Anxiolytic Drugs Research Articles

Characterization of pharmaco-EEG fingerprint and sleep-wake profiles of Lavandula angustifolia Mill. essential oil inhalation and diazepam administration in rats

Ethnopharmacological relevanceLavandula angustifolia Mill. Essential oil (Lavender EO) has a long history of medicinal use and is particularly claimed to possess anxiolytic and sedative properties. Lavender EO aromatherapy has been used to reduce distress and improve insomnia naturally. Increasing evidence appeared to show similarities between the effects of lavender EO and the anxiolytic drugs, benzodiazepines. However, its effects on sleep-wake and electrical brain patterns in comparison to that of the standard anxiolytic, diazepam, remained to be explored. Aim of the studyThe aim of this work was to investigate electroencephalography (EEG) profiles and sleep-pattern elicited by lavender EO inhalation compared to that of diazepam, a standard anxiolytic drug in in vivo rat model. Materials and methodsAdult male Wistar rats were anesthetized for electrode implantation on the frontal and parietal skulls. EEG signals were recorded for 180 min following intraperitoneal injection of diazepam (10 mg/kg) or during continuous inhalation of lavender EO (200 μL) or distilled water (control). Fast Fourier transform was used for the analyses of EEG power spectra and sleep-wake parameters. ResultsDuring a 30–60 min period, diazepam and lavender EO significantly increased frontal powers of 0.78–45.31 and 7.03–18.36 Hz, respectively. Both treatments also increased parietal powers with lower magnitudes of significant change. Significant increases in some frequency ranges remained until a 60–90 min period. Sleep-wake analyses also revealed that diazepam significantly reduced time spent in wake, increased time spent in non-rapid eye movement (NREM), increased episode duration of NREM, decreased numbers of wake episode and decreased rapid eye movement (REM) sleep latency. On the other hand, lavender EO only significantly decreased wake episodes and latency to REM sleep. Lavender EO inhalation reduced numbers of wake episode but maintain normal time spent in wake, NREM and REM sleeps. ConclusionsThese findings might suggest beneficial and distinct anxiolytic-like effects of lavender EO for sleep enhancing purposes.

β-sitosterol reduces anxiety and synergizes with established anxiolytic drugs in mice

SummaryAnxiety and stress-related conditions represent a significant health burden in modern society. Unfortunately, most anxiolytic drugs are prone to side effects, limiting their long-term usage. Here, we employ a bioinformatics screen to identify drugs for repurposing as anxiolytics. Comparison of drug-induced gene-expression profiles with the hippocampal transcriptome of an importin α5 mutant mouse model with reduced anxiety identifies the hypocholesterolemic agent β-sitosterol as a promising candidate. β-sitosterol activity is validated by both intraperitoneal and oral application in mice, revealing it as the only clear anxiolytic from five closely related phytosterols. β-sitosterol injection reduces the effects of restraint stress, contextual fear memory, and c-Fos activation in the prefrontal cortex and dentate gyrus. Moreover, synergistic anxiolysis is observed when combining sub-efficacious doses of β-sitosterol with the SSRI fluoxetine. These preclinical findings support further development of β-sitosterol, either as a standalone anxiolytic or in combination with low-dose SSRIs.

SP-004 - Radiosynthesis and biological evaluation of [18F]R91150, a selective 5-HT2A receptor antagonist for PET imaging

Serotonergic 5-HT2A receptors in cortical and forebrain regions are an important substrate for the neuromodulatory actions of serotonin in the brain. They have been implicated in the etiology of many neuropsychiatric disorders and serve as a target for antipsychotic, antidepressant, and anxiolytic drugs. Positron emission tomography imaging using suitable radioligands can be applied for in vivo quantification of receptor densities and receptor occupancy for therapy evaluation. Recently, the radiosynthesis of the selective 5-HT2AR antagonist [18F]R91150 was reported. However, the six-step radiosynthesis is cumbersome and time-consuming with low radiochemical yields (RCYs) of <5%. In this work, [18F]R91150 was prepared using late-stage Cu-mediated radiofluorination to simplify its synthesis. The detailed protocol enabled us to obtain RCYs of 14 ± 1%, and the total synthesis time was reduced to 60 min. In addition, autoradiographic studies with [18F]R91150 in rat brain slices revealed the typical uptake pattern of 5-HT2A receptor ligands.

