Antidepressant activity of Spathodea campanulata in mice and predictive affinity of spatheosides towards type A monoamine oxidase.

The antidepressant activity of Spathodea campanulata flowers was evaluated in mice and in silico. When tested at doses of 200 and 400 mg/kg, the methanol extract of S. campanulata (MESC) showed dose-dependent antidepressant activity in the force swim test (FST), tail suspension test (TST), lithium chloride-induced twitches test and the open field test. In FST and TST, animals treated with MESC demonstrated a significant decrease in the immobility period compared to the control group. The lithium chloride-induced head twitches were significantly reduced following administration of MESC. The latter, at the dose of 400 mg/kg, also significantly reduced locomotor activity. Following administration of MESC, changes in the levels of serum corticosterone, and of norepinephrine, dopamine, serotonin, 4-hydroxy-3-methoxyphenylglycol (MHPG), 4-dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5-HIAA) were measured in different brain regions using HPLC. The presence of spatheoside A (m/z 541) and spatheoside B (m/z 559) in MESC was detected using HPLC/ESI-MS. These two iridoids demonstrated a high predictive binding affinity for the active site of the type A monoamine oxidase (MAO-A) enzyme with scores of 99.40 and 93.54, respectively.  These data suggest that S. campanulata flowers warrants further investigation as a source of novel templates for antidepressive drugs.

Saffron Extract-Induced Improvement of Depressive-Like Behavior in Mice Is Associated with Modulation of Monoaminergic Neurotransmission.

Depressive disorders represent a major public health concern and display a continuously rising prevalence. Importantly, a large proportion of patients develops aversive side effects and/or does not respond properly to conventional antidepressants. These issues highlight the need to identify further therapeutic strategies, including nutritional approaches using natural plant extracts with known beneficial impacts on health. In that context, growing evidence suggests that saffron could be a particularly promising candidate. This preclinical study aimed therefore to test its antidepressant-like properties in mice and to decipher the underlying mechanisms by focusing on monoaminergic neurotransmission, due to its strong implication in mood disorders. For this purpose, the behavioral and neurobiochemical impact of a saffron extract, Safr'Inside™ (6.5 mg/kg per os) was measured in naïve mice. Saffron extract reduced depressive-like behavior in the forced swim test. This behavioral improvement was associated with neurobiological modifications, particularly changes in serotonergic and dopaminergic neurotransmission, suggesting that Safr'Inside™ may share common targets with conventional pharmacological antidepressants. This study provides useful information on the therapeutic relevance of nutritional interventions with saffron extracts to improve management of mood disorders.

Alterations of amygdala-prefrontal cortical coupling and attention deficit/hyperactivity disorder-like behaviors induced by neonatal habenula lesion: normalization by Ecklonia stolonifera extract and its active compound fucosterol.

Alterations of monoamine transmission in mesocorticolimbic regions have been suggested in the pathophysiology of attention deficit/hyperactivity disorder (ADHD). The habenula is an important brain area in regulation of monoamine transmission. In this study, we investigated behavioral and electrophysiological alterations induced by neonatal habenula lesion (NHL) in rats. In NHL rats, age-dependent behavioral alterations relevant to the ADHD symptoms, such as hyperlocomotion, impulsivity, and attention deficit, were observed. Local field potentials (LFPs) in mesocorticolimbic regions of anesthetized rats were examined with in vivo electrophysiological recordings. Abnormally enhanced synchronization of slow (delta) and fast (gamma) LFP oscillations between the amygdala (AMY) and prefrontal cortex (PFC) was found in juvenile, but not in adult, NHL rats. We further examined the effects of an extract and the active compound from the perennial large brown algae Ecklonia stolonifera (ES), which have previously been demonstrated to modulate monoamine transmission, on these NHL-induced alterations. One week of ES extract treatments normalized the NHL-induced behavioral alterations, whereas the active compound fucosterol improved attention deficit and impulsivity, but not hyperlocomotion, in NHL rats. Consistent with the behavioral effects, ES extract treatments also normalized augmented AMY-PFC coupling. These results suggest that altered limbic-cortical information processing may be involved in ADHD-like behavioral alterations induced by NHL, which could be ameliorated by the natural substance, such as ES that affects monoamine transmission.

