Antipsychotic-induced epigenomic reorganization in frontal cortex of individuals with schizophrenia.

Genome-wide association studies have revealed >270 loci associated with schizophrenia risk, yet these genetic factors do not seem to be sufficient to fully explain the molecular determinants behind this psychiatric condition. Epigenetic marks such as post-translational histone modifications remain largely plastic during development and adulthood, allowing a dynamic impact of environmental factors, including antipsychotic medications, on access to genes and regulatory elements. However, few studies so far have profiled cell-specific genome-wide histone modifications in postmortem brain samples from schizophrenia subjects, or the effect of antipsychotic treatment on such epigenetic marks. Here, we conducted ChIP-seq analyses focusing on histone marks indicative of active enhancers (H3K27ac) and active promoters (H3K4me3), alongside RNA-seq, using frontal cortex samples from antipsychotic-free (AF) and antipsychotic-treated (AT) individuals with schizophrenia, as well as individually matched controls (n=58). Schizophrenia subjects exhibited thousands of neuronal and non-neuronal epigenetic differences at regions that included several susceptibility genetic loci, such as NRG1, DISC1, and DRD3. By analyzing the AF and AT cohorts separately, we identified schizophrenia-associated alterations in specific transcription factors, their regulatees, and epigenomic and transcriptomic features that were reversed by antipsychotic treatment; as well as those that represented a consequence of antipsychotic medication rather than a hallmark of schizophrenia in postmortem human brain samples. Notably, we also found that the effect of age on epigenomic landscapes was more pronounced in frontal cortex of AT-schizophrenics, as compared to AF-schizophrenics and controls. Together, these data provide important evidence of epigenetic alterations in the frontal cortex of individuals with schizophrenia, and remark for the first time on the impact of age and antipsychotic treatment on chromatin organization.

Air pollution exposure increases ABCB1 and ASCT1 transporter levels in mouse cortex.

Membrane transporters are important for maintaining brain homeostasis by regulating the passage of solutes into, out of, and within the brain. Growing evidence suggests neurotoxic effects of air pollution exposure and its contribution to neurodegenerative disorders, including Alzheimer's disease (AD), yet limited knowledge is available on the exact cellular impacts of exposure. This study investigates how exposure to ubiquitous solid components of air pollution, ultrafine particles (UFPs), influence brain homeostasis by affecting protein levels of membrane transporters. Membrane transporters were quantified and compared in brain cortical samples of wild-type and the 5xFAD mouse model of AD in response to subacute exposure to inhaled UFPs. The cortical ASCT1 and ABCB1 transporter levels were elevated in wild-type and 5xFAD mice subjected to a 2-week UFP exposure paradigm, suggesting impairment of brain homeostatic mechanisms. This study provides new insight on the molecular mechanisms underlying adverse effects of air pollution on the brain.

The neuropeptide cycloprolylglycine produces antidepressant-like effect and enhances BDNF gene expression in the mice cortex.

BACKGROUND: Cycloprolylglycine (CPG) is an endogenous dipeptide with a wide range of psychotropic activity and putative therapeutic potential for depression. A small but growing body of data suggests that antidepressant-like effect of CPG is associated with neuroplastic changes in the brain or 5-HT system modulation. However, the mechanisms of the dipeptide action remain elusive. AIMS: Here, we characterize the effects of chronic CPG administration on behavior and genes expression of antidepressants sensitive catalepsy (ASC) mice strain, characterized by depressive-like behavior. METHODS: ASC mice were injected with saline, fluoxetine (10 mg/kg/day), or CPG (1 and 2 mg/kg/day) during 2 weeks. Behavior was studied using the open field test, novel object test, elevated plus maze test, forced swim test, and tail suspension test (TST). The expressions of genes coding BDNF, CREB, 5-HT1A and 5-HT2A receptors, TPH2, and SERT in the brain were measured with quantitative real-time reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Chronic intraperitoneal administration of 1 and 2 mg/kg of CPG revealed the significant antidepressant-like effect by decreasing immobility time in the TST. At the same time, CPG did not negatively affect locomotor activity, cognition, or anxiety. In the real-time quantitative polymerase chain reaction (PCR) assay, chronic CPG treatment (2 mg/kg for 14 days) increased Bdnf mRNA level in the frontal cortex. CONCLUSIONS: Our findings extend the evidence for the effectiveness of CPG to reduce depressive-like behaviors. The antidepressant-like effect of CPG is mediated, as least in part, by BDNF-dependent mechanism. The exact mechanism remains to be elucidated, and further studies are warranted.