Current Approaches to the Search of Anxiolytic Drugs

Current Approaches to the Search of Anxiolytic Drugs

Therapeutic Potential of Cannabidiol and WIN 55, 212‐2‐mesylate for Treatment of Anxiety

As the medicalization of marijuana occurs across the United States, the psychoactive component of the cannabis plant, Delta9-Tetrahydrocannabinol (THC), has gained recognition for its therapeutic potential. Meanwhile, its non-psychoactive counterpart, cannabidiol (CBD), has been marketed to treat Parkinson's disease, Chron's disease, dystonia, attention-deficit hyperactivity disorder (ADHD), inflammation, depression, fibromyalgia, epilepsy, and most commonly, anxiety. Given the over the counter accessibility of CBD and the fact that anxiety disorders are the most common type of mental illness in the United States, our objective was to access the therapeutic potential of cannabinoid receptor agonists and antagonists for treatment of anxiety. We hypothesized that CBD might be anxiolytic when chronically administered to a newly found mouse model of anxiety and attention deficit (Kv1.3-/- mice). Similarly to THC, WIN 55, 212-2-mesylate (WIN) is an agonist for the cannabinoid receptors CB1 and CB2, but it is not known to have any psychoactive properties. CBD is an antagonist for CB1 and CB2 receptors, and we used a CBD isolate to ensure purity. Our methods employed two-month-old Kv1.3-/- or wildtype mice that were phenotyped for anxiety behaviors using three assays, namely the elevated plus maze (EPM), the light-dark box (LDB), and the marble burying test. Mice were dosed daily, 30 minutes prior to performing a behavioral test. Mice of both sexes were separated into cohorts in which they were designated to receive an intraperitoneal injection of either drug (WIN55 = 1 mg/kg; CBD = 5 mg/kg) or vehicle solution at equivalent volume. Acute cohorts were defined as daily dosage for 5 days and chronic cohorts were treated with 20 doses over a 30 day interval. Without drug treatment, both genotypes exhibited anxiety-like behaviors in the LDB and EPM tasks, preferring dark side or closed arms of the apparatuses, respectively. For acute WIN treatment, Kv1.3-/- mice showed lessened anxiety in the LDB (increased time in light, decreased time in dark), however, following chronic WIN treatment, they showed no change in LDB behavior. In contrast, in wildtype mice, neither acute nor chronic WIN treatment changed LDB behaviors. Both acute and chronic WIN treatment in Kv1.3-/- mice mitigated anxiety in the EPM test (mice decreased time in the closed arms), whereas the same in wildtype mice showed no effect of anxiety if acutely administered and heightened anxiety following chronic treatment (mice increased time in closed arms). For cohorts treated acutely with CBD, Kv1.3-/- mice showed enhanced anxiety behaviors in the LDB (mice decreased time in light and increased time in dark). Mice of both genotypes showed enhanced anxiety behaviors in the EPM (mice increased time in the closed arms) following acute CBD treatment.In conclusion, our data did not support our hypothesis and showed that CBD may act as an anxiogenic drug in both wildtype and Kv1.3-/- mice.WIN acted as an anxiolytic drug for mice with trait anxiety (Kv1.3-/-), which was ineffective in these mice long-term, and ineffective acutely in wildtype mice exposed to state anxiety.

Diazepam causes sedative rather than anxiolytic effects in C57BL/6J mice

Diazepam has been broadly accepted as an anxiolytic drug and is often used as a positive control in behavioral experiments with mice. However, as opposed to this general assumption, the effect of diazepam on mouse behavior can be considered rather controversial from an evidence point of view. Here we revisit this issue by studying the effect of diazepam on a benchmark task in the preclinical anxiety literature: the elevated plus maze. We evaluated the minute-by-minute time-course of the diazepam effect along the 10 min of the task at three different doses (0.5, 1 and 2 mg/kg i.p. 30 min before the task) in female and male C57BL/6J mice. Furthermore, we contrasted the effects of diazepam with those of a selective serotoninergic reuptake inhibitor (paroxetine, 10 mg/kg i.p. 1 h before the task). Diazepam had no anxiolytic effect at any of the tested doses, and, at the highest dose, it impaired locomotor activity, likely due to sedation. Noteworthy, our results held true when examining male and female mice separately, when only examining the first 5 min of the task, and when animals were subjected to one hour of restrain-induced stress prior to diazepam treatment. In contrast, paroxetine significantly reduced anxiety-like behavior without inducing sedative effects. Our results therefore suggest that preclinical studies for screening new anxiolytic drugs should be cautious with diazepam use as a potential positive control.