Anti-depressant like effects of quercetin 4'-O-glucoside from Allium cepa via regulation of brain oxidative stress and monoamine levels in mice subjected to unpredictable chronic mild stress.

Objectives: Depression is a common neuropsychiatric disorder. The available pharmacotherapy is ineffective for a substantial proportion of patients and has numerous side effects. Therefore, finding safer drugs for the management of depression is of paramount importance. The present study was aimed to identify the compound responsible for anti-depressant like effects of Allium cepa outer scale extract (ACE) and to elucidate its mechanism of action. Methods:The anti-depressant compound from ACE was separated using bioactivity guided fractionation. Furthermore, mouse model of unpredictable chronic mild stress (UCMS) induced depressive behaviour was employed to investigate the anti-depressant like activity and potential mechanism of bioactive compound using behavioural tests (forced swim test (FST), sucrose preference test (SPT), open field test (OFT)) as well as by assessing brain oxidative stress, monoamine oxidase A and serotonin levels. Results:ACE and its ethylacetate fraction (EF) showed marked anti-depressant like effects in mice in the FST model. Chromatographic and spectroscopic studies of EF lead to the isolation of quercetin and quercetin 4'-O-glucoside (QG). Of these, QG (20 mg/kg) treated animals showed activity similar to that shown by fluoxetine in mice using FST. Thus, QG was tested for anti-depressant like activity against UCMS induced depressive behaviour in mice. Treatment of UCMS- exposed mice with QG (20 mg/kg) improved UCMS induced behaviour anomalies and restored brain biochemical parameters (oxidative stress, MAO-A activity and serotonin levels). Discussion:QG is responsible for anti-depressant like effects of ACE possibly via prevention of brain oxidative stress and restoring serotonin levels by inhibiting MAO-A activity.

Chemical Composition of Essential Oil from Flower of 'Shanzhizi' (Gardenia jasminoides Ellis) and Involvement of Serotonergic System in Its Anxiolytic Effect.

Gardenia jasminoides Ellis is a famous fragrant flower in China. Previous pharmacological research mainly focuses on its fruit. In this study, the essential oil of the flower of 'Shanzhizi', which was a major variety for traditional Chinese medicine use, was extracted by hydro distillation and analyzed by GC-MS. Mouse anxiety models included open field, elevated plus maze (EPM), and light and dark box (LDB), which were used to evaluate its anxiolytic effect via inhalation. The involvement of monoamine system was studied by pretreatment with neurotransmitter receptor antagonists WAY100635, flumazenil and sulpiride. The monoamine neurotransmitters contents in the prefrontal cortex (PFC) and hippocampus after aroma inhalation were also analyzed. The results showed that inhalation of G. jasminoides essential oil could significantly elevated the time and entries into open arms in EPM tests and the time explored in the light chamber in LDB tests with no sedative effect. WAY100635 and sulpiride, but not flumazenil, blocked its anxiolytic effect. Inhalation of G. jasminoides essential oil significantly down-regulated the 5-HIAA/5-HT in the PFC and reduced the 5-HIAA content in hippocampus compared to the control treatment. In conclusion, inhalation of gardenia essential oil showed an anxiolytic effect in mice. Monoamine, especially the serotonergic system, was involved in its anxiolytic effect.

Perinatal Docosahexaenoic Acid Supplementation Improves Cognition and Alters Brain Functional Organization in Piglets.

