LC-MS/MS analysis of Shenghui decoction component and its effect on learning and memory and neuroprotection in sleep deprivation model mice.

BACKGROUND: In recent years, sleep problems have emerged as a significant factor in the development of diseases that influence cognitive function. The inflammatory response may have a role in the neurobiological processes of sleep deprivation, resulting in impairment of memory and learning. Shenghui Decoction (SHD) is a classic formula in Chinese medicine used to treat forgetfulness and insomnia. However, it remains unclear whether the anti-inflammatory effects of SHD are specifically linked to the inhibition of P2X7R and p38MAPK. METHODS: Analysis of chemical constituents of Shenghui Decoction based on UPLC-Q-TOF-MS / MS. The learning and memory competency of the mice was assessed using the new object recognition and Morris water maze tests. The morphology of hippocampus neurons was observed using HE staining, and the expression of inflammatory factors was measured using ELISA and immunofluorescence. The expression of P2X7R and p38MAPK in the hippocampus was analyzed via real-time PCR and Western blotting. Additionally, the components absorbed into the bloodstream of SHD were analyzed. RESULTS: The study found that SHD contains 47 chemical constituents, including phenolic acids, flavonoids, iridoids, and triterpenoids. In addition, it was observed that SHD significantly improved the learning and memory abilities of the mice. SHD also improved the morphology of hippocampus neurons. The expression of inflammatory factors was decreased in the SHD-treated mice. Additionally, the expression of P2X7R and p38MAPK was decreased in the hippocampus of the SHD-treated mice. Fifteen prototype chemical constituents were detected in blood. CONCLUSIONS: The study suggests that SHD could be a viable treatment for cognitive impairments associated with brain inflammation. The therapeutic effects of SHD are likely due to its chemical components, including phenolic acids, flavonoids, iridoids, and triterpenoids. SHD can improve learning and memory impairment caused by sleep deprivation through the P2X7R/p38MAPK inflammatory signaling pathways.

Single dose creatine improves cognitive performance and induces changes in cerebral high energy phosphates during sleep deprivation.

The inverse effects of creatine supplementation and sleep deprivation on high energy phosphates, neural creatine, and cognitive performances suggest that creatine is a suitable candidate for reducing the negative effects of sleep deprivation. With this, the main obstacle is the limited exogenous uptake by the central nervous system (CNS), making creatine only effective over a long-term diet of weeks. Thus far, only repeated dosing of creatine over weeks has been studied, yielding detectable changes in CNS levels. Based on the hypothesis that a high extracellular creatine availability and increased intracellular energy consumption will temporarily increase the central creatine uptake, subjects were orally administered a high single dose of creatinemonohydrate (0.35 g/kg) while performing cognitive tests during sleep deprivation. Two consecutive 31P-MRS scans, 1H-MRS, and cognitive tests were performed each at evening baseline, 3, 5.5, and 7.5 h after single dose creatine (0.35 g/kg) or placebo during sub-total 21 h sleep deprivation (SD). Our results show that creatine induces changes in PCr/Pi, ATP, tCr/tNAA, prevents a drop in pH level, and improves cognitive performance and processing speed. These outcomes suggest that a high single dose of creatine can partially reverse metabolic alterations and fatigue-related cognitive deterioration.

The effect of 24-hour sleep deprivation and anaerobic exercise on the expression of BAX, BCL2, BMAL1 and CCAR2 genes in peripheral blood mononuclear cells after L-arginine supplementation.