Objective and comprehensive re-evaluation of anxiety-like behaviors in mice using the Behavior Atlas

Various animal models of anxiety have been developed to evaluate anxiety and anxiolytic drugs. However, non-uniform measuring paradigms, variability in apparatus use and individual differences in animals confound study results. In this study, when all animals were included in the data analysis, we found no significant differences between control and stressed mice using standard behavioral paradigms for assessing anxiety (elevated plus maze and open field test). To provide a better assessment of anxiety, we therefore used a machine learning approach to analyze the behavioral patterns of each animal, and selected typical subjects in each group for use as a training set according to classical anxiety parameters. Spontaneous behaviors in these animals were captured by multi-view cameras and decomposed into sub-second modules using Behavior Atlas, and six behavioral features providing statistically significant difference between stressed and control mice were identified. Combined with low-dimensional embedding and clustering, new features were used to discriminate stressed mice from controls, in both the training set and all objects. Our results show Behavior Atlas is a powerful approach for identifying new potential biomarkers in an unbiased fashion. Our approach can complement classical measuring paradigms to objectively and comprehensively evaluate anxiety-like behaviors.

Time trends in hospitalizations with anxiolytic, sedative, or hypnotic drug use disorder: a 17-year U.S. national study

Background Limited epidemiological national data are available for anxiolytic, sedative, or hypnotic drug (ASH) use disorder hospitalizations. Objective To examine the time-trends in and outcomes of ASH use disorder hospitalizations. Methods Rates of ASH use disorder hospitalizations and associated healthcare utilization and mortality were examined using the U.S. National Inpatient Sample data (NIS) from 1998 to 2014. Multivariable-adjusted logistic regression assessed the association of demographic, medical comorbidity (using validated composite score of 17 conditions, the Deyo-Charlson index), and hospital characteristics with healthcare utilization (total hospital charges, length of hospital stay [LOS], and discharge to a non-home setting) and inpatient mortality for hospitalizations with ASH use disorder. Results There were an estimated 1,171,673 weighted ASH use disorder hospitalizations. The ASH use disorder hospitalization rates increased 3.12-fold from 96 to 299 per 100,000 NIS hospitalizations from 1998–2000 to 2013–2014. In the same period, associated non-home discharge rate increased 3.33-fold from 12.9 to 43 and in-hospital mortality rate increased 3.17-fold from 0.46 to 1.46 per 100,000 (all p values ≤ .002). In the multivariable-adjusted analyses, older age, black race/ethnicity, Deyo-Charlson index score of 2 or higher, non-private insurance payer, higher income, hospital region, urban setting hospital and a larger hospital bed size, were significantly associated with higher healthcare utilization outcomes and/or mortality. Female sex was associated with higher healthcare utilization outcomes, but lower in-hospital mortality. Conclusions This study confirmed the rising ASH use disorder hospitalization burden in the United States. An increasing inpatient mortality and non-home discharge rate for hospitalizations with ASH use disorder are concerning. The identification of modifiable and non-modifiable risk factors associated with outcomes should allow prognostication and designing of interventions to improve outcomes.

8-Substituted Triazolobenzodiazepines: In Vitro and In Vivo Pharmacology in Relation to Structural Docking at the α1 Subunit-Containing GABAA Receptor.