Epidemiologic studies associate maternal docosahexaenoic acid (DHA)/DHA-containing seafood intake with enhanced cognitive development; although, it should be noted that interventional trials show inconsistent findings. We examined perinatal DHA supplementation on cognitive performance, brain anatomical and functional organization, and the brain monoamine neurotransmitter status of offspring using a piglet model. Sows were fed a control (CON) or a diet containing DHA (DHA) from late gestation throughout lactation. Piglets underwent an open field test (OFT), an object recognition test (ORT), and magnetic resonance imaging (MRI) to acquire anatomical, diffusion tensor imaging (DTI), and resting-state functional MRI (rs-fMRI) at weaning. Piglets from DHA-fed sows spent 95% more time sniffing the walls than CON in OFT and exhibited an elevated interest in the novel object in ORT, while CON piglets demonstrated no preference. Maternal DHA supplementation increased fiber length and tended to increase fractional anisotropy in the hippocampus of offspring than CON. DHA piglets exhibited increased functional connectivity in the cerebellar, visual, and default mode network and decreased activity in executive control and sensorimotor network compared to CON. The brain monoamine neurotransmitter levels did not differ in healthy offspring. Perinatal DHA supplementation may increase exploratory behaviors, improve recognition memory, enhance fiber tract integrity, and alter brain functional organization in offspring at weaning.

Antidepressant-like effect of hydroalcoholic extract from barks of Rapanea ferruginea: Role of monoaminergic system and effect of its isolated compounds myrsinoic acid A and B.

Major Depressive Disorder (MDD) is a highly disabling condition and has been linked to increased inflammatory mediators. Hydroalcoholic extract from barks of Rapanea ferruginea (HEBRF) and the majoritary compounds-myrsinoic acid A (MAA) and B (MAB)-have been studied due to their anti-inflammatory potential, but there is no evidence about its antidepressant-like effects. This research investigated the HEBRF, MAA, and MAB antidepressant-like effect, besides the involvement of the monoaminergic system and MAO-A activity in the HEBRF antidepressant-like effect. HEBRF (50-300 mg/kg, p.o.), MAA (5-30 mg/kg, p.o.) or MAB (3-60 mg/kg, p.o.) were administrated to mice, and behavioral parameters were assessed using the tail suspension test (TST), splash test (ST) and open field test (OFT). The involvement of monoaminergic system in the HEBRF antidepressant-like effect was established through the pretreatment of mice with antagonists. The influence triggered by HEBRF in the monoamine oxidase A (MAO-A) activity was evaluated in the hippocampus (HIP) and prefrontal cortex (PFC) of mice. HEBRF (100-300 mg/kg) promoted antidepressant-like effect in the TST and augmented the total time of grooming in the ST, without compromising the locomotor activity. Pretreatment of mice with serotoninergic, dopaminergic, and noradrenergic antagonists, reversed the HEBRF antidepressant-like effect. Besides, HEBRF inhibited the MAO-A activity in the HIP and PFC. Moreover, MAA (5 mg/kg) and MAB (3 mg/kg) also promoted antidepressant-like and anti-anhedonic effects in mice. Data showed that monoaminergic system is involved in the HEBRF antidepressant-like effect, besides MAA and MAB possibly could be responsible for these pharmacological effects.

Effect of the warming and tonifying kidney- yang recipe on monoamine neurotransmitters and pathological morphology of hippocampus tissue in depression model rats.

OBJECTIVE: To study the molecular mechanism of warming and tonifying kidney-yang recipe (WTKYR) in the treatment of depression. METHODS: SD rats were divided into a control group, model group, WTKYR group, and fluoxetine group. Each group consisted of 21 rats. The chronic unpredictable mild stress model was used. Body weighing and SPT were performed regularly. After treatment, histopathology of the brain tissue was performed, and concentrations of 5-HT (5-hydroxytryptamine), NE (norepinephrine), and DA (dopamine) in the hippocampus were determined. RESULTS: The WTKYR group showed higher body weight and sucrose consumption than the control groups. Moreover, the concentrations of 5-HT, NE, and DA in the hippocampus were significantly different in the WTKYR group in comparison to those in the other groups. The hippocampus histomorphology of the WTKYR group exhibited less dematous pyramidal cells and mild inflammatory cell infiltration. CONCLUSION: The treatment effect of WTKYR in depression may be based on improvement in the content of 5-HT, NE, and DA in the hippocampus, extenuating edema of the cortical surface and pyramidal cells and decreasing the infiltration of inflammatory cells into hippocampus tissue.