Sleep deprivation disrupt the circadian clock and exercise performance. Defective oxidative stress caused by sleep deprivation may affect the expression of genes involved in cell apoptosis. Since a number of studies have shown the anti-apoptotic effect of L-arginine, so the aim of this study was to evaluate the effect of eight weeks of L-arginine supplementation on the expression of brain and muscle ARNT-like protein 1 (BMAL1), cell cycle and apoptosis regulator 2 (CCAR2), and BAX and BCL2 genes during sleep deprivation and acute anaerobic exercise. Participants included 20 healthy men age 26-35 years, randomized into the L-arginine intervention group (n = 10) and a placebo control (n = 10). The running-based anaerobic sprint test (RAST) was used for anaerobic exercise. Intervention subjects took one 1000 mg L-arginine tablet daily for 8 weeks. The Real-Time PCR method was used to determine apoptosis gene expression in peripheral blood mononuclear cells (PBMCs). Acute anaerobic exercise and sleep deprivation both increased the expression of BAX and CCAR2 genes, and decreased the expression of BCL2 and BMAL1 genes (p < 0.05 for all). L-arginine supplementation increased the expression of BMAL1 and BCL2 genes and decreased the expression of BAX and CCAR2 genes relative to control (p < 0.05). L-Arginine controlled the increase in expression of BAX and CCAR2 genes and the decrease in expression of BCL2 and BMAL1 genes in response to sleep deprivation and acute anaerobic exercise (p < 0.05). Our results showed that 24-hour sleep deprivation and acute anaerobic exercise increased the expression of pro-apoptotic genes (BAX and CCAR2) and decreased the expression of anti-apoptotic genes (BCL2 and BMAL1), although the effect of sleep deprivation is greater. In this situation, L-arginine supplementation may balance the apoptotic state of peripheral blood mononuclear cells. However, any recommendation about this needs further research.

Anandamide improves food intake and orexinergic neuronal activity in the chronic sleep deprivation induction model in rats by modulating the expression of the CB1 receptor in the lateral hypothalamus.

Sleep deprivation alters orexinergic neuronal activity in the lateral hypothalamus (LH), which is the main regulator of sleep-wake, arousal, appetite, and energy regulation processes. Cannabinoid receptor (CBR) expression in this area is involved in modulating the function of orexin neurons. In this study, we investigated the effects of endocannabinoid anandamide (AEA) administration on improving food intake and appetite by modulating the activity of orexin neurons and CB1R expression after chronic sleep deprivation. Adult male Wistar rats (200-250 g) were randomly divided into three groups: control + vehicle (Control), chronic sleep deprivation + vehicle (SD), and chronic sleep deprivation +20 mg/kg AEA (SD + A). For SD induction, the rats were kept in a sleep deprivation device for 18 h (7 a.m. to 1 a.m.) daily for 21 days. Weight gain, food intake, the electrical power of orexin neurons, CB1R mRNA expression in hypothalamus, CB1R protein expression in the LH, TNF-α, IL-6, IL-4 levels and antioxidant activity in hypothalamus were measured after SD induction. Our results showed that AEA administration significantly improved food intake (p < 0.01), Electrical activity of orexin neurons (p < 0.05), CB1R expression in the hypothalamus (p < 0.05), and IL-4 levels (p < 0.05). AEA also reduced mRNA expression of OX1R and OX2R (p < 0.01 and p < 0.05 respectively), also IL-6 and TNF-α (p < 0.01) and MDA level (p < 0.05) in hypothalamic tissue. As a consequence, AEA modulates orexinergic system function and improves food intake by regulating the expression of the CB1 receptor in the LH in sleep deprived rats.

Sleep-wake patterns are altered with age, Prdm13 signaling in the DMH, and diet restriction in mice.

Old animals display significant alterations in sleep-wake patterns such as increases in sleep fragmentation and sleep propensity. Here, we demonstrated that PR-domain containing protein 13 (Prdm13)+ neurons in the dorsomedial hypothalamus (DMH) are activated during sleep deprivation (SD) in young mice but not in old mice. Chemogenetic inhibition of Prdm13+ neurons in the DMH in young mice promotes increase in sleep attempts during SD, suggesting its involvement in sleep control. Furthermore, DMH-specific Prdm13-knockout (DMH-Prdm13-KO) mice recapitulated age-associated sleep alterations such as sleep fragmentation and increased sleep attempts during SD. These phenotypes were further exacerbated during aging, with increased adiposity and decreased physical activity, resulting in shortened lifespan. Dietary restriction (DR), a well-known anti-aging intervention in diverse organisms, ameliorated age-associated sleep fragmentation and increased sleep attempts during SD, whereas these effects of DR were abrogated in DMH-Prdm13-KO mice. Moreover, overexpression of Prdm13 in the DMH ameliorated increased sleep attempts during SD in old mice. Therefore, maintaining Prdm13 signaling in the DMH might play an important role to control sleep-wake patterns during aging.