In order to develop improved anxiolytic drugs, 8-substituted analogs of triazolam were synthesized in an effort to discover compounds with selectivity for α2/α3 subunit-containing GABAA subtypes. Two compounds in this series, XLi-JY-DMH (6-(2-chlorophenyl)-8-ethynyl-1-methyl-4H-benzo [f][1,2,4]triazolo[4,3-a][1,4]diazepine) and SH-TRI-108 [(E)-8-ethynyl-1-methyl-6-(pyridin-2-yl)-4H-benzo [f][1,2,4]triazolo[4,3-a][1,4]diazepine], were evaluated for in vitro and in vivo properties associated with GABAA subtype-selective ligands. In radioligand binding assays conducted in transfected HEK cells containing rat αXβ3γ2 subtypes (X = 1,2,3,5), no evidence of selectivity was obtained, although differences in potency relative to triazolam were observed overall (triazolam > XLi-JY-DMH > SH-TRI-108). In studies with rat αXβ3γ2 subtypes (X = 1,2,3,5) using patch-clamp electrophysiology, no differences in maximal potentiation of GABA-mediated Cl− current was obtained across subtypes for any compound. However, SH-TRI-108 demonstrated a 25-fold difference in functional potency between α1β3γ2 vs. α2β3γ2 subtypes. We evaluated the extent to which this potency difference translated into behavioral pharmacological differences in monkeys. In a rhesus monkey conflict model of anxiolytic-like effects, triazolam, XLi-JY-DMH, and SH-TR-108 increased rates of responding attenuated by shock (anti-conflict effect) but also attenuated non-suppressed responding. In a squirrel monkey observation procedure, both analogs engendered a profile of sedative-motor effects similar to that reported previously for triazolam. In molecular docking studies, we found that the interactions of the 8-ethynyl triazolobenzodiazepines with the C-loop of the α1GABAA site was stronger than that of imidazodiazepines XHe-II-053 and HZ-166, which may account for the non-sedating yet anxiolytic profile of these latter compounds when evaluated in previous studies.

Anxiolytic and antidepressant effects of cannabidiol: a systematic review

Objetctive: Realize a systematic review on articles about cannabidiol (CBD) as an anxiolytic and antidepressant drug. Methodology: A systematic review in PubMed, Science Direct and PsycINFO databases taking into consideration articles published in English and Portuguese from 2008 to 2018 with animal experimentation. Results: Eleven articles with experimental studies on animals were included. All studies exhibited anxiolytic and antidepressant activities after CBD use. Conclusion: It was proven by several experiments the anxiolytic and antidepressant activity of CBD, however there is still a need of more preclinicals and clinicals studies to elucidate its mechanisms.

Characteristics of unipolar depression in psychiatric inpatients

IntroductionUnipolar depression is daily encountered in psychiatry.ObjectivesTo describe the socio-demographic and clinical characteristics of patients with unipolar depression.MethodsThis is a cross-sectional, descriptive study carried out at the psychiatric department of the University Hospital of Mahdia. We have included patients with unipolar depression. The data were collected from patients’ medical files using a pre-established 37-item questionnaire.ResultsWe have collected 53 patients. The mean age was 44 years. The majority of patients were female (56.6%) and unemployed (70%). 47.2% of patients were married. 72% of patients had a low socio-economic level. They were smokers in 45.3% of cases. Alcohol consumption was found in 24.5% of cases. A family history of mood disorder and suicide or attempted suicide were present in 7% and 13.2% of the cases respectively. 7% of the patients had a history of a postpartum thymic episode. The mean number of depressive episodes was 2.5. Personal history of suicide attempts was found in 40% of cases. The mean age of the first thymic episode was 35 years. At the psychiatric examination, psychomotor retardation was present in 64% of cases, anxiety distress in 58.5% of cases, psychotic, melancholic and atypical characteristics in 30%, 13.2% and 5.7% of cases respectively. 81% of patients were treated with anxiolytic drugs in combination with an antidepressant. Antipsychotic treatment was combined in 45% of cases and electro-convulsive therapy in 9.4% of cases.ConclusionsOur patients presented predictive criteria of bipolarity. Therefore, vigilance is necessary in their medical management.

Radiosynthesis and Biological Evaluation of [18F]R91150, a Selective 5-HT2A Receptor Antagonist for PET-Imaging.