Supplemental taurine during adolescence and early adulthood has sex-specific effects on cognition, behavior and neurotransmitter levels in C57BL/6J mice dependent on exposure window.

The mammalian brain goes through final maturation during late adolescence and early adulthood with sex differences in timing. The key cellular processes, including changes in neurotransmitter receptor density and synaptic pruning, make this age uniquely vulnerable to neurotoxic insults. Teenagers and young adults are the major consumers of energy drinks, which contain high levels of taurine and caffeine. Taurine is one of the most abundant amino acids in the central nervous system, but the effects of supplemental taurine consumption during adolescence has not been well studied. We conducted an initial short-term exposure study with 0.12% taurine in drinking water and a long-term exposure dose-response study using 0.06 and 0.12% taurine in male and female C57BL/6J mice. We examined a broad range of cognitive functions and behaviors and measured neurotransmitter levels. We found no significant differences in anxiety, open field locomotor activity, or sensorimotor gating. However, we found impairments in novel object recognition and sex differences in Morris water maze. When taurine treatment stopped before behavioral experiments began, male mice had significant impairments in spatial learning and memory. In the dose-response study when taurine treatment continued throughout behavioral experiments, females had significant impairments. We also found sex differences in neurotransmitter levels with females having higher levels of glutamate, DOPAC and 5-HIAA. We conclude that both females and males are at risk from excess taurine consumption during final brain maturation.

Participation of the nucleus accumbens dopaminergic system in the antidepressant-like actions of a diet rich in omega-3 polyunsaturated fatty acids.

The beneficial effects of omega (ω)-3 polyunsaturated fatty acid (PUFA) supplementation on major depressive disorder have been actively studied, but the underlying mechanism remains unknown. The present study examined the involvement of the nucleus accumbens (NAc) dopaminergic systems in behavioral changes in mice fed a diet high in ω-3 PUFAs. Mice fed a diet containing about double the amount of ω-3 PUFAs (krill oil (KO) diet) exerted shorter immobility times in the forced swim test (FST) than mice fed a control diet, containing only α-linolenic acid (ALA) as ω-3 PUFAs. The shorter immobility times were observed in both male and female mice. A dopamine metabolite, 3,4-dihydroxyphenylacetic acid, increased in the NAc in male mice fed the KO diet when compared with those fed the control diet. In addition, dopamine, 3-methoxytyramine, and homovanillic acid increased in the NAc in female mice fed the KO diet. Notably, the effects of the KO diet on the immobility time in the FST were abolished by microinjection of sulpiride, an antagonist of D2-like receptors, into the NAc. A similar microinjection of an antagonist selective for D1-like receptors, SKF83566, also abolished the reduction in immobility in the FST. Moreover, we found that tyrosine hydroxylase-positive cells increased in the ventral tegmental area (VTA) in mice fed the KO diet. These results suggest that modulation of the VTA-NAc dopaminergic pathway is one of the mechanisms by which a KO diet rich in ω-3 PUFAs reduces the immobility behavior in the mouse FST.