Chinese traditional formula Kaixin San suppressed ferroptosis of hippocampal neurons and cardiomyocytes in mice with paradoxical sleep deprivation.

ETHNOPHARMACOLOGICAL RELEVANCE: Kaixin San (KXS) is one of the most famous traditional Chinese formulas prescribed by Sun Simiao in 652 Christian era. It is composed of Panax ginseng C.A.Mey, Polygala tenuifolia, Poria cocos and Acorus calamus var. angustatus Besser. KXS is widely used for the treatment of emotion-thought disease, such as settling fright, quieting the spirit and nourishing the heart. However, whether KXS benefits hippocampal neurons and myocardial cells of mice impaired by paradoxical sleep deprivation (PSD) and its mechanism remains unclear. AIM OF THE STUDY: This study was aimed to investigate the effect of KXS on hippocampal neuron and cardiac ferroptosis in rapid-eye-movement (REM) sleep deprived mice and clarify its potential mechanism. MATERIALS AND METHODS: PSD was induced by a modified multi-platform method. Morris water maze (MWM) was used to detect the ability of learning and memory. Cardiac morphological changes were assessed by hematoxylin and eosin (HE) staining. Heart rate was detected by a PowerLab multichannel physiological recorder. Serum levels of atrial natriuretic peptide (ANP) and lactate dehydrogenase (LDH) were measured with biochemical kits. Transmission electron microscopy (TEM), immunofluorescent, and Western blotting analysis were used to observe the process and pathway of ferrotosis in hippocampus tissue and heart tissue of PSD mice. RESULTS: KXS administration improved the impaired learning and memory of PSD mice. It prevented the damage of mitochondria in the hippocampus and heart of PSD mice. KXS also alleviated the myocardial injury, such as morphological damage, abnormal heart rate, serum ANP, and serum LDH induced by PSD. Further study disclosed that KXS reversed the expressions of proteins involved in ferroptosis such as TFRC, SLC7A11/xCT, GPX-4, ACSL4, and FTH1 in hippocampus and heart tissues. CONCLUSIONS: KXS improved learning and memory of mice with REM sleep deprivation, which was closely associated with suppressed ferroptosis in hippocampal neurons and myocardiocytes.

Melatonin protects against body weight gain induced by sleep deprivation in mice.

Sleep deprivation is an epidemic phenomenon in modern society. Lack of sleep has been shown to result in metabolic and endocrine disorders that predispose to obesity and other chronic metabolic diseases. Melatonin is a sleep-related neurohormone and affected by the circadian rhythm and light/dark cycles. Melatonin has recently been used to ameliorate diet-induced or night light-induced energy metabolic imbalance. However, the effect of melatonin on sleep deprivation-induced obesity has been poorly characterized. This study focuses on the protective effects of melatonin on lipid metabolism and body weight homeostasis in sleep-deprived mice. Mice subjected to sleep deprivation had significantly decreased plasma melatonin content and increased food intake and body weight gain compared to that of control. Meanwhile, the transcription factor PPARγ protein in liver increased, but there were no significant changes in hepatic circadian proteins BMAL1 and REV-ERBα after 10 consecutive days of sleep deprivation. Moreover, melatonin supplementation increased liver AMPKα/PPARα signaling pathway activity, which leads to lipid catabolism and reduced fat accumulation. These findings suggested that melatonin may be a potential agent for protecting against sleep deprivation-induced obesity.

Brassica rapa L. (Tibetan turnip) prevents sleep-deprivation induced cognitive deficits via the inhibition of neuroinflammation and mitochondrial depolarization.

