Tail Suspension Test Research Articles

Activation of Hippocampal Neuronal NADPH Oxidase NOX2 Promotes Depressive-Like Behaviour and Cognition Deficits in Chronic Restraint Stress Mouse Model.

Nicotinamide adenosine dinucleotide phosphate oxidases (NOX) play important roles in mediating stress-induced depression. Three NOX isotypes are expressed mainly in the brain: NOX2, NOX3 and NOX4. In this study, the expression and cellular sources of these NOX isoforms was investigated in the context of stress-induced depression. Chronic restraint stress (CRS)-induced depressive-like behaviour and cognitive deficits were evaluated by tail suspension tests, forced swimming tests and the Morris water maze test. Hippocampal NOX expression was determined by immunofluorescence staining and western blotting. The hippocampal levels of the brain-derived neurotrophic factor (BDNF) mRNA were determined via quantitative real-time -polymerase chain reaction. Glucocorticoid levels in the hippocampus were measured using ELISA kits. In the mouse CRS model, a significant increase in NOX2 expression was observed in the hippocampus, whereas no significant changes in NOX3 and NOX4 expression were detected. Next, NOX2 expression was primarily localised to neurons (NeuN+) but not microglia (Iba-1+) or astrocytes (GFAP+). Treatment with gp91ds-tat, a specific NOX2 inhibitor, effectively mitigated the behavioural deficits induced by CRS. The decreased expression of the BDNF mRNA in the hippocampus of CRS mice was restored upon gp91ds-tat treatment. A positive correlation was identified between neuronal NOX2 expression and serum glucocorticoid levels. Our study indicated that neuronal NOX2 may be a critical mediator of depression-like behaviours and spatial cognitive deficits in mice subjected to CRS. Blockade of NOX2 signalling may be a promising therapeutic strategy for depression.

Diethyl butylmalonate attenuates cognitive deficits and depression in 5×FAD mice

BackgroundAlzheimer’s disease (AD), characterized by cognitive impairment and depression, is currently one of the intractable problems due to the insufficiency of intervention strategies. Diethyl butylmalonate (DBM) has recently attracted extensive interest due to its anti-inflammatory role in macrophages. However, it is still unknown whether DBM has a beneficial effect on cognitive deficits and depression.MethodsDBM was administrated to 5×FAD and C57BL/6J mice by intraperitoneal injection. Novel object recognition, Y-maze spatial memory, Morris water maze and nest building tests were used to evaluate cognitive function. Moreover, the tail suspension test, forced swimming test, open field test and the elevated plus maze test were used to assess depression. Transmission electron microscopy, Golgi-Cox staining, immunofluorescence, RT-qPCR and western blot were utilized to determine the neuropathological changes in the hippocampus and amygdala of mice.ResultsMultiple behavioral tests showed that DBM effectively mitigated cognitive deficit and depression in 5×FAD mice. Moreover, DBM significantly attenuated synaptic ultrastructure and neurite impairment in the hippocampus of 5×FAD mice, paralleled by the improvement of the deficits of PSD95 and BDNF proteins. In addition, DBM decreased the accumulation of microglia and downregulated neuroinflammation in the hippocampus and amygdala of 5×FAD mice.ConclusionThis study provides evidence that DBM ameliorates cognitive deficits and depression via improvement of the impairment of synaptic ultrastructure and neuroinflammation, suggesting that DBM is a potential drug candidate for treating AD-related neurodegeneration.

ANTIDEPRESSANT-LIKE ACTIVITY OF AQUEOUS EXTRACT OF ROSA DAMASCENA IN MICE

Objective: Plant-based drugs have the potential to be very effective substitutes for prescription antidepressants. Rosa damascena has therapeutic potential as an analgesic, anticonvulsant, antitussive, bronchodilatory, antibacterial, anti-diabetic, anti-inflammatory, antioxidant, and laxative. Given this context, the goal of the current study was to assess Rosa damascena's potential antidepressant effects. Methods: Maceration was used to create an aqueous extract of Rosa damascena. The Tail Suspension Test (TST) on BALB/c mice and the Forced-Swimming test (FST) on C57BL/6 mice were used to quantify the antidepressant activity. Mice were divided into three groups: control (saline), standard (citalopram and desipramine), and Rosa damascena aqueous extract (n = 6 per group). Intraperitoneally (1 ml/100 g) injections of drugs were administered. Analysis of variance was used to examine the data, and then LSD post-hoc tests were performed. The data are expressed as mean±SEM. Results: Antidepressant-positive controls, citalopram and desipramine, significantly decreased the time of immobility in the FST and TST as compared to the vehicle control group (p<0.001). In FST, the immobility durations were significantly reduced by the Rosa damascena aqueous extract at a dose of 40 mg/kg compared to lesser doses of the same extract (10 and 20 mg/kg) (p<0.001). Similarly, the 40 mg/kg dose of Rosa damascena aqueous extract significantly reduced the length of immobility in TST (p<0.001). Conclusion: The present findings demonstrate Rosa damascena's antidepressant-like effects in mice. Further research is necessary to determine the underlying mechanism by which Rosa damascena generates effects akin to those of an antidepressant in light of this observation.