Serotonergic 5-HT2A receptors in cortical and forebrain regions are an important substrate for the neuromodulatory actions of serotonin in the brain. They have been implicated in the etiology of many neuropsychiatric disorders and serve as a target for antipsychotic, antidepressant, and anxiolytic drugs. Positron emission tomography imaging using suitable radioligands can be applied for in vivo quantification of receptor densities and receptor occupancy for therapy evaluation. Recently, the radiosynthesis of the selective 5-HT2AR antagonist [18F]R91150 was reported. However, the six-step radiosynthesis is cumbersome and time-consuming with low radiochemical yields (RCYs) of <5%. In this work, [18F]R91150 was prepared using late-stage Cu-mediated radiofluorination to simplify its synthesis. The detailed protocol enabled us to obtain RCYs of 14 ± 1%, and the total synthesis time was reduced to 60 min. In addition, autoradiographic studies with [18F]R91150 in rat brain slices revealed the typical uptake pattern of 5-HT2A receptor ligands.

Development of superabsorbent hydrogel based on Gum Arabic for enhanced removal of anxiolytic drug from water

The growing consumption of anxiolytic drugs like diazepam (DZP) has aggravated the problem of persistent organic pollutants in water. Due to its characteristics, the removal of DZP from water and wastewater is a challenging task. As an effort to deals with this issue, in this study, we report the development of a hydrogel based on Gum Arabic (GA) grafted with poly(acrylic acid) (GA-g-PAAc) to be used in the adsorptive removal of DZP from water. The hydrogel formation was confirmed by Fourier-transform infrared (FTIR) spectroscopy and thermal analysis (TGA/DTG) analyses. Images obtained by scanning electron microscopy (SEM) revealed that GA-g-PAAc hydrogel exhibits a porous morphology while swelling experiments suggest a superabsorbent characteristic (degree of swelling> 600%). From batch experiments, it was found that the removal of DZP reached remarkable percentages (>80%) before 300 min in moderate experimental conditions (pH 7, 25 °C, 150 mg of adsorbent). The adsorption of DZP on GA-g-PAAc followed the pseudo-first order kinetics, and the mechanism was described by the linear Langmuir isotherm. The maximum adsorption capacity (qmax) was calculated to be 15.16 mg g−1 (at 25 °C), which is comparable or superior to other adsorbent materials used in DZP removal. Reuse experiments showed that GA-g-PAAc keeps appreciable adsorption ability even after five reuse cycles. The results reported here suggest this superabsorbent hydrogel could be a promising adsorbent material to treat water contaminated by anxiolytic drugs, like DZP.

Crystal Structure and Thermal Properties of Phenibut, Phenibut H2O and Phenibut HCl: a Case for Phase Stability Based on Structural Considerations

AbstractPhenibut is an anxiolytic drug approved for medical use in many eastern European states. With the exception of the HCl Salt of Phenibut no crystal structure related research has been conducted on this substance. Herein, the crystal structures of Phenibut and Phenibut⋅H2O are presented, including crystal packing analysis based on interaction energy calculations. IR spectra are shown alongside powder diffraction data and thermogravimetric analysis to characterize and compare structural as well as thermal properties of the examined Phenibut forms. Single crystal diffraction is used in conjunction with Crystal Explorer based Hirshfeld analysis to carefully identify the bonding interaction properties in each compound. Finally, a case is made regarding stability of the compared crystalline phases based on the conducted structural analyses and the quantification of the molecular interaction energies.

Synthesis and characterization of molecularly imprinted polymers for the selective extraction of oxazepam from complex environmental and biological samples.

Oxazepam, one of the most frequently prescribed anxiolytic drugs, is not completely removed from wastewater with conventional treatment processes. It can thus be found at trace levels in environmental water, with human urine constituting the major source of contamination. This study focused on the development and characterization of molecularly imprinted polymers (MIPs) for the selective solid-phase extraction of oxazepam at trace levels from environmental water and human urine samples. Two MIPs were synthesized, and their selectivity in pure organic and aqueous media were assayed. After optimizing the extraction procedure adapted to a large sample volume to reach a high enrichment factor, the most promising MIP was applied to the selective extraction of oxazepam from environmental water. Extraction recoveries of 83 ± 12, 92 ± 4 and 89 ± 10% were obtained using the MIP for tap, mineral and river water, respectively, while a recovery close to 40% was obtained on the corresponding non-imprinted polymer (NIP). Thanks to the high enrichment factors, a limit of quantification (LOQ) of 4.5ngL-1 was obtained for river water. A selective extraction procedure was also developed for urine samples and gave rise to extraction recoveries close to 95% for the MIP and only 23% for the NIP. Using the MIP, a LOQ of 357ngL-1 was obtained for oxazepam in urine. The use of the MIP also helped to limit the matrix effects encountered for the quantification of oxazepam in environmental samples and in human urine samples after extraction on an Oasis HLB sorbent.

