Hovenia Dulcis (DHM) effects beyond EtOH pharmacokinetics

It has been reported that Hovenia relieves hangover by decreasing blood EtOH concentrations, promoting alcohol clearance, and enhancing the alcohol metabolic enzymes, ADH and ALDH (Kim et al., 2000; Chen et al., 2006). In this study, we showed that DHM, like other flavonoids, has a relatively weak ability to reduce the rate of rise of blood alcohol concentration. However, this cannot account for the actions of DHM on blocking EtOH effects in vivo, since when we decreased the doses of DHM to 0.3 and 0.5 mg/kg, DHM apparently did not affect EtOH pharmacokinetics while still strongly counteracting EtOH-induced LORR (Fig. 1B), suggesting potency of DHM. When we increased the dose of EtOH (4 g/kg), 1 mg/kg DHM did not have a significant effect on the magnitude nor the time course of plasma [EtOH] (Table 1), but greatly reduced the EtOH-induced LORR. In this study, we demonstrated a likely more important mechanism. DHM has direct effects on GABAARs, the major targets of EtOH that contribute to AWS and EtOH dependence. More importantly, the DHM effects on EtOH intoxication and GABAAR plasticity can be reversed by flumazenil in vivo (Fig. 1) and in vitro (Figs. 4, 5). These results indicate that DHM has complex interactions with GABAARs that counteract EtOH effects. DHM potentiates GABAARs in CNS neurons and retains efficacy in potentiating GABAARs even after EtOH exposure/withdrawal, which induces tolerance to EtOH (Figs. 6, 9); thus, it may be an effective pharmacotherapy for patients who are tolerant to other medications for alcoholism and AWS such as BZs.



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