Magnolol Induces Sleep Via The Benzodiazepine Site Of GABA_A Receptor In Mice

Magnolol is an active ingredient of the bark of Magnolia officinalis. Recently, the research showed that magnolol not only has the effects of anti-bacteria, muscle-relaxtion and anti-cancer but also exerts anti-epileptic effects. Therefore, we hypothesize that magnolol might have sleep-promoting effects. GABA is the most abundant inhibitory neurotransmitter in the mammalian central nervous system. The benzodiazepine site of GABAA receptor is an important target for drugs used in the treatment of insomnia. It has been reported that magnolol has antiepileptic effect via GABAA receptors. In the current study, we investigated the roles and mechanism of magnolol in sleep, with focuses on GABAA receptors.Method:Male SPF C57BL/6J mice were used. We monitored sleep-wake behaviors by recording electroencephalogram and electromyogram of freely moving mice. Immunohistochemistry was carried out to count the expression of c-Fos in sleep promoting neurons of ventrolateralpreoptic area (VLPO) and of arousal histaminergic tuberommamillary nucleus (TMN).Results:The results showed that magnolol administered i.p. at a dose of5or25mg/kg could significantly shorten the sleep latency, increase the amount of non-rapid eye movement (non-REM, NREM) and rapid eye movement (REM) sleep for3h after administration with an increase in the number of NREM and REM sleep episodes. Magnolol at doses of5and25mg/kg increased the number of bouts of wakefulness but decreased their duration. On the other hand, magnolol increased the number of state transitions from wakefulness to NREM sleep and subsequently from NREM sleep to wakefulness. Immunohistochemical study showed that magnolol increased c-Fos expression in the neurons of VLPO, a sleep center in the anterior hypothalamus, and decreased c-Fos expression in the arousal TMN, which was located in the caudolateral hypothalamus. The sleep-promoting effects and changes in c-Fos induced by magnolol were reversed by flumazenil, an antagonist at the benzodiazepine.Conclusion:Magnolol induces sleep via the benzodiazepine site of GABAA receptor in mice.