Study on the Effects of Kandhamal Haladi in Benzo [a]Pyrene-Induced Behavioral Changes in Adult Zebrafish (Danio rerio)

The aquatic ecosystem provides a base for the environmental pollutants that have potential to induce the anxiety-like behavioral response in aquatic animals. Benzo[a]pyrene (B[a]P) is a polycyclic aromatic hydrocarbon commonly associated with anxiety-like behavior. Kandhamal haladi (KH) has been used traditionally as anxiolytic drug. The present study is aimed to evaluate the anxiolytic role of Kandhamal haladi following exposure to waterborne B[a]P. Wild-type zebrafish (Danio rerio) were assigned as naive, control (dimethyl sulfoxide), B[a]P, KH, and B[a]P + KH groups. Behavioral studies showed reversal in scototaxis (light and dark preference) behavior in B[a]P group and reinstated by KH cosupplementation in B[a]P + KH group. Video-aided analysis of zebrafish behavior presents an increased range of behavioral endpoints, some of which are not available using manual observations. This protocol describes technique for accurate, consistent and fast video-aided measurements of zebrafish locomotion and anxiety-related behavior. The novel tank diving test and light/dark box experiments showed the anxiety response and allows comparison of anxiety induced behavior in experimental versus control groups. Cosupplementation of B[a]P with KH restored the normal scototaxis behavior of adult zebrafish. The findings confirmed anxiolytic nature of Kandhamal haladi.

Anticholinergic Activity of Psychotropic Drugs and Cognitive Impairment Among Participants Aged 45 and Over: The CONSTANCES Study.

Psychotropic drugs such as anxiolytics, antidepressants and antipsychotics may have anticholinergic properties that could directly affect patients' cognition. Our objective was to assess the relationship between exposure to anticholinergic-positive (AC+) psychotropic drugs and cognitive impairment compared with psychotropic drugs without anticholinergic activity (AC-). This analysis included participants (aged 45-70 years) enrolled between January 2012 and October 2017 in the CONSTANCES cohort treated with psychotropic drugs (antidepressants n=2602, anxiolytics n=1195, antipsychotics n=197) in the 3 years preceding cognitive assessment. Within each drug class, the Anticholinergic Cognitive Burden scale was used to classify drugs as either AC+ or AC-. Cognitive impairment was defined as a score below - 1 standard deviation from the standardized mean of the neuropsychological score. We used multiple logistic regression models and matching on propensity score to estimate the relationship between anticholinergic activity and cognitive impairment. Our analyses did not show any increased risk of cognitive impairment for AC+ antidepressants and anxiolytics, with the exception of a slight increase for AC+ antidepressants in episodic memory (odds ratio [OR] 1.19; 95% confidence interval [CI] 1.05-1.36). Conversely, we found a more marked increase in risk with AC+ antipsychotics on executive function (Trail Making Test-A [TMT-A], OR 4.49 [95% CI 2.59-7.97] and TMT-B, OR 3.62 [95% CI 2.25-5.89]). Our results suggest there is no clinically relevant association between the anticholinergic activity of antidepressant and anxiolytic drugs and cognitive impairment in middle-aged adults. An association could exist between AC+ antipsychotics and executive function.