Evaluation of efficiency omega 3 fatty acid improves the behavioural phenotype and protects against oxidative stress against MPP+ induces Parkinson's disease in mice.

This experiment proposed to study the efficiency omega 3 fatty acid on behavioural phenotype of Parkinson's disease (PD) in mice. Totally 7 groups (each group 6 mice) were used in this assessment, each groups were treated with saline (control), MPP+, L-DOPA, Omega 3 oil, Omega 3 oil (three different concentrations) +MPP+ separately. The behavioral assessments such as bar test, open field test, maze test, hang test were noted on 7th, 14th, 21st and 28th day. After the examination period, the tested animals' midbrains and frontal cortex were dissected to analyze TBARS, GSH, Catalase, Superoxide Dismutase and Glutathione Peroxidase assay. In the bar test, 500mg omega 3 fatty acid administrated mice showed a high cataleptic scores. In open field Test, significant reductions in behavior analysis were observed from the tested mice group. Maze test and hang test doesn't show much difference. In biochemical test, tested groups showed promising results compared to control group. The result strongly proved that the omega 3 fatty acid has remarkable abilities to control the neurodegenerative diseases.

Peri- and intraoperative EEG signatures in newborns and infants.

OBJECTIVE: The electroencephalographic derived indices have been developed for adult patients, however these monitors have not been validated for infants. METHODS: Frontal EEGs were recorded in 115 infants aged <1 year [0-3-months (N = 27), 4-6-months (N = 30), 7-9-months (N = 29) and 10-12-months (N = 29)] who received general anaesthesia with sevoflurane. Total power (µV2) and relative ß-, α-, θ-, δ-power (%) were analyzed. Additionally, in 20 EEGs event marker were added (baseline, loss of consciousness, intraoperative situation, extubation) to assess perioperative EEG dynamics. RESULTS: Newborns show a mean relative δ-power at 80% in intraoperative EEG compared to infants (10-12 months) showing 47.5%. Relative ß-power and α-power are low in newborns (mean 3.2% and 4.6%; respectively), with a marked increase in the older infants (4-6 months) (mean 10.9% and 14.4%; respectively). EEG dynamic in newborns from baseline (relative δ-power of 88%) to the intraoperative situation (80.5%) are discrete. In contrast infants >6-months have a strong reduction of relative δ-power from baseline to the intraoperative situation, which corresponds to an increase of faster frequencies. CONCLUSIONS: Age dependent perioperative EEG signatures can be demonstrated in infants younger than one year. SIGNIFICANCE: We demonstrate significant differences in EEG readouts between newborns and infants which questions our monitoring systems in paediatric anaesthesia.

Prolonged epigenomic and synaptic plasticity alterations following single exposure to a psychedelic in mice.

Clinical evidence suggests that rapid and sustained antidepressant action can be attained with a single exposure to psychedelics. However, the biological substrates and key mediators of psychedelics' enduring action remain unknown. Here, we show that a single administration of the psychedelic DOI produces fast-acting effects on frontal cortex dendritic spine structure and acceleration of fear extinction via the 5-HT2A receptor. Additionally, a single dose of DOI leads to changes in chromatin organization, particularly at enhancer regions of genes involved in synaptic assembly that stretch for days after the psychedelic exposure. These DOI-induced alterations in the neuronal epigenome overlap with genetic loci associated with schizophrenia, depression, and attention deficit hyperactivity disorder. Together, these data support that epigenomic-driven changes in synaptic plasticity sustain psychedelics' long-lasting antidepressant action but also warn about potential substrate overlap with genetic risks for certain psychiatric conditions.

Structural and Functional Brain Imaging in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia Treated With Chemotherapy: A Systematic Review.

