Elsevier

European Journal of Pharmacology

Volume 853, 15 June 2019, Pages 220-228
European Journal of Pharmacology

Behavioural pharmacology
Dihydromyricetin ameliorates memory impairment induced by acute sleep deprivation

https://doi.org/10.1016/j.ejphar.2019.03.014Get rights and content

Abstract

Dihydromyricetin (DHM), the major bioactive flavonoid ingredient extracted from the leaves of Ampelopsis grossedentata (Hand.-Mazz) W.T. Wang displays multiple pharmacological activities, including oxidation resistance, anti-tumour properties and free radical scavenging capacities. However, the role of DHM in sleep deprivation (SD)-induced memory impairments and its underlying molecular mechanisms are unclear. The aim of the present study was to evaluate the effects of DHM on oxidative stress and its role in ameliorating memory impairment induced by acute SD. DHM (100, 50, 25 mg/kg) and melatonin (10 mg/kg) were administered to mice via oral gavage. The open field test was used to evaluate motor function. Spatial learning and memory were assessed using the Morris water maze task. Malondialdehyde, glutathione, and glutathione disulfide levels, as well as superoxide dismutase enzyme activity, were assessed to determine the level of oxidative stress. In addition, we employed quantitative real-time PCR assays to examine the gene expression of 29 key proteins, including protein kinase A (PKA), cAMP response element binding protein (CREB), and adcy1. The levels of proteins including those of GABABRS, GABAARα5, GluR1, BDNF and PSD95, were detected by western blotting. The results showed that DHM significantly attenuated SD-induced spatial learning and memory impairments (P < 0.01). The possible underlying mechanisms of DHM may be attributed to its ability to reduce oxidative stress and restore synaptic plasticity.

Introduction

Modern fast-paced lifestyles and the sustained stress of professional commitments in current society often disrupt normal sleep. Knutson et al. investigated trends in the prevalence of short sleep (defined as < 6 h sleep/night) and concluded that nearly 30% of full-time workers were short sleepers over the investigated period (Knutson et al., 2010). In other words, sleep deprivation (SD) occurs frequently. SD occurs when an individual fails to conform to the mean sleep time and generally sleeps for less than 6 h a day (Havekes et al., 2012). Numerous epidemiological and laboratory studies have indicated that memory consolidation is more susceptible to the effects of SD than to the effects of physical disorders such as diabetes, obesity, and hypertension (Gais and Born, 2004, Rasch and Born, 2013). This result is also suggested by the fact that SD has been shown to impair hippocampus-dependent learning and memory (Park et al., 2008, Silber et al., 2007, Yun et al., 2010), an effect that may be linked to the alteration of the key signalling molecules associated with memory consolidation and synaptic plasticity (Monsey et al., 2011, Steward and Worley, 2002).

Pharmacological interventions, such as modafinil, caffeine, and donepezil, are often the first choice for improving the adverse effects of SD. However, the use of these drugs has been linked to such side effects as memory loss, disorientation, habituation, and daytime fatigue (Magnuson et al., 1998, Pallarés et al., 2013, Sadzuka et al., 2010, Smith, 2003, Tanaka et al., 2009). Ampelopsis grossedentata (Hand.-Mazz) W.T. Wang is a traditional caffeine-free tea that works globally to promote health and improve sleep quality. The leaves of this plant are rich in polyphenols and flavonoids, and the main compound is dihydromyricetin (DHM; also called Ampelopsin) (Gui-Xia et al., 2004, Xiong et al., 2001). DHM has been reported to display multiple pharmacological activities, such as anti-inflammatory, antimicrobial, anti-hypertensive, antioxidative, hepatoprotective, and anti-carcinogenic effects (Chen et al., 2015, Chen et al., 2012, Shi et al., 2015, Wang et al., 2016). Our previous research showed that DHM can protect PC12 cells from oxidative stress (Jiang et al., 2014). In addition, recent studies have reported that DHM treatment not only improves symptoms but also reverses the progressive neuropathology in mouse models of Alzheimer's disease (AD), including reducing Aβ peptides, while restoring gephyrin levels, GABAergic transmission and functional synapses (Liang et al., 2014a, Liang et al., 2014b, Shen et al., 2012). Another study confirmed that DHM is a promising candidate medication for alcohol use disorders that competitively inhibits BZ-site [3H]flunitrazepam binding (IC50, 4.36 μM), suggesting that DHM interaction with EtOH involves the BZ sites on GABAARs (Liang et al., 2014a, Liang et al., 2014b, Shen et al., 2012). However, to the best of our knowledge, the effects of DHM on memory impairment induced by SD have not yet been studied.

The exact mechanism underlying the learning and memory impairment induced by SD is still unknown. In general, it is believed that SD enhances oxidative stress in various brain regions, especially in the hippocampus, which may be caused by the generation of reactive oxygen species (ROS) and by changes in brain-derived neurotrophic factor (BDNF) (Yirmiya and Goshen, 2011). Thus, this oxidative damage to different brain regions complicates long-term potentiation (LTP) and results in memory deficits (Fukui et al., 2002, Jhoo et al., 2004). It is well known that deficiency in BDNF-related hippocampal gene expression impairs hippocampus-dependent learning (Heldt et al., 2007).

Thus, the present study aimed to explore the potential neuroprotective effects of DHM. The results indicated that the administration of DHM significantly restored SD-induced memory impairments. We further demonstrated that its mechanism of action may be attributed to its ability to reduce oxidative stress and restore synaptic plasticity.

Section snippets

Animals and administration

Seventy-two male Institute of Cancer Research (ICR) mice (6–8 weeks, 25–30 g) were purchased from the Vital River Laboratory Animal Technology Co., Ltd., Beijing, China. Mice were housed at (23 ± 2) °C under a 12-h light and dark cycle and were allowed free access to food and water. All animal care procedures and interventions were performed in accordance with the guidelines and policies for animal surgery under the control of the Chinese Academy of Medical Sciences and Peking Union Medical

DHM promotes recovery from SD-induced memory impairment

The results of the OFT showed that there were no significant differences in the motor function and exploration behaviours of the animals in the DHM100, DHM50, DHM25, and MTG groups (P > 0.05, Fig. 2).

We examined the effects of DHM and melatonin administration on experimental SD in a mouse model. As Fig. 3A and B show, there were no significant differences in the total distance travelled or the average speed across all groups, indicating that SD, DHM and melatonin did not affect the motor

Discussion

The results of the present study showed that DHM significantly attenuated SD-induced memory impairments. DHM elicited potent neuroprotective effects against SD-induced lesions in the hippocampus. Accordingly, our data demonstrated that DHM reduced oxidative stress and maintained synaptic plasticity, both of which may contribute to these neuroprotective effects.

Previous reports have shown that DHM exhibits powerful antioxidative effects (Hou et al., 2015a, Hou et al., 2015b, Jiang et al., 2014)

Author contributions

J.M., L.X. and P.X. conceived and designed the experiments; H.L. performed the experiments and wrote the paper; X.S. and F.Y. analysed the data.

Funding

This work was supported by the National Natural Science Foundation of China (No. 81573576), the CAMS Innovation Fund for Medical Sciences (CIFMS 2016-I2M-2-003) and Guangxi Science and Technology Foundation and Talents Project (Gui Ke AD17129044).

Conflicts of interest

The authors declare that they have no conflict of interest.

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