alcohol intoxication; alcohol use disorder; loss of righting reflex; GABA(A) RECEPTOR SUBTYPES; IN-VITRO; ALCOHOL; FLAVONOIDS; LIVER; MEDICATIONS; MODULATION; PLASTICITY; DEPENDENCE; TRANSPORT;
D O I
10.3390/ijms22147460
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Dihydromyricetin is a natural bioactive flavonoid with unique GABA(A) 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 mu M x h (male) and 0.7 mu M x 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 alpha 5 beta 3 gamma 2 GABA(A) receptors expressed in Xenopus oocytes suggest dihydromyricetin (10 mu M) potentiates GABAergic activity (+43.2%), and the metabolite 4-O-methyl-dihydromyricetin (10 mu M) 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.
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页数:14
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