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.

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.

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.

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.

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.

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.

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.

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.

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.

Zhile Capsule Exerts Antidepressant-Like Effects through Upregulation of the BDNF Signaling Pathway and Neuroprotection.

Major depressive disorder is now becoming a common disease in daily life, and most patients do not have satisfactory treatment outcomes. We herein evaluated the therapeutic effects of Zhile capsule and clarified the molecular mechanism. A rat model of chronic unpredictable mild stress-induced depression was established to assess the antidepressant-like effects of Zhile by using the sucrose preference test, open field test, forced swim test, tail suspension test and HPLC. Systems pharmacology was then performed to unravel the underlying mechanism which was confirmed by western blot, enzyme-linked immunosorbent assay, and qPCR. Zhile alleviated depression-like behaviors by upregulating the cAMP-CREB-BDNF (brain-derived neurotrophic factor) axis to exert neuroprotective effects. It may be beneficial to depressive patients in clinical practice.

Hyperbaric oxygen therapy restored traumatic stress-induced dysregulation of fear memory and related neurochemical abnormalities.

Individuals with posttraumatic stress disorder (PTSD) are characterized by fear memory problems and hypocortisolemia of which traumatic stress-induced monoaminergic disruption over infralimbic (IL) cortex is considered the key mechanism. Hyperbaric oxygen therapy (HBOT) has recently proven its utility in treating several mental disorders but remains unexplored for PTSD. The present study aimed to examine the effects of 5-day HBO paradigm on traumatic stress (single prolonged stress, SPS, an animal model of PTSD)-induced dysregulation of fear memory/anxiety profiles and related abnormalities in IL monoamines and plasma corticosterone. Rats were randomly assigned to four groups (CON-sham, CON-HBOT, SPS-sham, and SPS-HBOT) and received Pavlovian fear conditioning test or elevated-T maze (ETM). The extracellular and tissue levels of monoamines over the IL cortex and the activity of the hypothalamus-pituitary-adrenal axis (i.e., the plasma corticosterone level and expression of the glucocorticoid receptor (GR) in the IL, hippocampus, amygdala, and hypothalamus) were measured. The results demonstrated that HBOT restored behaviorally the SPS-impaired fear extinction retrieval ability and SPS-induced conditioned anxiety, and neurochemically the SPS-reduced IL monoamines efflux level, and the corticosterone profiles. The present study shows some positive effects of HBOT in both behavioral and neurochemical profiles of PTSD outcomes.

Anxiolytic actions of Nardostachys jatamansi via GABA benzodiazepine channel complex mechanism and its biodistribution studies.

Nardostachys jatamansi has profound applications against pharmacological interventions and is categorized as a hypno-sedative drug according to Ayurveda. In the present study probable mechanism of anxiolytic action of Nardostachys jatamansi extract (NJE) was studied using behavioral anxiolytic tests (Elevated plus maze, Open field test, Light dark box test, and Vogel's conflict test) in mice. Mice were treated orally with NJE (250 mg/kg) for 3, 7 and 14 days or diazepam (1 mg/kg) followed by behavioral assessment and estimation of monoamine neurotransmitters, GABA, and antioxidant enzymes. Treatment of mice for 7 days caused an increase in time spent in open arms in elevated plus maze, number of line crossings in open field test, increased time spent in lit compartment of light-dark box test, an increase in number of licks made and shocks accepted in Vogel's conflict test, with results comparable to diazepam and this treatment also caused a significant increase in monoamine neurotransmitters and GABA in brain and tissue antioxidant parameters. Co-treatment of NJE with flumazenil (GABA-benzodiazepine antagonist; 0.5 mg/kg i.p) or picrotoxin (GABAA gated chloride channel blocker; 1 mg/kg i.p) caused a blockage/antagonised anxiolytic actions of NJE by causing a significant reduction in time spent in open arms of elevated plus maze, an decrease in number of line crossing in open field test and also number of shocks and licks accepted in Vogel's conflict test. Further, NJE was radiolabelled with technetium99m at their hydroxyl groups following which purity as well as in vivo and in vitro stability of radiolabelled formulations was evaluated. The blood kinetics and in vivo bio-distribution studies were carried out in rabbits and mice respectively. Labeled formulation was found to be stable in vitro (96 to 93% stability) and in vivo (96 to 92% stability). The labeled compound was cleared rapidly from blood (within 24 h) and accumulated majorly in kidneys (11.65 ± 1.33), liver (6.07 ± 0.94), and blood (4.03 ± 0.63) after 1 h. However, a small amount was observed in brain (0.1 ± 0.02) probably because of its inability to cross blood-brain barrier. These results highlight biodistribution pattern of NJE, and also indicated that a 7-day treatment with NJE produced significant anxiolytic effects in mice and also a significant increase in brain monoamine and GABA neurotransmitter levels and suggests that anxiolytic effects of NJE are primarily and plausibly mediated by activating GABAergic receptor complex.