Background: The effect of chemotherapy on brain development in long-term survivors of pediatric acute lymphoblastic leukemia (ALL) was systematically reviewed. Methods: A systematic search of Pubmed, Scopus, and PsycINFO databases was conducted to identify articles published between January 2000 and February 2020 that implemented magnetic resonance imaging to assess brain structure and function in pediatric ALL survivors (diagnosed younger than 21 years of age). The review included articles that were published on children diagnosed with ALL between 0 and 21 years of age and treated with chemotherapy-only protocols. Articles meeting the inclusion criteria described survivors on average of 5 years or more from diagnosis and were peer-reviewed articles and original studies. Results: The search yielded 1975 articles with 23 articles meeting inclusion criteria. The review revealed that survivors had statistically significant alterations in brain anatomy, most commonly a smaller hippocampus and impaired microstructural white matter integrity in frontal brain regions. Survivors also had impaired brain function including lower brain network efficiency and altered resting state connectivity. Survivors also displayed widespread reductions in brain activation (ie, frontal, temporal, parietal brain regions) during cognitive tasks. Conclusion: Although the neurotoxic effects of cancer treatment are reduced in the absence of cranial radiation, survivors treated on chemotherapy-only protocols still display long-term alterations in brain structure and function, which contribute to lifelong neurocognitive late effects.

Brain Metabolic Profile after Intranasal vs. Intraperitoneal Clomipramine Treatment in Rats with Ultrasound Model of Depression.

BACKGROUND: Molecular mechanisms of depression remain unclear. The brain metabolome after antidepressant therapy is poorly understood and had not been performed for different routes of drug administration before the present study. Rats were exposed to chronic ultrasound stress and treated with intranasal and intraperitoneal clomipramine. We then analyzed 28 metabolites in the frontal cortex and hippocampus. METHODS: Rats' behavior was identified in such tests: social interaction, sucrose preference, forced swim, and Morris water maze. Metabolic analysis was performed with liquid chromatography. RESULTS: After ultrasound stress pronounced depressive-like behavior, clomipramine had an equally antidepressant effect after intranasal and intraperitoneal administration on behavior. Ultrasound stress contributed to changes of the metabolomic pathways associated with pathophysiology of depression. Clomipramine affected global metabolome in frontal cortex and hippocampus in a different way that depended on the route of administration. Intranasal route was associated with more significant changes of metabolites composition in the frontal cortex compared to the control and ultrasound groups while the intraperitoneal route corresponded with more profound changes in hippocampal metabolome compared to other groups. Since far metabolic processes in the brain can change in many ways depending on different routes of administration, the antidepressant therapy should also be evaluated from this point of view.

Dexmedetomidine does not compromise neuronal viability, synaptic connectivity, learning and memory in a rodent model.

Recent animal studies have drawn concerns regarding most commonly used anesthetics and their long-term cytotoxic effects, specifically on the nervous tissue. It is therefore imperative that the search continues for agents that are non-toxic at both the cellular and behavioural level. One such agent appears to be dexmedetomidine (DEX) which has not only been found to be less neurotoxic but has also been shown to protect neurons from cytotoxicity induced by other anesthetic agents. However, DEX's effects on the growth and synaptic connectivity at the individual neuronal level, and the underlying mechanisms have not yet been fully resolved. Here, we tested DEX for its impact on neuronal growth, synapse formation (in vitro) and learning and memory in a rodent model. Rat cortical neurons were exposed to a range of clinically relevant DEX concentrations (0.05-10 µM) and cellular viability, neurite outgrowth, synaptic assembly and mitochondrial morphology were assessed. We discovered that DEX did not affect neuronal viability when used below 10 µM, whereas significant cell death was noted at higher concentrations. Interestingly, in the presence of DEX, neurons exhibited more neurite branching, albeit with no differences in corresponding synaptic puncta formation. When rat pups were injected subcutaneously with DEX 25 µg/kg on postnatal day 7 and again on postnatal day 8, we discovered that this agent did not affect hippocampal-dependent memory in freely behaving animals. Our data demonstrates, for the first time, the non-neurotoxic nature of DEX both in vitro and in vivo in an animal model providing support for its utility as a safer anesthetic agent. Moreover, this study provides the first direct evidence that although DEX is growth permissive, causes mitochondrial fusion and reduces oxygen reactive species production, it does not affect the total number of synaptic connections between the cortical neurons in vitro.

