Dihydromyricetin Prevents Fetal Alcohol Exposure-Induced Behavioral and Physiological Deficits: The Roles of GABAA Receptors in Adolescence

Abstract

Fetal alcohol exposure (FAE) can lead to a variety of behavioral and physiological disturbances later in life. Understanding how alcohol (ethanol, EtOH) affects fetal brain development is essential to guide the development of better therapeutics for FAE. One of EtOH's many pharmacological targets is the c-aminobutyric acid type A receptor (GABA A R), which plays a prominent role in early brain development. Acute EtOH potentiates inhibitory currents carried by certain GABA A R subtypes, whereas chronic EtOH leads to persistent alterations in GABA A R subunit composition, localization and function. We recently introduced a flavonoid compound, dihydromyricetin (DHM), which selectively antagonizes EtOH's intoxicating effects in vivo and in vitro at enhancing GABA A R function as a candidate for alcohol abuse pharmacotherapy. Here, we studied the effect of FAE on physiology, behavior and GABA A R function of early adolescent rats and tested the utility of DHM as a preventative treatment for FAE-induced disturbances. Gavage administration of EtOH (1.5, 2.5, or 5.0 g/kg) to rat dams on day 5, 8, 10, 12, and 15 of pregnancy dose-dependently reduced female/male offspring ratios (largely through decreased numbers of female offspring) and offspring body weights. FAE (2.5 g/kg) rats tested on postnatal days (P) 25-32 also exhibited increased anxiety and reduced pentylenetetrazol (PTZ)-induced seizure threshold. Patchclamp recordings from dentate gyrus granule cells (DGCs) in hippocampal slices from FAE (2.5 g/kg) rats at P25-35 revealed reduced sensitivity of GABAergic miniature inhibitory postsynaptic currents (mIPSCs) and tonic current (I tonic ) to potentiation by zolpidem (0.3 lM). Interestingly, potentiation of mIPSCs by gaboxadol increased, while potentiation of I tonic decreased in DGCs from FAE rats. Coadministration of EtOH (1.5 or 2.5 g/kg) with DHM (1.0 mg/kg) in pregnant dams prevented all of the behavioral, physiological, and pharmacological alterations observed in FAE offspring. DHM administration alone in pregnant rats had no adverse effect on litter size, progeny weight, anxiety level, PTZ seizure threshold, or DGC GABA A R function. Our results indicate that FAE induces long-lasting alterations in physiology, behavior, and hippocampal GABA A R function and that these deficits are prevented by DHM co-treatment of EtOH-exposed dams. The absence of adverse side effects and the ability of DHM to prevent FAE consequences suggest that DHM is an attractive candidate for development as a treatment for prevention of fetal alcohol spectrum disorders.

Hypothalamic-pituitary-adrenal axis and behavioral dysfunction following early binge-like prenatal alcohol exposure in mice

“…This effect in females was also supported by increased time spent in the open arms on the elevated plus maze. The increased anxiety-like behavior in male GD7 Alc mice corroborates previous studies focusing on more moderate alcohol exposure throughout gestation (Carneiro et al, 2005; Dursun et al, 2006; Hellemans et al, 2008; Liang et al, 2014); however, the decrease in anxiety-like behavior in female GD7 Alc mice is novel compared to these previous findings. Subsequent analysis of the light-dark and elevated plus maze tests revealed that female mice showed a significant positive correlation between all behavioral measurements analyzed during both tests; that is, as light exploration during light-dark testing increased, so did open-arm exploration during the elevated plus maze.…”

“…Both rodents (Kim, Giberson, Yu, Zoeller, & Weinberg, 1999; Lee, Imaki, Vale, & Rivier, 1990; Nelson et al, 1986; Taylor, Branch, Liu, & Kokka, 1982; Weinberg, 1992) and primates (Schneider, Moore, Kraemer, Roberts, & DeJesus, 2002) exposed prenatally to alcohol display enhanced HPA axis reactivity to multiple types of stressors, including morphine administration, restraint stress, footshock, cardiac puncture, and cold stress. Furthermore, an overall increase in depression-like symptoms as measured on the forced swim task (Carneiro et al, 2005; Hellemans, Verma, et al, 2010; Wilcoxon, Kuo, Disterhoft, & Redei, 2005) and anxiety-like behavior as measured on the elevated plus maze (Carneiro et al, 2005; Dursun, Jakubowska-Doğru, & Uzbay, 2006; Liang et al, 2014) was found in rats. These changes in anxiety-like behavior can be directly linked to changes in HPA axis activity, as evidenced by increased corticosterone (CORT) levels after testing on the elevated plus maze or open field in prenatal alcohol-exposed females, but not males (Hellemans, Verma, Yoon, Yu, & Weinberg, 2008; Osborn, Kim, Steiger, & Weinberg, 1998).…”

Acute prenatal exposure to ethanol on gestational day 12 elicits opposing deficits in social behaviors and anxiety-like behaviors in Sprague Dawley rats

“…While this was unexpected, much of the literature is inconsistent regarding the effects of prenatal ethanol exposure on anxiety-like behaviors. Many studies have found increased [35, 37–39, 44], while some studies have shown decreased anxiety-like behaviors following prenatal ethanol exposure [40, 41, 43]. A recent study by Wieczorek and colleagues found increased anxiety-like responses in the LDB, but decreases in the EPM [42].…”

Anti-inflammatory effects of dihydromyricetin in a mouse model of asthma

“…1A, which is similar to that of myrecetin, a natural flavonoid found in berries, grapes, vegetables, herbs, fruits and other plants with anticancer activities (9,10). Previous studies have indicated that DHM exhibits a range of biological and pharmacological activities, including hepatic protection (11,12), attenuation of cardiomyocyte hypertrophy (13), antimicrobial activity, anti-oxidation and antitumor effects (14–17). …”