Brassica rapa L., an edible, feeding and medicinal plant cultivated on the Tibetan plateau with altitudes above 3800 m, has several pharmacological effects. However, its therapeutic effects against memory impairment and central fatigue have yet to be conclusively established. In this study, the Y-maze and Morris water maze tasks revealed that Brassica rapa L. aqueous extract (BE) significantly ameliorated cognitive deficits of sleep deprivation (SD)-treated mice. Moreover, BE treatment partially alleviated SD-induced reductions in the levels of peripheral energy metabolism, and significantly decreased inflammatory factor levels in serum and hippocampus. In addition, BE treatment significantly relieved central fatigue and stabilized the excitability as well as activities of neurons by regulating the levels of hypothalamus tryptophan metabolites and striatum neurotransmitters. The neuroprotective effects of BE were also confirmed using glutamate-treated HT22 cells, whereby BE pretreatment significantly attenuated intracellular ROS production and mitochondrial depolarization via adenosine 5'-monophosphate activated protein kinase/peroxisome proliferators-activated receptors (AMPK/PPAR-γ) signaling pathways. Thus, BE might probably prevent SD-induced learning and memory deficits by inhibiting neuroinflammation and restoring mitochondrial energy metabolism in the hippocampus. These findings imply that BE is a potential complementary therapy for those suffering from deficient sleep or neurometabolic disorders, although this needs verification by prospective clinical studies.

Sleep deprivation affects sex hormones secretion by regulating the expression of the circadian clock gene in the hypothalamus and pituitary via the PI3K/Akt signaling pathway in pregnant rats.

Sleep deprivation (SD) has many deleterious health effects and occurs in more than 70% of pregnant women. However, the changes in sex hormones and relevant mechanisms after SD have not been well clarified. The aim of the present study was to explore the effects of SD on the secretion of sex hormones and the underlying mechanisms. Twelve pregnant Wistar rats were divided into control (CON, n = 6) and SD (n = 6) groups. Pregnant rats in the SD group were deprived of sleep for 18 h, and allowed free rest for 6 h, and then the above procedures were repeated until delivery. The CON group lived in a 12 h light/dark light cycle environment. Estradiol (E2) and progesterone (P4) levels were detected by enzyme-linked immunosorbent assay (ELISA), and the expression of circadian clock genes, Bmal1, Clock and Per2, in hypothalamus and pituitary gland tissues were evaluated by immunohistochemistry (IHC) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The PI3K and Akt phosphorylation levels in the hypothalamic and pituitary tissues were determined by Western blot. The results showed that, compared with the CON group, the SD group exhibited significantly reduced serum E2 and P4 levels, down-regulated Bmal1, Clock and Per2 expression, as well as decreased phosphorylation levels of PI3K and Akt. But there was no significant difference of the total PI3K and Akt protein expression levels between the two groups. These results suggest that SD might affect the expression of the circadian clock genes in the hypothalamus and pituitary via PI3K/Akt pathway, and subsequently regulate the secretion of sex hormones in the pregnant rats, which hints the important roles of SD-induced changes of serum sex hormone levels in the pregnant rats.

Acute Sleep Deprivation-Induced Anxiety and Disruption of Hypothalamic Cell Survival and Plasticity: A Mechanistic Study of Protection by Butanol Extract of Tinospora cordifolia.

Since sleep is a key homeostatic phenomenon of the body, therefore understanding the complex etiology of the neurological outcome of sleep deprivation (SD) such as anxiety, depression, cognitive dysfunctions, and their management is of utmost importance. The findings of the current study encompass the neurobehavioral as well as hormonal, and neuroinflammatory changes in serum and hypothalamus region of the brain as an outcome of acute SD and their amelioration by pre-treatment with butanol extract of Tinospora cordifolia. SD group animals showed anxiety-like behavior as evident from Elevated Plus Maze data and higher serum cortisol levels, whereas, pre-treatment with B-TCE showed anxiolytic activity and also reduced cortisol levels which was corroborated by an increase in leptin and insulin levels. Further, SD induced elevation of serum pro-inflammatory cytokines IL-6, TNF-α, IL-1ß, and MCP-1 and subsequent activation of astroglial cells in the hypothalamus was suppressed in B-TCE pre-treated animals. The current findings suggest that besides the cortical structures, hypothalamus region's synaptic plasticity and cell survival are adversely impacted by acute SD. Further active ingredients present in B-TCE may be useful for the management of SD-induced anxiety, systemic inflammation, and neuroinflammation by targeting hypothalamic BDNF-TrkB/PI3K-Akt pathways.