Real time monitoring of dopamine release evoked by mitragynine (Kratom): An insight through electrochemical sensor.

BACKGROUND: Mitragynine, the major indole alkaloid from Mitragyna speciosa has been reported previously to possess abuse liability. However, there are insufficient data suggesting the mechanism through which this pharmacological agent causes addiction. AIMS: In this study, we investigated the effects of mitragynine on dopamine (DA) level and dopamine transporter (DAT) expression from the rat's frontal cortex. METHODS: DA level was recorded in the brain samples of animals treated with acute or repeated exposure for 4 consecutive days with either vehicle or mitragynine (1 and 30 mg/kg) using electrochemical sensor. Animals were then decapitated and the brain regions were removed, snap-frozen in liquid nitrogen and immediately stored at -80 °C. DA level was quantified using Enzyme linked immunosorbent assay (ELISA) kits and DAT gene expression was determined using quantitative real time polymerase chain reaction (RT-qPCR). RESULTS/OUTCOME: Mitragynine (1 and 30 mg/kg) did not increase DA release following acute treatment, however, after repeated exposure at day 4, mitragynine significantly and dose dependently increased DA release in the frontal cortex. In this study, we also observed a significant increase in DAT mRNA expression at day 4 in group treated with mitragynine (30 mg/kg). CONCLUSION/INTERPRETATION: Data from this study indicates that mitragynine significantly increased DA release when administered repeatedly, increased in DAT mRNA expression with the highest tested dose (30 mg/kg). Therefore, the rewarding effects observed after mitragynine administration could be due to its ability to increase DA content in certain areas of the brain especially the frontal cortex.

Escitalopram Targets Oxidative Stress, Caspase-3, BDNF and MeCP2 in the Hippocampus and Frontal Cortex of a Rat Model of Depression Induced by Chronic Unpredictable Mild Stress.

In recent years, escitalopram (ESC) has been suggested to have different mechanisms of action beyond its well known selective serotonin reuptake inhibition. The aim of this study is to investigate the effects of escitalopram on oxidative stress, apoptosis, brain-derived neurotrophic factor (BDNF), Methyl-CpG-binding protein 2 (MeCP2), and oligodendrocytes number in the brain of chronic unpredictable mild stress-induced depressed rats. The animals were randomised in four groups (8 in each group): control, stress, stress + ESC 5 and stress + ESC 5/10. ESC was administered for 42 days in a fixed dose (5 mg/kg b.w.) or in an up-titration regimen (21 days ESC 5 mg/kg b.w. then 21 days ESC 10 mg/kg b.w.). Sucrose preference test (SPT) and elevated plus maze (EPM) were also performed. ESC improved the percentage of sucrose preference, locomotion and anxiety. ESC5/10 reduced the oxidative damage in the hippocampus and improved the antioxidant defence in the hippocampus and frontal lobe. ESC5/10 lowered caspase 3 activity in the hippocampus. Escitalopram had a modulatory effect on BDNF and the number of oligodendrocytes in the hippocampus and frontal lobe and also improved the MeCP2 expressions. The results confirm the multiple pathways implicated in the pathogenesis of depression and suggest that escitalopram exerts an antidepressant effect via different intricate mechanisms.

Characterization of dopamine D2 receptor coupling to G proteins in postmortem brain of subjects with schizophrenia.