Intermittent fasting promotes anxiolytic-like effects unrelated to synaptic mitochondrial function and BDNF support

Anxiety disorders are linked to mitochondrial dysfunction and decreased neurotrophic support. Since anxiolytic drugs target mitochondria, non-pharmacological approaches to improve mitochondrial metabolism such as intermittent fasting (IF) may cause parallel behavioral benefits against anxiety disorders. Here, we investigated whether a chronic IF regimen could induce anxiolytic-like effects concomitantly to modulation in mitochondrial bioenergetics and trophic signaling in mice brain. A total of 44 Male C57BL/6 J mice (180 days old) were assigned to two dietary regimens: a normal, ad libitum diet (AL group) and an alternate-day fasting (IF group), where animals underwent 10 cycles of 24 h food restriction followed by 24 h ad libitum access. Animals underwent the open field test, dark/light box and elevated plus maze tasks. Isolated nerve terminals were obtained from mice brain and used for mitochondrial respirometry, hydrogen peroxide production and assessment of membrane potential dynamics, calcium handling and western blotting. We showed that IF significantly alters total daily food intake and food consumption patterns but not body weight. There were no differences in the exploratory and locomotory parameters. Remarkably, animals from IF showed decreased anxiety-like behavior. Mitochondrial metabolic responses in different coupling states and parameters linked with H2O2 production, Ca2+ buffering and electric gradient were not different between groups. Finally, no alterations in molecular indicators of apoptotic death (Bax/Bcl-2 ratio) and neuroplasticity (proBDNF/BDNF and synaptophysin were observed). In conclusion, IF exerts anxiolytic-like effect not associated with modulation in synaptic neuronergetics or expression of neurotrophic proteins. These results highlight a potential benefit of intermittent fasting as a nutritional intervention in anxiety-related disorders.

Recent Advances in the Synthesis of β-Carboline Alkaloids.

β-Carboline alkaloids are a remarkable family of natural and synthetic indole-containing heterocyclic compounds and they are widely distributed in nature. Recently, these alkaloids have been in the focus of interest, thanks to their diverse biological activities. Their pharmacological activity makes them desirable as sedative, anxiolytic, hypnotic, anticonvulsant, antitumor, antiviral, antiparasitic or antimicrobial drug candidates. The growing potential inherent in them encourages many researchers to address the challenges of the synthesis of natural products containing complex β-carboline frameworks. In this review, we describe the recent developments in the synthesis of β-carboline alkaloids and closely related derivatives through selected examples from the last 5 years. The focus is on the key steps with improved procedures and synthetic approaches. Furthermore the pharmacological potential of the alkaloids is also highlighted.

Evaluation of Shoulder Pain, Depression and Sleep Quality in Hemiplejic Patients

Background: The aim of the study was to evaluate Hemiplegic Shoulder Pain (HSP), depression and sleep quality in hemiplegic patients. Methods: The research is a cross-sectional study conducted between 2018-2019 in Famagusta State Hospital. In the scope of the study, patients with hemiplegia who applied to the physical therapy and rehabilitation clinic were included consecutively. Clinical evaluations of the patients were performed and the parameters examined were as follows: age, gender, duration of hemiplegia diagnosis (weeks), education level, shoulder pain, Computerized Tomography (CT) results, family support status, and antidepressant, anxiolytic and antipsychotic drug use. The Pittsburgh Sleep Quality Index, Brunnstrom motor staging, Functional Ambulation Categories, Beck Depression Inventory were also applied to the patients. Results: The frequency of HSP in the study group was found to be 20% (n=10). No relationship was found between having shoulder pain in patients diagnosed with hemiplegia and parameters such as age, gender, hemiplegia duration, education level, family support, CT result, depression, sleep quality, ambulation status, and the use of antidepressants, anxiolytics or antipsychotics. It was found that those with HSP had significantly worse motor functions. In the univariate logistic regression analysis performed to elucidate the factors affecting sleep quality, it was found that none of the factors examined had an effect on sleep quality. In the multivariate logistic regression analysis including age, female gender, lack of family support, worsening of Brunnstrom upper extremity, lower extremity and hand motor functions, poor ambulation and poor sleep quality (which were found to be effective on depression with univariate logistic regression analysis), the absence of family support and higher score from the sleep quality scale were found to be associated with higher level of depression. Conclusion: As a result of the analyses, shoulder pain was not found to be associated with depression and sleep quality in hemiplegic patients. Lack of family support and poor sleep quality were the factors that independently increased the risk of depression in hemiplegic patients.