Xiaoyao Pill Improves the Affective Dysregulation of Sleep-deprived Female Mice by Inhibiting Brain Injury and Regulating the Content of Monoamine Neurotransmitter.

BACKGROUND: Sleep curtailment is a serious problem in many societies. Clinical evidence has shown that sleep deprivation is associated with mood dysregulation, formation of false memory, cardio-metabolic risk factors and outcomes, inflammatory disease risk, and all-cause mortality. The affective disorder dysregulation caused by insufficient sleep has become an increasingly serious health problem. However, to date, not much attention has been paid to the mild affective dysregulation caused by insufficient sleep, and there is no clear and standard therapeutic method to treat it. The Xiaoyao Pill is a classic Chinese medicinal formula, with the effect of dispersing stagnated hepatoqi, invigorating the spleen, and nourishing the blood. Therefore, it is most commonly used to treat gynecological diseases in China. In the present study, the effects of the Xiaoyao Pill on affective dysregulation of sleep-deprived mice and its underlying molecular mechanisms were investigated. METHODS: Forty adult female mice were used in the present study. The sleep deprivation model was established by improving the multi-platform water environment method. After 7 consecutive days of sleep deprivation, the mice were administrated low (LXYP, 0.32mg/kg) and high (HXYP, 0.64 mg/kg) doses of the Xiaoyao Pill for two weeks. Then, the body weight, behavioral deficits, and histopathology were evaluated. Meanwhile, the expression of c-fos protein and the concentrations of monoamine neurotransmitters in the hippocampus and prefrontal cortex were determined after two weeks of treatment. RESULTS: Xiaoyao Pill treatment significantly increased body weight and sucrose consumption and decreased the irritability scores of the sleep-deprived mice. Meanwhile, Xiaoyao Pill treatment prevented brain injury and inhibited the expression of c-fos protein in the hippocampus and prefrontal cortex. In addition, HXYP treatment significantly upregulated the levels of NE in the hippocampus and prefrontal cortex (p < 0.01). LXYP treatment significantly up-regulated the levels of 5-HT in the prefrontal cortex. Meanwhile, both HXYP and LXYP treatment significantly upregulated the levels of DA in the prefrontal cortex (p < 0.05 or p < 0.01) of sleep-deprived mice. CONCLUSION: The present study demonstrates that Xiaoyao Pill treatment prevented the behavioral deficits of mice induced by sleep deprivation by promoting the recovery of brain tissue injury and up-regulating the levels of NE, 5-HT, and DA in the brain tissue.

Butanol Extract of Tinospora cordifolia Alleviates Acute Sleep Deprivation-Induced Impairments in Cognitive Functions and Neuromuscular Coordination in Middle-Aged Female Rats.

Sleep deprivation due to present-day lifestyle and late-hours work commitments are associated with a broad spectrum of neurobehavioral complications. Moreover, women, as they age, become prone to the cumulative effects of menopause such as sleep disturbances, adiposity, and inflammation which are attributed to a compromised immuno-neuro-endocrine axis. So far, no effective therapeutic remedy is available to mitigate the adverse effects of SD. The current study was aimed to elucidate the neuroprotective potential of n-Butanol fraction obtained from hydroalcoholic extract of Tinospora cordifolia stem (B-TCE). Four groups of female rats are (1) Vehicle-undisturbed sleep, (2) Vehicle-sleep deprived (between 6 a.m. and 6 p.m.), (3) B-TCE oral feeding for 2 weeks and sleep deprivation, and (4) B-TCE alone undisturbed sleep group. Novel Object Recognition test was used to study cognitive impairments and Rotarod for motor coordination. Rats were then sacrificed to study the expression of various marker proteins in the hippocampus and piriform cortex regions of the brain by western blotting. SD was observed to impair the exploratory behavior and neuromuscular coordination, whereas, B-TCE pre-treatment was observed to ameliorate these behavioral functions'- impairments and further suppressed the changes in the expression of markers for synaptic plasticity, inflammation, cell survival, and apoptosis pathways. The current data suggest that B-TCE may be effective in the management of acute SD-associated impairments in learning and memory functions and neuromuscular coordination.