Extrastriatal monoaminergic dysfunction and enhanced microglial activation in idiopathic rapid eye movement sleep behaviour disorder.

BACKGROUND: The majority of patients diagnosed with idiopathic rapid eye movement sleep behaviour disorder (iRBD) progress over time to a Lewy-type α-synucleinopathy such as Parkinson's disease or dementia with Lewy bodies. This in vivo molecular imaging study aimed to investigate if extrastriatal monoaminergic systems are affected in iRBD patients and if this coincides with neuroinflammation. METHODS: We studied twenty-one polysomnography-confirmed iRBD patients with 18F-DOPA and 11C-PK11195 positron emission tomography (PET) to investigate extrastriatal monoaminergic function and microglial activation. Twenty-nine healthy controls (n = 9 18F-DOPA and n = 20 11C-PK11195) were also investigated. Analyses were performed within predefined regions of interest and at voxel-level with Statistical Parametric Mapping. RESULTS: Regions of interest analysis detected monoaminergic dysfunction in iRBD thalamus with a 15% mean reduction of 18F-DOPA Ki values compared to controls (mean difference = -0.00026, 95% confidence interval [-0.00050 to -0.00002], p-value = 0.03). No associated thalamic changes in 11C-PK11195 binding were observed. Other regions sampled showed no 18F-DOPA or 11C-PK11195 PET differences between groups. Voxel-level interrogation of 11C-PK11195 binding identified areas with significantly increased binding within the occipital lobe of iRBD patients. CONCLUSION: Thalamic monoaminergic dysfunction in iRBD patients may reflect terminal dysfunction of projecting neurons from the locus coeruleus and dorsal raphe nucleus, two structures that regulate REM sleep and are known to be involved in the early phase of PD. The observation of significantly raised microglial activation in the occipital lobe of these patients might suggest early local Lewy-type α-synuclein pathology and possibly an increased risk for later cognitive dysfunction.

Zanthoxylum alatum abrogates lipopolysaccharide-induced depression-like behaviours in mice by modulating neuroinflammation and monoamine neurotransmitters in the hippocampus.

CONTEXT: Depression is an inflammatory, commonly occurring and lethal psychiatric disorder having high lifetime prevalence. Zanthoxylum alatum Roxb. (Rutaceae), commonly called Timur, has high medicinal value and is used ethnomedicinally for the treatment of various diseases. OBJECTIVE: To evaluate the effect of hexane extract of Z. alatum seeds (ZAHE) on lipopolysaccharide (LPS)-induced depression-like behaviour in Swiss albino mice. MATERIALS AND METHODS: Mice were treated with ZAHE (100 and 200 mg/kg, p.o.) and imipramine (10 mg/kg injected i.p.) for 14 days. On 14th day of the treatment, depression-like behaviour was induced by LPS (0.83 mg/kg injected i.p.) and after 24 h of LPS administration, it was assessed by measuring behavioural parameters and biochemical estimations. RESULTS: Behavioural tests, including the open field test, forced swimming test, tail suspension test and sucrose preference test revealed that ZAHE (100 and 200 mg/kg, p.o.) and imipramine (10 mg/kg injected i.p.) alleviated the depression symptoms of LPS-induced mice. Moreover, ZAHE treatments reversed the LPS-induced alterations in the concentrations of norepinephrine and serotonin (5-HT) and inhibited the expression of brain-derived neurotrophic factor, pro-inflammatory cytokines and oxido-nitrosative stress in the mice. Acute toxicity was calculated to be LD50 > 2500 mg/kg. DISCUSSION AND CONCLUSIONS: This study showed that LPS-induced depression in mice was significantly prevented by ZAHE at both the dosages. In conclusion, ZAHE exhibited an antidepressant activity by altering monoaminergic neurotransmitters in the brain combined with its anti-inflammatory potential. Thus, it could be an effective therapeutic against inflammation-induced depression and other brain disorders.