SARM1 Deficiency Induced Depressive-like Behavior via AMPKα/p-eEF2 axis to Synapse Dysfunction

Sterile Alpha and TIR Motif Containing 1 (SARM1) are proteins implicated in various neurological processes; however, their role in depression remains unexplored. This study investigated the contribution of SARM1 to depressive-like behaviors in a chronic stress-induced depression model and SARM1 knockout (KO) mice. Depressive-like behaviors were assessed using a battery of behavioral tests, including the Open Field Test (OFT), the Forced Swim Test (FST), the Sucrose Preference Test (SPT), and the Tail Suspension Test (TST). Mitochondrial energy metabolism alteration, cytokine level changes, and other related molecular signalling protein expression were evaluated using ELISA and western blotting techniques to investigate the underlying mechanisms. Behavioral assessments (OFT, FST, SPT, TST) revealed depressive-like phenotypes in SARM1 KO mice, accompanied by altered mitochondrial energy metabolism (NAD+, ATP) in the cortex. Intriguingly, SARM1 depletion led to peripheral inflammation, as evidenced by elevated cytokine levels in plasma but not in brain regions (cortex). In addition, we found dysregulated energy metabolism, AMPK signaling, and synaptic plasticity in the cortex of SARM1 KO mice. Notably, AICAR (Acadesine), an AMPK activator, ameliorated depressive-like behaviors and synaptic dysfunction, while Compound C, an AMPK inhibitor, reversed these effects. Additionally, NH125, an eEF2 kinase inhibitor, improved depressive-like behaviors in SARM1 KO mice. These findings demonstrate that SARM1 is critical in regulating depressive-like behaviours through the AMPKα/p-eEF2 signalling pathway. Targeting AMPK signaling and synaptic function may offer novel therapeutic avenues for depression.

Ascorbic acid Mitigates behavioural disturbances associated with letrozole-induced PCOS via switching-off JAK2/STAT5 and JAK2/ERK1/2 pathways in rat hippocampus

PurposePolycystic ovary syndrome (PCOS) is an endocrine disorder with the highest prevalence among other disorders in sexually-active women. It is associated with broad-spectrum hormonal and metabolic disturbances with behavioural difficulties. Experimentally, letrozole administration causes similar findings. Ascorbic acid is powerful anti-oxidant; and its cellular levels decrease with “hyperglycemic and poor anti-oxidative” status, which is, a main hallmark of PCOS. Thus, ascorbic acid administration may prevent the induction of PCOS and its consequences.Basic procedures: Forty female rats were divided into four groups (n = 10 in each): normal control (CTRL), ascorbic acid (ASC), letrozole (LTZ), and ascorbic acid + letrozole (ASC + LTZ) group. Behavioural tests (Y-maze spontaneous alteration, tail suspension test, forced swimming test) were performed. In serum, hormones (testosterone, estradiol, progesterone), glycemia (blood glucose, insulin and HOMA-IR) and oxidative stress (SOD activity, GSH) markers were measured. In hippocampus, inflammation and apoptosis indicators (p-JAK2, p-STAT5, p-ERK1/2, NF-κB, BAX, Bcl2, BAX/Bcl2 ratio) and neurotransmitters (DA, 5-HT, NE, BDNF) were determined. Lastly, ovary histopathological investigation was conducted to confirm PCOS induction.Principal results: Letrozole induced PCOS with subsequent disturbances. Testosterone levels were augmented while estradiol and progesterone were declined. Fasting blood glucose, insulin, HOMA-IR and oxidative stress markers were elevated. The expression of p-JAK2, p-STAT5, p-ERK1/2, BAX and the levels of NF-κB were increased, but Bcl2 expression, monoamines and BDNF levels were lowered. Importantly, ASC abated the last mentioned parameters markedly. Major conclusions: Ascorbic acid mitigated the behavioural difficulties of PCOS possibly by switching-off JAK2/STAT5 and JAK2/ERK1/2 pathways in hippocampus along with its neurotransmission-improving, hormonal-normalizing, anti-hyperglycemic and anti-oxidative effects.