Neurogenesis in the rat neonate's hippocampus with maternal short-term REM sleep deprivation restores by royal jelly treatment.

BACKGROUND: Numerous studies have shown the effects of rapid eye movement sleep deprivation (REM-SD) on behavior and brain structures. The impact of REM-SD on learning and memory, thus neurogenesis, has been reported in previous studies. Royal jelly (RJ) is known as the wealthiest biological nutrient with various physiological properties. This study aimed to study the possible effect of RJ on neurogenesis of the rat hippocampus neonates following exposure of mother to REM-SD during pregnancy. METHODS: Thirty neonate rats from 15 pregnant Wistar rats were used. To induce REM-SD, the flowerpot method was used. The pregnant rats were divided into five groups (n = 3): group 1, no treatment; group 2, REM-SD; groups 3, 4, and 5, REM-SD +RJ. The former group received 72 h REM-SD during pregnancy (days 7, 14, 21), and the latter group received REM-SD + RJ (three trial groups). At week 4, the rat neonates of all groups were sacrificed (n = 6 each group). Their brains were fixed, removed, and prepared for Nissl and Hoechst 33342 staining. By using real time polymerase chain reaction methode the brain-derived neurotrophic factor BDNF gene expression was studied (RT-PCR), brain-derived neurotrophic factor (BDNF) gene expression was studied. The results were analyzed statistically, and the Pv  < .05 was considered significant. RESULTS: The results showed a significant decrease in the number of neurons in the hippocampus of neonatal rats of REM-SD mothers compared to the neonates of the mother with REM-SD + RJ. REM-SD also led to an increase in apoptosis reaching the neonates from the REM-SD + RJ animals. High expression of BDNF was observed in the hippocampus of the neonates from REM-SD + RJ treated mothers. CONCLUSION: RJ acts as a neuroprotective agent that could compensate for the effects of REM-SD on learning and memory via restoring neurogenesis.

Antimania-Like Effect of Panax ginseng Regulating the Glutamatergic Neurotransmission in REM-Sleep Deprivation Rats.

Previous studies have shown the therapeutic properties of ginseng and ginsenosides on hyperactive and impulsive behaviors in several psychiatric diseases. Herein, we investigated the effect of Panax ginseng Meyer (PG) on hyperactive/impulsive behaviors in a manic-like animal model, sleep deprivation (SD) rats. Male rats were sleep-deprived for 48 h, and PG (200 mg/kg) was administered for 4 days, from 2 days prior to the start of SD to the end date of SD. The elevated plus maze (EPM) test showed that PG alleviated the increased frequency of entries into and spent time within open arms by SD. In order to investigate the molecular mechanism on this effect of PG, we assessed differentially expressed genes (DEGs) in the prefrontal cortex of PG-treated SD rats using RNA sequencing (RNA-seq) and performed gene-enrichment analysis for DEGs. The gene-enrichment analysis showed that PG most prominently affected the glutamatergic synapse pathway. Among the glutamatergic synapse pathway genes, particularly, PG enhanced the expressions of glutamate transporter Slc1a3 and Slc1a2 reduced in SD rats. Moreover, we found that PG could inhibit the SD-induced phosphorylation of the NR2A subunit of the NMDA receptor. These results suggested that PG might have a therapeutic effect against the manic-like behaviors, regulating the glutamatergic neurotransmission.

Sleep deprivation aggravated lipopolysaccharide/D-galactosamine-induced acute liver injury by suppressing melatonin production.