Effects of Zuojin pill on depressive behavior and gastrointestinal function in rats with chronic unpredictable mild stress: Role of the brain-gut axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Zoujin pill (ZJP), a medication used to treat gastrointestinal disorders since the 15th Century in China, have been reported to exert anti-depressant effects in various models. STUDY AIM: To assess the effects of ZJP on gastrointestinal function and depressive behavior in rats under chronic unpredictable mild stress (CUMS), and to examine the underlying mechanisms related to brain-gut axis. METHODS: The rats suffered the stressor once daily for 5 weeks. ZJP (0.6 and 1.2 g/kg) and fluoxetine (15 mg/kg) as positive control were administered to the rats through gastric intubation once daily for 5 consecutive weeks. The anti-depression effects were compared by performing sucrose preference tests and open field tests. Gastrointestinal motility was investigated by determining the gastrointestinal transit rate and by electrogastrogram. The serum levels of the gastrointestinal hormone (GAS, MOT, VIP, SP), inflammatory cytokine (IL-1ß, IL-6; , TNFα) and glucagon-like peptide-1 (GLP-1) were assayed by enzyme-linked immunosorbent assay. For monoamine neurotransmitters (NE, 5-HT, DA), the levels were determined by high-performance liquid chromatography and electrochemical detection in conjunction, which was applied on the samples taken from the hypothalamus, hippocampus, and striatum. RESULTS: The depression-like symptoms among rats under CUMS were significantly relieved by ZJP administration (0.6 and 1.2 g/kg). Gastrointestinal motility was also improved by restoring gastric electrical rhythm and promoting gastrointestinal propulsion. The ZJP at 0.6 g/kg dosage obviously up-regulated 5-HT and DA levels in hippocampus. The ZJP at 1.2 g/kg dosage could increase 5-HT and DA levels in hypothalamus, striatum, and hippocampus, while down-regulated the NE level in hypothalamus and hippocampus. ZJP also reversed the alterations in serum gastrointestinal hormones. Furthermore, treatment with ZJP significantly reduced levels of IL-1ß, IL-6 and TNF-α and increased serum GLP-1 compared with the CUMS group. Fluoxetine also exerted similar anti-depressant effects in the absence of effects on gastrointestinal motility and the levels of serum hormone, inflammatory cytokine and GLP-1. CONCLUSION: ZJP imposed anti-depressant and gastrointestinal regulating functions in rats under CUMS, suggesting potential clinical application. .

Chronic social defeat stress: Impacts on ethanol-induced stimulation, corticosterone response, and brain monoamine levels.

BACKGROUND: Chronic exposure to stress may dysregulate the hypothalamic-pituitary-adrenal axis and brain monoamine levels, contributing to the development of ethanol dependence. Exposure to chronic social defeat stress may impact ethanol-related effects, neural, and endocrine functions. AIM: This study assessed ethanol-induced locomotor activity, corticosterone responses, and brain monoamine levels in Swiss albino mice 10 days post-exposure to chronic social defeat stress. METHODS: During a period of 10 days, male Swiss mice were exposed to daily defeat episodes, followed by housing with an aggressive mouse for 24 h. Control mice were housed in pairs and rotated every 24 h. Ten days post-stress, locomotor behavior was recorded after a challenge with ethanol (2.2 g/kg; intraperitoneal) or saline. After the test, blood and brain samples were collected for determination of plasma corticosterone and brain monoamines across different brain areas through high-performance liquid chromatography. RESULTS: Defeated mice failed to show a stimulant locomotor response to ethanol, while controls displayed the expected ethanol-induced stimulation. Ethanol increased plasma corticosterone levels, with lower corticosterone secretion in defeated mice. Brain monoamines were affected by social defeat and ethanol, varying in different brain regions. Social stress reduced levels of dopamine, noradrenaline, and serotonin in the hypothalamus. Defeated mice presented reduced serotonin and dopamine levels in the frontal cortex. In the striatum, ethanol treatment increased dopamine levels in controls, but failed to do so in defeated mice. CONCLUSIONS: Our results suggest that chronic exposure to social defeat blunted ethanol-induced locomotor stimulation, and reduced ethanol-induced corticosterone secretion. Social stress promoted differential reductions in brain monoamine levels in the hypothalamus and frontal cortex and blunted ethanol-induced dopamine increases in the striatum.

Reduced home cage and social activity in Pou3f2⊿ mice.