Xylopia parviflora (A. rich.) benth. Mitigates anxiety behavior and chronic mild stress-induced depression-like behavior in mice: The involvement of biogenic amine neurotransmitters, cyclooxygenase-2 and stress biomarkers in its antidepressant activity

BackgroundXylopia parviflora is a novel botanical in Modern Chinese Medicine that contains bioactive constituents including alkaloids, flavonoids, and terpenoids, which are the pharmacologically active components in various Chinese herbal formulations such as Coptis chinensis (alkaloid-rich herbs), Ginkgo biloba (flavonoid-rich herbs) and Artemisia annua (terpenoid-rich herbs). ObjectiveThis investigation sought to evaluate the anxiolytic and antidepressant-like effects of the hydroethanol leaf extract of Xylopia parviflora using mouse models. We elucidated the roles of noradrenaline, serotonin, cyclooxygenase-2, and reactive oxidative species in mediating its antidepressant effects, providing a fresh perspective on the pharmacological activity of Xylopia parviflora. MethodsThe acute toxicity of XPE was assessed following OECD guideline 420. Established behavioral tests were used to evaluate the anxiolytic (including the hole-board, open field, elevated plus maze, and light/dark exploration assessments) and antidepressant (encompassing the forced swim and tail suspension tests) effects of the extract. Mice received treatments of distilled water (10 mL/kg, serving as the negative control), fluoxetine (20 mg/kg, acting as the reference medication), and XPE (at doses of 50, 100, and 200 mg/kg). The concentrations of noradrenaline, serotonin, and COX-2 within the brain tissue were quantified using ELISA kits. The levels of antioxidant biomarkers were evaluated using standardized commercial assay kits. ResultsThe oral/intraperitoneal LD50 for the extract was established at 2000 mg/kg. In the behavioral assessments designed to measure anxiolytic effects, XPE significantly mitigated anxiety levels in mice, as evidenced by an increase in exploratory behaviors (including head dips, sectional crossings, general square crossings, rearing, and assisted rearing) and an increased time spent in the brightly illuminated compartments. Concerning the antidepressant evaluations, XPE significantly reduced depression-like behaviors in mice, which was indicated by an increased latency to immobility and a decrease in the duration of immobility. XPE was found to modulate noradrenaline and serotonin transmissions, attenuate oxidative species, and inhibit COX-2 activity. ConclusionThe findings above demonstrate that Xylopia parviflora possesses anxiolytic and antidepressant-like activities. The antidepressant property of XPE, as revealed in this study, may be attributable to the enhancement of biogenic amines (specifically noradrenaline and serotonin), the suppression of oxidative species, and the inhibition of COX-2 activity.

Fructus Arctii Mitigates Depressive Disorder via the Let-7e-Modulated Toll-Like Receptor (TLR) Signaling Pathway.

Depressive disorder is a common and serious public health challenge globally. Fructus arctii is a traditional medicinal plant ingredient with diverse pharmacological effects. This study aimed to investigate the therapeutic potential of Fructus arctii in alleviating depressive-like behaviors. We established a chronic unpredictable mild stress (CUMS)-induced depression mouse model to assess the antidepressant effects of Fructus arctii. BV2 cells treated with lipopolysaccharide (LPS) were used to mimic neuronal damage. Behavioral tests, including the sucrose preference test, tail-suspension test, and forced swim test, were conducted to evaluate the impact of Fructus arctii on depressive-like behaviors. Let-7e expression was detected by RT-qPCR, and TLR4 signaling pathway activation was evaluated by western blot analysis, which also assessed the inflammatory response by measuring levels of IL-6, IL-1β, MCP-1, TNF-α, and iNOS. Immunohistological analysis was conducted to detect the expression of microglia markers. Luciferase reporter assays verified the interaction between let-7e and TLR4. Fructus arctii administration effectively alleviated depressive-like behaviors induced by CUMS in mice, as evidenced by improved sucrose preference and reduced immobility time in behavioral tests. Mechanistically, Fructus arctii reversed the CUMS-induced downregulation of let-7e and upregulation of TLR4 and MyD88 protein levels in mice hippocampus tissues. In addition, Fructus arctii suppressed microglial activation and reduced the levels of inflammatory factors by upregulating let-7e. Let-7e was verified to bind to TLR4, thereby negatively regulating its expression. TLR4 overexpression reversed the suppressive effect of let-7e upregulation on inflammatory reactions and microglial activation. Furthermore, intracerebroventricular injection of let-7e agomiR alleviated depressive-like behavior and inhibited microglial activation in vivo. In summary, Fructus arctii mitigates depression by regulating the let-7e/TLR4/MyD88 pathway, offering new insights into potential depression therapies.

