Paeoniflorin Promotes Non-rapid Eye Movement Sleep via Adenosine A1 Receptors

Abstract

Paeoniflorin (PF, C 23 H 28 O 11 ), one of the principal active ingredients of Paeonia Radix, exerts depressant effects on the central nervous system. We determined whether PF could modulate sleep behaviors and the mechanisms involved. Electroencephalogram and electromyogram recordings in mice showed that intraperitoneal PF administered at a dose of 25 or 50 mg/kg significantly shortened the sleep latency and increased the amount of non-rapid eye movement (NREM). Immunohistochemical study revealed that PF decreased c-fos expression in the histaminergic tuberomammillary nucleus (TMN). The sleep-promoting effects and changes in c-fos induced by PF were reversed by 8-cyclopentyl-1,3-dimethylxanthine (CPT), an adenosine A 1 receptor antagonist, and PF-induced sleep was not observed in adenosine A 1 receptor knockout mice. Whole-cell patch clamping in mouse brain slices showed that PF significantly decreased the firing frequency of histaminergic neurons in TMN, which could be completely blocked by CPT. These results indicate that PF increased NREM sleep by inhibiting the histaminergic system via A 1 receptors.

Ethanol inhibits histaminergic neurons in mouse tuberomammillary nucleus slices via potentiating GABAergic transmission onto the neurons at both pre- and postsynaptic sites

“…In the present study, we used whole-cell patch-clamp recordings to examine the effects of ethanol on neurons in slices prepared from the TMN in glutamic acid decarboxylase 67-green fluorescent protein (GAD67-GFP) knock-in mice. GAD67-GFP was used to identify histaminergic neurons because GAD67 is expressed in the histaminergic neurons in the TMN [18] . We found that ethanol suppressed the activity of histaminergic neurons in the TMN by directly hyperpolarizing the membrane potential and by potentiating GABAergic transmission mediated by GABA A receptors and under the tight regulation of GABA B autoreceptors.…”

“…Male GAD67-GFP knock-in mice (weighing 16-20 g, 4-8 weeks old) in which GFP is expressed in GABAergic neurons under the control of the endogenous GAD67 promoter [18,19] were used for electrophysiological and immunohistochemical studies. Mice were maintained in the Laboratory Animal Center of Fudan University.…”

“…Coronal brain slices (250 µm thick) containing the TMN were prepared as described previously [18] . Briefly, the GAD67-GFP mice were anesthetized using isoflurane and killed by decapitation.…”

“…Thereafter, frozen sections were cut at 30 μm in coronal planes using a freezing microtome (Leica Microsystems, Wetzlar, Germany). Immunohistochemistry was performed in accordance with the free-floating method described previously [18,23] . In general, the sections were incubated with rabbit anti-histidine decarboxylase (HDC) antibody (1:800; Progen, Germany) for 24 h on a rotary shaker at 4 °C.…”

Systems Pharmacology Based Study of the Molecular Mechanism of SiNiSan Formula for Application in Nervous and Mental Diseases

“…Many pharmacological researches have reported liquiritigenin (GC12, 67.9%, 0.18), naringenin (GC16, 53.00%, 0.21), kaempferol (SY12, 42.06%, 0.24), and formononetin (GC6, 68.33%, 0.21) have many clinical indications, such as antidepressant-like effect [25, 26] and attenuating Alzheimer's-like learning in memory deficits [27, 28]. In addition, paeoniflorin (SY26, 32.07%, 0.40) has significant sedative effect, hypnotic effect, and promoting nonrapid eye movement sleep effect as the function of regulating sleep disorder [29, 30]. Then, we found that Licochalcone A (GC8, 42.78%, 0.29), Licochalcone B (GC27, 75.13%, 0.26), neohesperidin (ZS8, 61.75, 0.27), and glycyrrhizic acid (GC32, 31.78%, 0.55) which are contained in Radix Glycyrrhizae and Immature Bitter Orange have the anti-inflammatory and antioxidant function.…”