Pou3f2/Brn2 is a transcription factor that helps to determine the cellular identity of neocortical or hypothalamic neurons. Mammalian Pou3f2 contains three homopolymeric amino acids that are not present in amphibian Pou3f2. These amino acids contribute to monoamine function, which may play specific roles in mammalian development and behavior. Previous work has indicated that Pou3f2⊿ mice, which lack the homopolymeric amino acids, exhibited declined maternal activity and impaired object and spatial recognition. The current study, analyzed weight gain, brain development, home cage activity, social interaction, and response to novel objects in Pou3f2⊿ mice to determine which aspects of behavior were affected by monoamine dysregulation. Compared to their wild type counterparts, Pou3f2⊿ mice showed decreased social interaction and reduced home cage activity during their active phase. However, they showed normal weight gain, brain development, and responses to novelty. These results indicate that monoamine dysregulation in Pou3f2⊿ mice may specifically affect basal activity and social development, without altering non-social motivation.

Umbelliferone modulates depression-like symptoms by altering monoamines in a rat post-traumatic stress disorder model.

Post-traumatic stress disorder (PTSD) is a debilitating psychological disease that is triggered by traumatic events. It is known to cause various complications, including anxiety and depression. Umbelliferone (UMB) is a natural product of the coumarin family. This substance has been reported to exert antioxidant, anti-inflammatory, neuroprotective, and other biological effects. We used the open field test (OFT) and the forced swimming test (FST) to examine the effects of UMB on depression-like symptoms in rats after exposure to a single prolonged stress (SPS), which led to dysregulated activation of the serotonergic system. Male rats were given UMB (20, 40, or 60 mg/kg, intraperitoneal injection) once daily for 14 days after exposure to an SPS. Daily UMB administration significantly improved depression-like behaviors on the FST, increased the number of lines crossed in the central zone of the OFT, and reduced freezing behavior in both contextual and cued fear conditioning. UMB treatment attenuated the SPS-induced decrease in serotonin (5-HT) concentrations in the hippocampus and amygdala. The increased 5-HT concentration during UMB treatment was partially due to a decrease in the ratio of 5-hydroxyindoleacetic acid/5-HT in the hippocampus of rats with PTSD. According to our results, UMB has an antidepressant effect in rats exposed to an SPS, suggesting that this natural product of the coumarin family can be used to effectively treat PTSD.

Uncovering pharmacological mechanisms of Zhi-Zi-Hou-Po decoction in chronic unpredictable mild stress induced rats through pharmacokinetics, monoamine neurotransmitter and neurogenesis.

ETHNOPHARMACOLOGICAL RELEVANCE: Zhi-Zi-Hou-Po decoction (ZZHPD), a classical Chinese prescription, has been reported to improve depressive behaviors in clinic. However, definite pharmacological effects and mechanisms of ZZHPD on monoaminergic system and hippocampal neurogenesis are ambiguous. It need to be further illuminated. AIM OF THE STUDY: Our study is designed to reveal pharmacological mechanisms of ZZHPD on depression through pharmacokinetics, monoamine neurotransmitters and neurogenesis. MATERIALS AND METHODS: Chronic unpredictable mild stress (CUMS) is used to establish rats model of depression. Then, the antidepressant effects of ZZHPD are evaluated by detecting body weight, sucrose preference and forced swimming test. The regulatory functions of ZZHPD on monoaminergic system are assessed by measuring monoamine neurotransmitters, neurotransmitter precursor substances, synthesized rate-limiting enzymes and transporters. Finally, potential molecular mechanism of ZZHPD on hippocampal neurogenesis is evaluated by investigating newborn immature neuron and newborn mature neuron. RESULTS: Our results show that ZZHPD remarkably normalizes CUMS-induced decline in weight gain, decrease of sucrose consumption rate in sucrose preference test and increase of immobility time in forced swimming test. Moreover, ZZHPD significantly reverses CUMS-induced reduction of 5-hydroxytryptamine (5-HT), dopamine (DA), tryptophan (Trp), tyrosine (Tyr), tryptophan hydroxylase2 (TPH2) and tyrosine hydroxylase (TH), whereas decreases level of serotonin transporter (SERT) in CUMS-induced rats. Finally, ZZHPD obviously improves CUMS-induced decrease of newborn immature neuron and newborn mature neuron in dentate gyrus of hippocampus. CONCLUSION: This study demonstrates that ZZHPD can alleviate CUMS-induced depression-like behaviors. It is probably attributed to the fact that ZZHPD could enhance monoaminergic system and hippocampal neurogenesis. Our findings provide the new perspectives on molecular targets of ZZHPD, and it will facilitate its clinical application.