Moringa oleifera Lam. seed lectin (WSMoL) reduces chronic stress-induced anxiety and depression in mice by lessening inflammation and balancing brain chemicals

Phyto-based treatments for anxiety and depression are gaining attention. The efficacy of the water-soluble Moringa oleifera seed lectin (WSMoL) in reducing acute anxiolytic and depressive-like behaviors in mice has been previously demonstrated. In the present study, it was evaluated the effects of WSMoL on reducing anxiety and depressive-like symptoms in a mouse model of unpredictable chronic mild stress (UCMS). The animals were divided into groups and exposed to a four-week UCMS regimen. Following this, the mice received daily intraperitoneal injections of vehicle (non-stressed and UCMS control groups), WSMoL (2 or 4 mg/kg), or fluoxetine (10 mg/kg) for 21 days. Neurobehavioral tests included the open field test and elevated plus maze test to assess anxiety-like behavior, and the tail suspension test and sucrose preference test to evaluate depression-like behavior. Biochemical analyses measured serum corticosterone and cytokines as well brain levels of cytokines and monoamines. All tests indicated that WSMoL significantly (p < 0.05) reversed the anxiety and depression-like behaviors induced by UCMS. The stress protocol increased serum corticosterone levels and WSMoL treatment was not able to normalize corticosterone secretion. WSMoL treatment reduced serum and brain levels of IL-2, IL-6, and TNF-α, indicating reduced neuroinflammation, and increased brain levels of dopamine, serotonin, and noradrenaline. In summary, WSMoL mitigated UCMS-induced anxiety and depression-like behaviors by reducing neuroinflammation and modulating brain monoamine levels.

Hippocampal SENP3 mediates chronic stress-induced depression-like behaviors by impairing the CREB-BDNF signaling.

Impaired signaling between cyclic adenosine monophosphate response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in the hippocampus is generally considered to be the cause of depression. The mechanisms underlying the impairment of CREB-BDNF signaling under stress conditions are largely unclear. Small ubiquitin-like modifier (SUMO) specific peptidase 3 (SENP3) is a molecule that can regulate SUMOylation of target proteins related to synaptic plasticity. Its dynamic changes have been reported to be associated with neuronal damage in various models of central nervous disorders such as cerebral ischemia and traumatic brain injury. However, its role in depression is completely unknown. This problem was addressed in the present study. Our results showed that chronic unpredictable stress (CUS) triggered a specific increase in SENP3 expression in the hippocampus of non-stressed mice. Overexpression of SENP3 in the hippocampus of non-stressed mice elicited depression-like behaviors in the tail suspension test, forced swimming test, and sucrose preference test, accompanied by impairment of the CREB-BDNF signaling cascade in the hippocampus. Conversely, genetic silencing of SENP3 in the hippocampus suppressed the development of depression-like behaviors. Furthermore, infusion of SENP3-shRNA into the hippocampus failed to suppress CUS-induced depression-like behaviors when mice received genetic silencing CREB or BDNF in the hippocampus or inhibition of the BDNF receptor by K252a. Taken together, these results suggest that abnormally elevated SENP3 in the hippocampus leads to the development of depression-like behavior by impairing the CREB-BDNF signaling cascade. SENP3 in the hippocampus could be a promising target for the development of new antidepressants.

To explore the therapeutic effects of shRNA1 and shRNA4 on Parkinson’s disease mice based on the mutation of the SNCA gene of α-synuclein

Based on the SNCA gene mutation of α-synuclein, the therapeutic effects of shRNA1 and shRNA4 on Parkinson’s mice were explored, and the migration mechanism of α-synuclein was explored. Methods: SNCA+/+ mice were used to induce the production of α-synuclein using tuberculin pff to establish Parkinson’s mouse models. AAV-shRNA1 and AAV-shRNA4 were used to set up control and experimental groups in different brain regions and at different times. The open field test, tail suspension test and immunofluorescence were used to explore the therapeutic effect of shRNA4 and the migration mechanism of α-synuclein. Results: ShRNA4 has a significant inhibitory effect on P-α-syn in the brains of Parkinson’s mice compared to shRNA1, and it also shows significant behavioral improvement. The α-synuclein in the olfactory bulb (OB) has undergone whole-brain invasion, while the α-synuclein in the dorsal striatum (CPu) has only undergone invasion in downstream brain regions. Conclusion: Tail vein injection of shRNA4 can have a significant inhibitory effect on α-synuclein and symptomatic treatment in Parkinson’s mice, and the earlier the treatment is initiated, the better the effect.