BACKGROUND: Alterations of dopamine D1 (D1R) and D2 receptor (D2R) are proposed in schizophrenia but brain neuroimaging and postmortem studies have shown controversial results in relation to D1R and D2R density. Besides, scarce information on the functionality of brain D1R and D2R is available. The present study characterized G-protein activation by D1R and D2R agonists in postmortem human brain. Furthermore, D2R functional status was compared between schizophrenia and control subjects. METHODS: G-protein receptor coupling was assessed in control caudate nucleus and frontal cortex by [35S]GTPγS-binding stimulation induced by increasing concentrations (10-10-10-3 M) of dopamine, and the selective dopaminergic agonists SKF38393 (D1R) and NPA (D2R). Concentration-response curves to NPA stimulation of [35S]GTPγS binding were analyzed in antipsychotic-free (n = 10) and antipsychotic-treated (n = 7) schizophrenia subjects and matched controls (n = 17). RESULTS: In caudate, [35S]GTPγS-binding responses to agonists were compatible with the existence of functional D2R. In contrast, stimulations in cortex showed responses that did not correspond to D1R or D2R. [35S]GTPγS-binding activation by NPA in caudate displayed biphasic curves with similar profile in schizophrenia (EC50H = 7.94 nM; EC50L = 7.08 µM) and control (EC50H = 7.24 nM; EC50L = 15.14 µM) subjects. The presence or absence of antipsychotic medication did not influence the pharmacological parameters. CONCLUSIONS: Feasibility of functional evaluation of dopamine receptors in postmortem human brain by conventional [35S]GTPγS-binding assays appears to be restricted to signalling through inhibitory Gi/o proteins. These findings provide functional information about brain D2R status in subjects with schizophrenia and do not support the existence of D2R supersensitive in this mental disorder.

Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo.

Psilocybin is a serotonergic psychedelic with untapped therapeutic potential. There are hints that the use of psychedelics can produce neural adaptations, although the extent and timescale of the impact in a mammalian brain are unknown. In this study, we used chronic two-photon microscopy to image longitudinally the apical dendritic spines of layer 5 pyramidal neurons in the mouse medial frontal cortex. We found that a single dose of psilocybin led to ∼10% increases in spine size and density, driven by an elevated spine formation rate. The structural remodeling occurred quickly within 24 h and was persistent 1 month later. Psilocybin also ameliorated stress-related behavioral deficit and elevated excitatory neurotransmission. Overall, the results demonstrate that psilocybin-evoked synaptic rewiring in the cortex is fast and enduring, potentially providing a structural trace for long-term integration of experiences and lasting beneficial actions.

Single Exposure to the Cathinones MDPV and α-PVP Alters Molecular Markers of Neuroplasticity in the Adult Mouse Brain.

Synthetic cathinones have gained popularity among young drug users and are widely used in the clandestine market. While the cathinone-induced behavioral profile has been extensively investigated, information on their neuroplastic effects is still rather fragmentary. Accordingly, we have exposed male mice to a single injection of MDPV and α-PVP and sacrificed the animals at different time points (i.e., 30 min, 2 h, and 24 h) to have a rapid readout of the effect of these psychostimulants on neuroplasticity in the frontal lobe and hippocampus, two reward-related brain regions. We found that a single, low dose of MDPV or α-PVP is sufficient to alter the expression of neuroplastic markers in the adult mouse brain. In particular, we found increased expression of the transcription factor Npas4, increased ratio between the vesicular GABA transporter and the vesicular glutamate transporter together with changes in the expression of the neurotrophin Bdnf, confirming the widespread impact of these cathinones on brain plasticity. To sum up, exposure to low dose of cathinones can impair cortical and hippocampal homeostasis, suggesting that abuse of these cathinones at much higher doses, as it occurs in humans, could have an even more profound impact on neuroplasticity.

A role of noradrenergic receptors in anxiolytic-like effect of high CRF in the rat frontal cortex.