OBJECTIVE: Sleep loss is common in patients with liver injury, but the effects of sleep deprivation (SD) on liver injury remain unclear. In the present study, the potential effects of SD on acute liver injury and the underlying mechanisms have been investigated. METHODS: The sleep of male BALB/c mice has been deprived by using a modified multiple platform water bath for 3 days and acute liver injury was induced by intraperitoneal injection of lipopolysaccharide (LPS) and D-galactosamine (D-Gal). The degree of liver injury was detected by aminotransferase determination, histopathology and survival rate analysis. Inflammatory response and melatonin (MT) were measured by enzyme-linked immunosorbent assay (ELISA). In addition, hepatocyte apoptosis was determined by caspase activity measurement and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. RESULTS: We observed that SD increased plasma aminotransferases, TUNEL-positive hepatocytes, histological abnormalities and mortality rates in mice with LPS/D-Gal treatment. SD also promoted LPS/D-Gal-induced production of TNF-α and upregulated hepatic caspase-8, caspase-9, and caspase-3 activities in LPS/D-Gal-exposed mice. In addition, SD significantly decreased MT contents in plasma of mice with acute liver injury, but supplementation with MT reversed these SD-promoted changes. CONCLUSION: Our data suggested that SD exacerbated LPS/D-Gal-induced liver injury via decreasing melatonin production.

Corilagin ameliorates sleep deprivation-induced memory impairments by inhibiting NOX2 and activating Nrf2.

Sleep deprivation (SD) can induce cognitive and memory impairments. This impairment is in part due to oxidative stress damage in the hippocampus region of the brain. Corilagin (CL), a polyphenol belonging to the tannin family and extracted from Terminalia chebula and Phyllanthus emblica, shows strong antioxidant and neuroprotective effects. NF-E2-related factor (Nrf2)/heme oxygenase-1 (HO-1) and NADPH oxidase (NOX) are critical targets involved in cellular defense mechanisms against oxidative injury. Thus, we hypothesized that CL could be a preventive treatment for SD-induced memory impairments by inhibiting NOX2 and activating Nrf2. The results from behavioral tests showed that administration of CL resulted in significantly better performance compared to the SD mice. CL significantly normalized the elevated MDA level and the reduced activity of GPx and SOD (P <0.05, p<0.01) caused by SD. In hippocampal tissues, CL effectively activated Nrf2/HO-1 signaling and downregulated NOX2 protein expression compared with SD (P <0.05, P <0.01). Meanwhile, in vitro findings showed that knockdown of Nrf2 blocked the protective effect of CL versus Glu-induced toxicity, while the effect of CL was enhanced in NOX2 siRNA-transfected neurons. Overall, these findings provided evidence that CL ameliorates SD-induced memory impairments in mice by inhibiting NOX2 and activating Nrf2.

Tea polyphenols protect learning and memory in sleep-deprived mice by promoting AMPA receptor internalization.

Chronic sleep loss caused lots of health problems, also including cognition impairment. Tea is one of the most popular drinks when people stay up late. Nevertheless, the effects of tea on sleep deprivation-induced cognition impairment are still unclear. In the present study, we found 24-h sleep deprivation (S-DEP) increased membrane α-amino-3-hydroxy-5-methyl-4-isoxa-zolep-propionate (AMPA) receptor level through a tumor necrosis factor α (TNFα)-dependent pathway in hippocampi. Blocking elevated TNFα level can protect S-DEP mice from impaired learning ability according to behavioral test. Tea polyphenols, major active compounds in green tea, suppressed TNFα production through downregulating TNFα converting enzyme (TACE) level. Meanwhile, tea polyphenols treatment could ameliorate recognition impairment and anxiety-like behaviors in S-DEP mice. The aforementioned results demonstrate cognition protective effects of tea polyphenols in S-DEP mice model, which provide a theoretical basis for the treatments of S-DEP-induced cognition impairment by targeting the TACE/TNFα/AMPA pathway.

Dynamics of Cortical Local Connectivity during Sleep-Wake States and the Homeostatic Process.

Sleep exerts modulatory effects on the cerebral cortex. Whether sleep modulates local connectivity in the cortex or only individual neural activity, however, is poorly understood. Here we investigated functional connectivity, that is, covarying activity between neurons, during spontaneous sleep-wake states and during and after sleep deprivation using calcium imaging of identified excitatory/inhibitory neurons in the motor cortex. Functional connectivity was estimated with a statistical learning approach glasso and quantified by "the probability of establishing connectivity (sparse/dense)" and "the strength of the established connectivity (weak/strong)." Local cortical connectivity was sparse in non-rapid eye movement (NREM) sleep and dense in REM sleep, which was similar in both excitatory and inhibitory neurons. The overall mean strength of the connectivity did not differ largely across spontaneous sleep-wake states. Sleep deprivation induced strong excitatory/inhibitory and dense inhibitory, but not excitatory, connectivity. Subsequent NREM sleep after sleep deprivation exhibited weak excitatory/inhibitory, sparse excitatory, and dense inhibitory connectivity. These findings indicate that sleep-wake states modulate local cortical connectivity, and the modulation is large and compensatory for stability of local circuits during the homeostatic control of sleep, which contributes to plastic changes in neural information flow.