Investigating the effect of chronic stress, depressive-like pathology and cognitive impairments on acute myocardial infarction: sex-differentiated effects

Abstract Background/Introduction Depression is an independent risk factor for cardiovascular disease (CVD) with the prevalence rates being higher in women than men in the general population and among patients with CVD. Furthermore, an association between myocardial infarction and cognitive deficits has been proposed, but the pathophysiological mechanisms that are responsible for the brain-heart axis interaction have not been elucidated. Purpose The present study aims to: 1) evaluate sex differences in the effect of chronic unpredictable stress (CUS) on myocardial infarct size (IS) and 2) determine the molecular pathways affected by CUS in the heart. Methods Adult male and female C57BL/6J mice, were randomly divided into 4 groups (n=7/group): CON (Control, sham surgery), iCON (Control, myocardial ischemia/reperfusion (IR)), STR (Stress, sham surgery) and iSTR (Stress, IR). Mice were intermittently exposed to the CUS protocol consisted of 4 different stressors for 6 consecutive weeks. Locomotor activity (open field-OF), anxiety-like alterations (OF, elevated plus-maze-EPM test), depressive-like pathology (tail suspension test- TST) and cognition (Y-maze and Novel Object Recognition-NOR tests) were evaluated. After behavioral evaluation, the animals were subjected to 30 min I followed by 24 h of R or sham surgery and infarct size (IS) was determined via double Evan’s Blue and triphenyltetrazolium chloride staining. In a second series of experiments (n=5/group), the ischemic part of the myocardium was collected at 24h R and subjected to label free proteomic analysis, in order to identify alterations associated with the effect of CUS and IR. Results CUS induced anxiety, depressive-like pathology and cognitive deficits as indicated by the increased time spent in the closed arms of the EPM (p&amp;lt;0.005), the increased immobility time (TST, p&amp;lt;0.05), the reduced preference for the novel object (NOR, p&amp;lt;0.05), and the significant body weight reduction (p&amp;lt;0.001), in both male and female mice. CUS significantly increased IS (p&amp;lt;0.001) in both male and female mice. Proteomic analysis revealed that CUS affected the heart proteome, related to endoplasmic reticulum stress, mitochondrial damage and apoptosis, of both sexes in the absence of IR. Female mice were more susceptible to IR damage in absence of CUS with 248 significant genes (FDR&amp;lt;0.05) being deregulated mainly belonging to Keap-Nrf2-ARE signaling pathway, in contrast to 168 significant genes in male mice. In male mice, CUS exacerbated the IR injury proteome changes mainly related to induction of apoptosis and mitochondrial dysregulation (292 significant genes, FDR&amp;lt;0.05 for males vs 102 for females). Conclusions Chronic exposure to stress increases depressive-like pathology and cognitive deficits, leading to heart proteome alterations and increased IS in both sexes. Sex differences were observed indicating that the coexistence of CUS and IR render the male heart more susceptible to myocardial damage.

Evaluation of Hesperidin-Zinc Complex as a Novel Therapeutic Agent for Depression Treatment in Rats

Introduction: The complex contains hesperidin and zinc. The zinc is essential micronutrient that is important for human metabolism and catalyzes over 100 enzymes. It can be used to treat Wilson disease, decreased immunity, acute and chronic diarrhea. The hesperidin is a bioflavonoid found in many citrus plants. It has numerous activities like antioxidant, antibacterial, antimicrobial, anti-inflammatory, used to treat inflammation, Hypotension, varicose veins, venous ulcer, oxidative stress. There is no scientific evidence to support the claim that the complex of hesperidin and zinc have antidepressant properties even though zinc and hesperidin both separately have been linked to antidepressant activity in the literature. Objectives: The aim of this research is to find out whether complex of hesperidin and zinc can prevent reserpine induced depression. Methods: Wistar rats were used in this study after acclimatization. The induction group will be induced with reserpine to produce the depression in rats. The experiment included various treatment group of high and low dose of the test drug. Rats were used for the assessments, based on behavioral parameter like tail suspension test (TST), forced swimming test (FST), and elevated plus maze test then histopathology of hippocampus, cortical and substantia nigra region has been analysed, and along with measuring the BDNF levels. Results: On reserpine induced depression, complex of Hesperidin and zinc at low dose (100 mg/kg) shows negligible improvement in depressed behavior, when compare with standard fluoxetine (10 mg/kg). On the other hand, high dose (200 mg/kg) of the complex shows greater improvement also showed normal morphology in all 3 regions of the brain and showed increased level of BDNF in brain compared to low dose (100 mg/kg). Conclusions: Hesperidin-zinc complex was discovered to be a successful antidepressant drug, according to the study's findings. According to the findings, however a high dose of complex is more effective at treating reserpine induced depression than a low dose of complex.