Corticotropin releasing factor (CRF) is a neuropeptide widely distributed in the brain as a hormonal modulator and neurotransmitter. The best known behavioral function of CRF is activation of stress and anxiety via the hypothalamus and limbic structures but the role of CRF in the cortex is still poorly understood. Our previous studies have shown anxiolytic-like effects of high doses of CRF injected into the Fr2 frontal cortex and involvement of CRF1 receptors (R) in that effect. These results seemed to be controversial as most other studies suggested anxiogenic and not anxiolytic effects of CRF1R stimulation. Since stress is associated with adrenergic system, in the present study, we focused on participation of alpha1 and alpha2 or beta adrenergic receptors in the anxiolytic-like effect of CRF. Moreover, we verified whether these effects of CRF in the Fr2 were really connected with CRF1R. Male Wistar rats were bilaterally microinjected with CRF in a dose of 0.2 µg/1 µl/site or with the specific agonist of CRF1R, stressin 1 (0.2-0.0125 µg/1 µl/site) into the Fr2 area. The elevated plus maze (EPM) test was performed 30 min later to assess the anxiolysis. An involvement of noradrenergic receptors in the CRF induced anxiolytic-like effect in the Fr2 was studied by pretreatment with the alpha1 antagonist prazosin, alpha2 agonist clonidine, alpha2 antagonist RS 79948 or beta antagonist propranolol, 20-30 min before CRF. The influence on anxiety was assessed in the EPM test. The results show that anxiolytic behavior after CRF microinjection into the Fr2 area seems to be mainly connected with the CRF1R activation because a similar effect was observed after stressin 1 administration and it was blocked by CRF1R antagonist. The results observed after administration of noradrenergic ligands indicated that anxiolytic effects of CRF in the Fr2 engaged the alpha1 and alpha2 adrenergic receptors but not beta receptors.

Antidementia Effects of Alternanthera philoxeroides in Ovariectomized Mice Supported by NMR-Based Metabolomic Analysis.

The crude ethanol extract of the whole plant of Alternanthera philoxeroides (Mart.) Griseb was investigated for its potential as antidementia, induced by estrogen deprivation, based on in vitro antioxidant activity, ß-amyloid aggregation inhibition and cholinesterase inhibitory activity, as well as in vivo Morris water maze task (MWMT), novel object recognition task (NORT), and Y-maze task. To better understand the effect of the extract, oxidative stress-induced brain membrane damage through lipid peroxidation in the whole brain was also investigated. Additionally, expressions of neuroinflammatory cytokines (IL-1ß, IL-6 and TNF-α) and estrogen receptor-mediated facilitation genes such as PI3K and AKT mRNA in the hippocampus and frontal cortex were also evaluated. These effects were confirmed by the determination of its serum metabolites by NMR metabolomic analysis. Both the crude extract of A. philoxeroides and its flavone constituents were found to inhibit ß-amyloid (Aß) aggregation.

Effects of Thai Local Ingredient Odorants, Litsea cubeba and Garlic Essential Oils, on Brainwaves and Moods.

The functional food market is growing with a compound annual growth rate of 7.9%. Thai food recipes use several kinds of herbs. Lemongrass, garlic, and turmeric are ingredients used in Thai curry paste. Essential oils released in the preparation step create the flavor and fragrance of the famous tom yum and massaman dishes. While the biological activities of these ingredients have been investigated, including the antioxidant, anti-inflammatory, and antimicrobial activities, there is still a lack of understanding regarding the responses to the essential oils of these plants. To investigate the effects of essential oil inhalation on the brain and mood responses, electroencephalography was carried out during the non-task resting state, and self-assessment of the mood state was performed. The essential oils were prepared in several dilutions in the range of the supra-threshold level. The results show that Litsea cubeba oil inhalation showed a sedative effect, observed from alpha and beta wave power reductions. The frontal and temporal regions of the brain were involved in the wave alterations. Garlic oil increased the alpha wave power at lower concentrations; however, a sedative effect was also observed at higher concentrations. Lower dilution oil induced changes in the fast alpha activity in the frontal region. The alpha and beta wave powers were decreased with higher dilution oils, particularly in the temporal, parietal, and occipital regions. Both Litsea cubeba and turmeric oils resulted in better positive moods than garlic oil. Garlic oil caused more negative moods than the others. The psychophysiological activities and the related brain functions require further investigation. The knowledge obtained from this study may be used to design functional food products.

Anodal tDCS applied to the left frontal cortex abrogates scopolamine­induced fear memory deficit via the dopaminergic system.