Dietary intake of polyunsaturated fatty acids alleviates cognition deficits and depression-like behaviour via cannabinoid system in sleep deprivation rats.

Sleep deprivation (SD) is a common feature in modern society. Prolonged sleep deprivation causes cognition deficits and depression-like behavior in the model of animal experiments. Endocannabinoid system are key modulators of synaptic function, which were related to memory and mood. Although the underlying mechanism remains unknown, several studies indicated the benefits of polyunsaturated fatty acids (PUFAs, linolenic acid, 39.7 %; linoleic acid, 28 %; and oleic acid, 22 %) on brain function through the endocannabinoid system. The present study aimed to evaluate the influence of dietary PUFAs on cognition deficits induced by sleep deprivation in Sprague Dawley rats. The rats were sleep deprivation continuously for 7 days and fed with PUFAs at three different dosages (2, 4 and 8 µl/g body weight) at the meantime. The effect of PUFAs on cognition was investigated by object recognition test while depressive-like behavior were detected using sucrose preference test and forced swim test. The mechanism of PUFAs was elucidated by hippocampal synaptic transmission analyses. The resluts revealed that SD led to the disorder of cognition and mood which was improved by the supplement of PUFAs. SD significantly increased the mEPSC frequency, and decreased the protein level of cannabinoid type-1 receptors (CB1R). These changes were restored by supplement of PUFAs, which showed a similar level to the control group. Behaviour tests showed that the positive effects on repairing cognition and anxiety disorders were almost completely abolished when the CB1R receptor antagonist rimonabant was applied to the SD rats. These findings indicated that PUFAs are a factor regulating cognition deficits and depression induced by SD via cannabinoid type-1 receptors.

Protective effects of Hydrocotyle umbellata var. bonariensis Lam. (Araliaceae) on memory in sleep-impaired female mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Hydrocotyle umbellata var.bonariensis Lam. (Hb), popularly known in Brazil as acariçoba and outside Brazil Hb by a number of names including marsh-pennywort, and many-flower, has traditionally been used in Ayurvedic medicine in the retardation of aging (Rasayana effect). AIM OF THE STUDY: The present study evaluated the effect of Hb treatment before and during paradoxical sleep deprivation (PSD) and sleep restriction (SR) on learning, memory, and acetylcholinesterase (AChE) brain activity. MATERIAL AND METHODS: Adult Swiss nulliparous female mice were randomly distributed among the experimental groups. The treated groups received the aqueous solution of Hb leaves orally at concentrations of 500 and 1.000 mg/kg. PSD and SR were induced by the multiple platform method, in which the animals remained for 3-days in PSD or 15-days in SR for 22 h per day. The collection of the vaginal epithelium occurred daily to determine the estrous cycle. Body mass gain was determined. The animals were submitted to the passive avoidance test and were then euthanized for the collection of brain tissue and the determination of cerebral cholinesterase activity. RESULTS: The aqueous solution of Hb was associated with a significant reduction in cholinesterase activity at both doses in the SR model, and at the dose of 1.000 mg/kg in the PSD model. Regarding the learning and memory test, the PSD group treated with 1.000 mg/kg presented significant improvement, whereas in the SR experiment none of the treated-groups showed any improvement in learning and memory. In the analysis of SR/PSD interference and/or Hb treatment on the estrous cycle, it was possible to observe that the treatment acted as a protector in the SR group, maintaining a normal cycle. CONCLUSIONS: The analyses showed that Hb was safe to use during periods of SR or PSD, acting as an adaptogen for these situations, in addition to being able to reduce cholinesterase activity, which suggests its neuroprotective action. In relation to the estrous cycle, Hb can act as a protector in SR situations.