6-Methoxyflavone improves anxiety, depression, and memory by increasing monoamines in mice brain: HPLC analysis and in silico studies

Abstract 6-Methoxyflavone (6-MOF) is a flavonoid that has been reported to be a GABA-A receptor agonist and reverses cisplatin-induced hyperalgesia and allodynia. Considering the varied neuropharmacological profile of 6-MOF, this study was intended to determine the pharmacological effects of 6-MOF on locomotion, anxiety, novel object recognition (NOR), depression, spatial memory, socialization behavior, nest-building behavior, and depression in various groups of mice. Selected groups of mice were injected with 25, 50, and 75 mg/kg 6-MOF. Using HPLC-UV, the frontal cortex, striatum, and hippocampus of the sacrificed mice were analyzed for the levels of vitamin C, dopamine, serotonin, noradrenaline, adenosine, and its metabolites. Statistical analysis showed significant results in socialization behavior and elevated plus maze with 75 mg/kg. In Y-maze, NOR 6-MOF showed significant results at all three doses, while in tail suspension test (TST), 50 and 75 mg/kg showed significant results; however, no statistical significance was observed in nest-building behavior; 50 and 75 mg/kg 6-MOF showed significant results in the Morris water maze. 6-MOF raised vitamin C levels in the frontal cortex and hippocampus. Serotonin, dopamine, and nor-adrenaline levels were raised in the hippocampus and striatum. It has also imparted region-specific neuroprotection by improving adenosine and its metabolite levels. In silico studies performed using PyRx have shown that the minimum binding energy of 6-MOF with antioxidant enzyme is −7.1 k/cal/mol. The binding energy showed that 6-MOF was successfully docked with an anti-oxidant enzyme. In conclusion, in silico and behavioral studies showed that 6-MOF can be a potential candidate for the treatment of cognitive decline, anxiety, and depression.

Antidepressant-like Effects of Cannabis sativa L. Extract in an Lipopolysaccharide Model: Modulation of Mast Cell Activation in Deep Cervical Lymph Nodes and Dura Mater.

Lipopolysaccharide (LPS)-induced neuroinflammation is a well-established model for studying depression-like behavior, driven by pro-inflammatory cytokines such as TNF-α and IL-1β. Mast cells (MCs) contribute to neuroinflammation by releasing mediators that exacerbate depressive-like symptoms. This study evaluates the antidepressant-like and anti-inflammatory effects of Cannabis sativa L. inflorescence extract (CSL) in an LPS-induced neuroinflammation model. Male C57BL/6 mice were intraperitoneally injected with CSL at doses of 10, 20, and 30 mg/kg, 30 min prior to LPS (0.83 mg/kg) administration. Depressive behaviors were assessed using the sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST). The neutrophil-to-lymphocyte ratio (NLR) was measured to assess systemic inflammation. Cytokine levels in the prefrontal cortex (PFC) were measured, and mast cell degranulation in the lymph nodes and dura mater was analyzed histologically (approval number: WKU24-64). CSL significantly improved depressive-like behaviors and decreased the NLR, indicating reduced systemic inflammation. CSL also significantly reduced TNF-α and IL-1β levels in the PFC. Furthermore, CSL inhibited MC degranulation in the deep cervical lymph nodes and dura mater, with the strongest effects observed at 30 mg/kg. CSL demonstrated antidepressant-like and anti-inflammatory effects in an LPS-induced neuroinflammation model, likely through the modulation of cytokine expression and mast cell activity. These results suggest the potential of CSL as a therapeutic option for treating inflammation-related depression.

Paroxetine Loaded Nanostructured Lipid Carriers Based In-situ Gel for Brain Delivery via Nasal Route for Enhanced Anti-Depressant Effect: In Vitro Prospect and In Vivo Efficacy.

This study focused on developing a thermosensitive gel with nanostructured lipid carriers (NLCs) loaded with paroxetine (PAR) to enhance the treatment and management of depression via nasal administration. Micro emulsion technique was utilized for the PAR-NLCs preparation. The acetyl alcohol and oleic acid were used in the ratio of 76:24. In the NLCs Tween 40, Span40 and Myrj 52 were used as a surfactant. The NLCs were then added into Poloxamer mixture to get thermosensitive NLCs based gel. Characterization, in vitro and in vivo studies were performed to check the efficiency of formulation in drug delivery. The entrapment efficiency of optimized PAR-NLCs was about 90%. The particle size, zeta potential and PDI were 155 ± 1.4nm, -25.9 ± 0.5mV, and 0.12 ± 0.01 respectively. The optimized gel showed a gelling temperature of 31.50 ± 0.50°C and a gelling time of 1 ± 0.12s with a pH of 6, suitable for nasal administration. The in vitro release assay of PAR-NLC-gel showed a cumulative release of about 59% in the first 6h after comparison with PAR-NLCs which showed almost 100%release. In vivo studies included forced swim test and tail suspension tests showed significant potential for treating depression when compared to PAR-NLCs. PAR-NLCs and NLCs based gel enhanced the tissue architecture and suppressed the expression of TNF-α in brain cortex from histological and immunohistochemical analysis. PAR- NLCs gel-based delivery system can prove to be an effective delivery system for brain targeting through nose for the better management of depression.