Anxiolytic Effect of Cedrol on Behavior and Brain Neurotransmitter Levels of Female Mice.

Cedrol has been reported to be effective in reducing anxiety of male mice. The limited application of females in animal models of anxiety makes it difficult to systematically investigate new drug substitutes with potential anxiolytic activity. In the present study, we investigated the behavioral response of female ICR mice to cedrol after intraperitoneal (i.p.) administration using the elevated plus maze (EPM) and the light-dark box (LDB) test, followed by determination of neurochemical changes in brain. The data suggested that cedrol at dose of 1200-1600 mg·kg-1 exhibited anxiolytic activity on the female mice, as reflected by greater percentage of entries into the open arms and time spent in the open arms in the EPM, and greater transitions between chambers and percentage of time spent in the light chamber in the LDB. Cedrol increased the level of 5-hydroxytryptamine (5-HT), decreased the level of dopamine (DA), reduced the ratio of 5-hydroxyindoleacetic acid (5-HIAA)/5-HT and increased the ratio of 3,4-dihydroxyphenyl acetic acid (DOPAC)/DA, compared with the control group, indicative of an anxiolytic-like effect on female mice via the 5-HTnergic or DAnergic pathways.

Pharmacological profiles of compounds in preworkout supplements ("boosters").

Preworkout supplements ("boosters") are used to enhance physical and mental performance during workouts. These products may contain various chemical substances with undefined pharmacological activity. We investigated whether substances that are contained in commercially available athletic multiple-ingredient preworkout supplements exert amphetamine-type activity at norepinephrine, dopamine, and serotonin transporters (NET, DAT, and SERT, respectively). We assessed the in vitro monoamine transporter inhibition potencies of the substances using human embryonic kidney 293 cells that expressed the human NET, DAT, and SERT. The phenethylamines ß-phenethylamine, N-methylphenethylamine, ß-methylphenethylamine, N-benzylphenethylamine, N-methyl-ß-methylphenethylamine, and methylsynephrine inhibited the NET and less potently the DAT similarly to D-amphetamine. ß-phenethylamine was the most potent, with IC50 values of 0.05 and 1.8 µM at the NET and DAT, respectively. These IC50 values were comparable to D-amphetamine (IC50 = 0.09 and 1.3 µM, respectively). The alkylamines 1,3-dimethylbutylamine and 1,3-dimethylamylamine blocked the NET but not the DAT. Most of the phenethylamines interacted with trace amine-associated receptor 1, serotonin 5-hydroxytryptamine-1A receptor, and adrenergic α1A and α2A receptors at submicromolar concentrations. None of the compounds blocked the SERT. In conclusion, products that are used by athletes may contain substances with mainly noradrenergic amphetamine-type properties.

Antidepressant-like effect of a standardized hydroethanolic extract of Asparagus adscendens in mice.

