Honokiol promotes non‐rapid eye movement sleep via the benzodiazepine site of the GABA_A receptor in mice

Abstract

BACKGROUND AND PURPOSE Decoctions of the Chinese herb houpu contain honokiol and are used to treat a variety of mental disorders, including depression. Depression commonly presents alongside sleep disorders and sleep disturbances, which appear to be a major risk factor for depression. Here, we have evaluated the somnogenic effect of honokiol and the mechanisms involved. EXPERIMENTAL APPROACH Honokiol was administered i.p. at 20:00 h in mice. Flumazenil, an antagonist at the benzodiazepine site of the GABAA receptor, was administered i.p. 15 min before honokiol. The effects of honokiol were measured by EEG and electromyogram (EMG), c‐Fos expression and in vitro electrophysiology. KEY RESULTS Honokiol (10 and 20 mg·kg−1) significantly shortened the sleep latency to non‐rapid eye movement (non‐REM, NREM) sleep and increased the amount of NREM sleep. Honokiol increased the number of state transitions from wakefulness to NREM sleep and, subsequently, from NREM sleep to wakefulness. However, honokiol had no effect on either the amount of REM sleep or EEG power density of both NREM and REM sleep. Honokiol increased c‐Fos expression in ventrolateral preoptic area (VLPO) neurons, as examined by immunostaining, and excited sleep‐promoting neurons in the VLPO by whole‐cell patch clamping in the brain slice. Pretreatment with flumazenil abolished the somnogenic effects and activation of the VLPO neurons by honokiol. CONCLUSION AND IMPLICATIONS Honokiol promoted NREM sleep by modulating the benzodiazepine site of the GABAA receptor, suggesting potential applications in the treatment of insomnia, especially for patients who experience difficulty in falling and staying asleep.

Magnolol, a major bioactive constituent of the bark of Magnolia officinalis, induces sleep via the benzodiazepine site of GABAA receptor in mice

“…In addition, magnolol increased the number of binding sites and the binding affinity on a 1 b 2 g 2 and a 1 b 2 combinations in in vitro saturation binding assays (Ai et al, 2001). Honokiol, another active ingredient of the Chinese herb houpo also does not alter the EEG power density of NREM sleep but increases NREM sleep without effects on REM sleep (Qu et al, 2012). Honokiol enhanced chloride currents through GABA A receptors of seven different subunit compositions and was most effective at those containing a 3 b 2 > a 2 b 2 > a 1 b 2 > a 1 b 1 subunits (Taferner et al, 2011), indicating that magnolol and honokiol may more effective on a 1 and a 3, respectively, than a 2 -containing receptors, and thus have less influence on EEG delta activity of NREM sleep.…”

Honokiol improves learning and memory impairments induced by scopolamine in mice

“…The doses of the honokiol were selected with reference to previous studies (Qu et al, 2012;Vavilala et al, 2013). Donepezil hydrochloride was used as the positive control (Xian et al, 2014).…”

Neuro-Modulating Effects of Honokiol: A Review

“…Honokiol (10 and 20 mg/kg) was found to significantly shorten sleep latency and to increase the amount of non-rapid eye movement sleep, though it had no effect on either the amount of rapid eye movement sleep or EEG power density. This group also found that honokiol excited sleep-promoting neurons in the ventrolateral preoptic areas (49). The sleep-promoting and anxiolytic effects of honokiol suggest a potential additional role for this neolignan in the anesthetic arena.…”