Exploring the Neuroprotective Behaviour and Hepatoprotective Effects of Plumbagin in MPTP-Induced Parkinson's Disease

Aims: Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, leading to motor symptoms like tremors and bradykinesia, as well as non-motor symptoms such as sleep disturbances and autonomic dysfunction. Recent research suggests a link between PD and liver dysfunction, including altered metabolism and elevated liver enzymes. Plumbagin, recognized for its antioxidant and neuroprotective properties, may offer therapeutic benefits. This study explores its effects on both motor and non-motor symptoms in MPTP-treated mice, as well as its impact on liver function through serum enzyme analysis. The aim is to assess the neuroprotective and hepatoprotective potential of plumbagin in countering MPTP-induced neurodegeneration and liver dysfunction. Methodology: Thirty mice (22-30g, 8-12 weeks old) were randomly assigned to five groups of six each. The experiment spanned 28 days, with the mice housed under controlled conditions and provided standard feed and water. Behavioral tests, including the Marble Burying and Tail Suspension tests, were conducted to assess anxiety and depressive-like behavior. Serum biochemistry, including ALT, AST, and BUN, was measured using standard ERBA kits to evaluate liver function health. Results: In the marble burying and tail suspension tests, MPTP-induced mice (DC group) exhibited significantly higher anxiety and depressive-like behaviors compared to the sham and plumbagin groups. Plumbagin treatment (PD) and levodopa (LS) significantly reduced these behavioral symptoms. Liver function markers (ALT, AST, ALP) and BUN levels were elevated in DC mice, indicating liver and kidney damage, while plumbagin treatment mitigated these effects, showing values comparable to the standard treatment (LS). Conclusion: This study demonstrates that MPTP exposure affects both the central nervous system and liver function, leading to anxiety, depression, and liver damage, as evidenced by elevated liver enzymes. Plumbagin showed protective effects, reducing these behavioral and biochemical changes through its antioxidant properties, suggesting its potential as a therapeutic agent against MPTP-induced neurotoxicity and hepatotoxicity. These findings suggest that future research should investigate plumbagin's clinical potential for treating Parkinson's disease and liver dysfunction, offering promise for its use in developing neuroprotective therapies.

An Assessment of Antidepressant Activity of Etlingera elatior Alone and in Combination with Fluoxetine

Aim: Present study deals to access the antidepressant activity of Etlingera elatior leaves extract in rodent. Background: Etlingera elatior is a species of herbaceous perennial plant in the family Zingiberaceae; native to Indonesia, Thailand, Malaysia and New Guinea. Depression is one of the most common mental disorders affecting humans, pathological basis of which is not fully understood. The current antidepressant drugs have several adverse effects including their effects on cognition. Therefore, natural product are being evaluated for their antidepressant activities. Objective: In this study, Etlingera elatior leaf extracts are being evaluated for antidepressant activity in rodent models. A wide range of synthetic medicines that can be used to treat depression which may exerts various side effects such as dry mouth, gastrointestinal problems, nausea, respiratory problems, cardiac arrhythmias, drowsiness, anxiety etc. Hence, it becomes essential to discover new anti-depressant drug with more potency, efficacy and safety profile than those of marketed synthetic drugs. Methods: Using the forced swimming test, the tail suspension test, mouse 5-HTP-induced head twitches and estimation of brain lipid peroxidation modelsthe antidepressant efficacy of Etlingera elatior ethanolic extract was examined. Imipramine was used as reference standards. result: According to our study, Etlingera elatior significantly (p0.01) reduced immobility in tail suspension, forced swimming, and 5-HTP-induced head twitches in mice with depression that were comparable to imipramine. Results: According to our study, Etlingera elatior significantly (p 0.01) reduced immobility in tail suspension, forced swimming, and 5-HTP-induced head twitches in mice with depression that were comparable to imipramine. Conclusion: Based on the results obtained we can conclude that Etlingera elatior leaves extract possess significant antidepressant activity. The antidepressant effectiveness of Etlingera elatior leaves extract can be confirmed in the future by adding more models, and attempts can also be made to isolate and characterise the phytoconstituents responsible for the pharmacological action.