OBJECTIVE: Asparagus adscendens Roxb. (Liliaceae), a traditional herbal medicine, has been used as an aphrodisiac and brain tonic in Asian countries. The aim of the present study is to investigate the antidepressant-like effect of standardized hydroethanolic extract of A. adscendens root and its possible mechanisms. MATERIALS AND METHODS: Mice administered with vehicle, imipramine (15 mg/kg/day; i.p.), and A. adscendens extract (AAE) (25, 50, and 100 mg/kg/day; i.p.) for 14 days were subjected to behavioral tests including forced swimming test (FST), tail suspension test (TST), and open-field test (OFT) on the 14th day. In order to explore the underlying mechanism behind an antidepressant effect of AAE, the brain monoamine levels, oxidative stress parameters, and serum corticosterone levels were monitored. RESULTS: Our results indicated that pretreatment of AAE (25, 50, and 100 mg/kg) for 14 days statistically significantly (P < 0.01) demonstrated antidepressant-like effect as evidenced by reduced immobility time in both FST (105, 78.6, and 53.6 s) and TST (97.6, 73.5, and 54.67 s), with no significant change in spontaneous locomotor activities as observed in OFT. Further, the behavioral improvement was supported by the statistically significantly (P < 0.05) enhanced levels of monoamines and reduced corticosterone level along with amelioration of oxidative stress in AAE-treated animals as compared to vehicle control group. Conclusion: Our findings clearly demonstrated the antidepressant-like effect of AAE, which might have been mediated through the modulation of monoaminergic system and by regulating hypothalamic-pituitary-adrenal axis with amelioration of oxidative stress.

The effect of Hordeum vulgare on the monoaminergic system modulating neural-thyroid dysfunction in hypothyroid female rats.

Thyroid hormones regulate the development and maturation of the brain by maintaining levels of neurotransmitters and their related metabolites. The present work emphasizes the neural dysfunction in the brain caused by hypothyroidism and the potential role of Hordeum vulgare (water soluble barley, (B)) in ameliorating these effects. The study was conducted on euothyroid and hypothyroid adult female rats. The induction of hypothyroidism was conducted by oral-administration of neo-mercazole (5.0 mg.kg-1) daily for thirty days prior the study and terminated at the end of the study. The groups were assigned as; euthyroid (EU) and hypothyroid (H) groups and other two groups were treated with 100 mg.kg-1 water soluble barley; daily for one month and assigned as (EU+B) and (H+B) groups. Compared with EU and EU+B groups, a reduction in fT4, and ERK1/2 levels and elevation in TSH in brain tissue, Moreover, a  significant elevation in 8-OH deoxyguanosine and caspase-3 levels, confirmed with increase percentage DNA-damage in the brain and thyroid tissues in hypothyroid control rats. Furthermore, a significant decrease in all monoamines levels in different brain areas and downregulation of dopamine and 5-hydroxytreptamin receptors transcription, with a significant increase in excitatory amino acids and no significant change in the levels inhibitory amino acids were recorded in control hypothyroid group. Treatment of hypothyroid group with Hordeum vulgare improved the above-mentioned adverse impact by ameliorating the thyroid hormone levels with depleting the DNA-degradation and elaborating the levels of neurotransmitters with related receptors and amino acids in brain areas.  Water soluble Hordeum vulgare as a phytonutrient, is safe and efficient agent in ameliorating the neural dysfunction resulting from hypothyroidism status in adult female rats.

Low temperature-aged garlic extract suppresses psychological stress by modulation of stress hormones and oxidative stress response in brain.

BACKGROUND: Garlic is a folk medicine known for its multiple physiological activities, but the neuro-modulatory effect of garlic against psychological stress has rarely been explored. The current study was conducted to determine the potential antipsychological stress effect of low temperature-aged garlic (LTAG). METHODS: After acute restraint stress exposure, mice were administered with raw garlic (RG, 500 mg/kg, p.o.) or LTAG (500 mg/kg, p.o.). We investigated corticosterone, cortisol, and monoamines levels, and the mRNA expression of genes relevant to oxidative stress. RESULTS: RG and LTAG treatment significantly decreased stress-related hormones such as corticotropin-releasing factor, adrenocorticotropic hormone, corticosterone, and cortisol. Moreover, RG and LTAG administration significantly restored acute restraint stress-induced changes in concentrations of brain neurotransmitters (serotonin, norepinephrine, dopamine, and epinephrine). In addition, RG and LTAG improved the antioxidant defense system by causing an increase in mRNA expression of superoxide dismutase, catalase, and glutathione peroxidase in the brain. CONCLUSION: This study suggests an antipsychological stress and neuroprotective effect of RG and LTAG under stress conditions.