Evidence suggests that transcranial direct current stimulation (tDCS) modulates conditioned fear memories and has effects on cognitive flexibility via the dopaminergic system. This study examines whether modulation of scopolamine­induced fear memory deficit by anodal tDCS could be mediated by the dopaminergic system. The male NMRI mice received scopolamine, 30 min before fear conditioning, and showed impaired contextual memory retention. Mice subjected to left frontal anodal stimulation for 20 or 30 min, before fear conditioning, impaired fear memory retrieval. Anodal application for 20 min significantly decreased scopolamine response on fear retention, while the one applied for 30 min did not alter. Moreover, anodal stimulation for 30 min abolished scopolamine­induced fear memory deficit. Dopaminergic antagonists SCH23390 and sulpiride, alone or in combination, prevented the abolishment effect of anodal stimulation on scopolamine­induced fear memory deficit, whereas they did not alter the impairing effect of scopolamine at the dose of 2 mg/kg. Our data suggest that anodal stimulation for 30 min abrogates the impairing effect of scopolamine on fear memory retention. This influence could be prevented by dopaminergic antagonists, indicating the involvement of the dopaminergic system in the effect of anodal stimulation on scopolamine­induced fear memory deficit.

Neuroprotective Effects of Rhynchophylline Against Aß1-42-Induced Oxidative Stress, Neurodegeneration, and Memory Impairment Via Nrf2-ARE Activation.

Extensive studies have shown that oxidative stress is a crucial pathogenic factor in Alzheimer's disease (AD). Nuclear factor E2-related factor 2 (Nrf2) is a master cytoprotective regulator against oxidative stress, and thus represents an attractive therapeutic target in AD. The goal of our study is to investigate the contribution of Nrf2 in Rhynchophylline (Rhy)-induced neuroprotection in AD. The data showed that intraperitoneal administration of Rhy (10 or 20 mg/kg) could ameliorate Aß1-42-induced cognitive impairment, evidenced by performance improvement in memory tests. The result of Antioxidant response element (ARE)-luciferase activity assay indicated that Rhy treatment improved ARE promoter activity. The results of reactive oxygen species (ROS), malondialdehyde (MDA) and glutathione (GSH) assessment in the frontal cortex and hippocampus showed that Rhy treatment could attenuate Aß1-42-induced oxidative stress to some extent, evidenced by reversion of these cytokines compared to Aß1-42 + Veh group. Rhy treatment also restored expression of Nrf2 and its downstream protein heme oxygenase-1 (HO-1), NAD(P)H/quinone oxidoreductase 1 (NOQ1), and recombinant glutamate cysteine ligase, modifier subunit (GCLM) in the frontal cortex and hippocampus of Aß1-42-treated mice. In addition, to investigate whether activation of Nrf2-mediated pathway is responsible for the neuroprotection of Rhy, Nrf2 siRNA was used in human neuroblastoma cells (SH-SY5Y). Interestingly, the results showed that the protective effects of Rhy, including anti-oxidative, anti-apoptosis and elevation of Nrf2 and its downstream proteins, were abolished in Nrf2 siRNA-transfected cells. These findings indicate that Rhynchophylline is protective against Aß1-42-induced neurotoxicity via Nrf2-ARE activation, and suggest that Rhy may serve as a potential candidate and promising Nrf2 activator for management of AD.

Acute Ramelteon Treatment Maintains the Cardiac Rhythms of Rats during Non-REM Sleep.

Sleep curtailment negatively affects cardiac activities and thus should be ameliorated by pharmacological methods. One of the therapeutic targets is melatonin receptors, which tune circadian rhythms. Ramelteon, a melatonin MT1/MT2 receptor agonist, has recently been developed to modulate sleep-wake rhythms. To date, the sleep-promoting effect of ramelteon has been widely delineated, but whether ramelteon treatment physiologically influences cardiac function is not well understood. To address this question, we recorded electrocardiograms, electromyograms, and electrocorticograms in the frontal cortex and the olfactory bulb of unrestrained rats treated with either ramelteon or vehicle. We detected vigilance states based on physiological measurements and analyzed cardiac and muscular activities. We found that during non-rapid eye movement (non-REM) sleep, heartrate variability was maintained by ramelteon treatment. Analysis of the electromyograms confirmed that neither microarousal during non-REM sleep nor the occupancy of phasic periods during REM sleep was altered by ramelteon. Our results indicate that ramelteon has a remedial effect on cardiac activity by keeping the heartrate variability and may reduce cardiac dysfunction during sleep.