Design, synthesis and biological evaluation of arylpropylamine derivatives as potential multi-target antidepressants

In this study, a series of novel arylpropylamine derivatives were designed, synthesized and evaluated as potential multi-target antidepressants. Among them, compound (R)-13j displayed unique pharmacological features, exhibiting excellent inhibitory potency against serotonin and noradrenaline transporters (SERT/NET) and high affinity for 5-HT2A/2C receptor, and showing low affinity for histamine H1, adrenergic α1 receptors and hERG channels (to reduce QT interval prolongation). Molecular docking studies provided a rational binding model of (R)-13j in complex with SERT and 5-HT2A/2C receptor. In animal models, compound (R)-13j dose-dependently reduced the immobility time in the tail suspension test (TST) and the forced swimming test (FST) in mice, with higher efficacy when compared to duloxetine, and showed no stimulatory effect on the locomotor activity. Moreover, compound (R)-13j significantly shortened the immobility time in the ACTH-induced rat model of treatment-resistant depression (TRD). Furthermore, compound (R)-13j also exhibited a higher threshold for acute toxicity than duloxetine. In addition, compound (R)-13j possessed a favorable pharmacokinetic profile in mice. Taken together, compound (R)-13j may constitute a novel class of drugs for the treatment of depression.

Electroacupuncture attenuates depressive-like behaviors in poststroke depression mice through promoting hippocampal neurogenesis and inhibiting TLR4/NF-κB/NLRP3 signaling pathway.

The aim of this study was to investigate the impact and underlying molecular mechanisms of electroacupuncture on mice with poststroke depression (PSD). Mice were randomly allocated into sham, PSD, and electroacupuncture groups. Mice in the PSD and electroacupuncture groups underwent middle cerebral artery occlusion (MCAO) surgery following with sedentary behavior. Electroacupuncture targeting Zusanli (ST36) acupoint was performed 24 h after MCAO for 4 weeks in electroacupuncture group. The sucrose preference test, forced swimming test, open field test, tail suspension test, elevated plus maze, Catwalk analysis, RNA sequencing, Nissl staining, Golgi staining, TUNEL staining, Edu labeling, and doublecortin staining were performed. Lymphocyte subsets in peripheral blood and the levels of IL-1β, IL-6, TNF-α, and expression of Iba1/CD86, Iba1/NLRP3, TLR4/p38/NF-κB/NLRP3 pathways in the hippocampus were detected. Electroacupuncture effectively protected against the development of depression-like symptoms. The number of granulosa cells and doublecortin-positive cells in the dentate gyrus (DG) were significantly decreased in PSD group, which were significantly upregulated ( P < 0.01) by electroacupuncture. Electroacupuncture also significantly reduced ( P < 0.05) TUNEL-positive cells in the DG and CA1. RNA-seq revealed that electroacupuncture may exert antidepressant effect by regulating the inflammation mediated by TLR4/NF-κB/NLRP3 pathway in hippocampus. Electroacupuncture remarkably elevated ( P < 0.01) the ratio of CD4+ to CD8+ T cells and percentage of CD3-CD49b+ cells in CD45+CD49b+ cells in the peripheral blood. Electroacupuncture significantly reduced ( P < 0.05) the high levels of IL-1β, IL-6, TNF-α, iba1, TLR4, p-p38, p-NF-κB, and NLRP3 and sedentary behavior. Electroacupuncture was observed to mitigate depression symptoms and increase hippocampal neurogenesis in mice with PSD, possibly by inhibiting TLR4/p38/NF-κB/NLRP3 pathways and improving the microglia-mediated inflammatory microenvironment in the hippocampus.

The role of circadian clock gene Arntl in the winter depression-like behavior in melatonin-proficient female CBA/N mice

Seasonal affective disorder (SAD), also known as winter depression, is a subtype of depression typically manifesting in winter. Typical symptoms of SAD, such as an increased need for sleep and carbohydrate cravings associated with increased appetite and weight, are distinct from those of major depression, and the underlying mechanisms of SAD remain unclear. Although laboratory mice are generally considered non-seasonal animals, we observed depression-like behaviors in melatonin-proficient female CBA/N mice maintained under winter-mimicking conditions. Transcriptome analysis of the brains of CBA/N mice maintained under winter- and summer-mimicking conditions revealed changes in the expression of circadian clock genes, including Arntl (also known as Bmal1). We generated Arntl-deficient, melatonin-proficient CBA/N mice using the speed congenic method to examine the role of Arntl in depressive behavior. The tail suspension test in these mice revealed a depressive phenotype. These results suggested that the circadian clock gene Arntl may be involved in winter depression-like behavior.