Immobility Time Research Articles

Exosomal PINK1 from Human Umbilical Cord Mesenchymal Stem Cells Attenuates Neurological Deficits and Inflammatory Responses after Intracerebral Hemorrhage in Mice.

This study investigated the therapeutic potential of exosomes from human umbilical cord mesenchymal stem cells (huMSCs), focusing on PTEN-induced kinase 1 (PINK1) and its impact on exosome efficacy. Postmodification, exosomes were administered to a murine model of intracranial hemorrhage (ICH). Assessments included brain edema, neurological function, anxiety-like behaviors, inflammatory responses, and microglial polarization. We observed that administration of exosomes from control huMSCs significantly reduced brain water content, indicating a reduction in brain edema, as quantitatively assessed through water content analysis. Neurological function, evaluated using a standard scoring system, showed marked improvement in animals treated with control exosomes compared with those receiving PINK1-deficient exosomes, highlighting the importance of PINK1 in mediating neurological recovery. Additionally, control exosomes substantially decreased anxiety-like behaviors in the Open Field Test, demonstrated by reduced immobility times and increased exploratory behavior. Inflammatory response assessments showed a favorable shift with decreased levels of pro-inflammatory cytokines (MCP-1, IL-1β, TNF-α) and increased levels of the anti-inflammatory cytokine IL-10 in the exosome-treated groups. Furthermore, analysis of microglial polarization revealed a shift toward the anti-inflammatory M2 phenotype, evidenced by decreased M1 markers (Cd86, Iba1) and increased M2 markers (Arg1, Cd206) in the control exosome-treated group. Taken together, we found that PINK1-deficient exosomes showed reduced therapeutic efficacy in ICH treatment compared with the exosomes with normal PINK1 expression. Our findings underscore the critical role of PINK1 in enhancing the therapeutic potential of huMSC-derived exosomes in ICH treatment.

Valeriana jatamansi jones improves depressive behavior in CUMS mice by modulating vitamin B12-related ileal homeostasis.

Valeriana jatamansi Jones (V. jatamansi) is a traditional Chinese medicine (TCM). It was recorded in Diannan Bencao, Compendium of Materia Medica and some local medical books and was described as useful in treating insomnia, distraction, poor mental health, vomiting and diarrhea. To investigate whether the antidepressant effect of V. jatamansi may operate through modulating vitamin B12-related ileal homeostasis using a chronic unpredictable mild stress (CUMS) mouse model. A CUMS-induced depression model was established in mice for five weeks, after which V. jatamansi extracts were administered for three weeks. At week eight, the forced swimming test and novelty-suppressed feeding test were conducted. H&E staining assessed ileal pathology, while 16S rDNA sequencing analyzed changes in ileal microbiota. Additionally, B12 in serum, cubilin (CUBN) and amnionless (AMN) in ileal tissue, methionine synthase (MS) and homocysteine (Hcy) in the hippocampus were measured using ELISA, and the correlations between them and ileal microbiota were explored. Mice in the model group exhibited significant depressive behavior. However, after treatment with V. jatamansi, immobility time and feeding latency were improved. H&E staining demonstrated the repairing effect of V. jatamansi on the ileum regarding tissue damage. The alpha and beta diversity of the ileal microbiota were regulated and converged to the normal group. Additionally, V. jatamansi modulated B12, CUBN, AMN, MS, and Hcy levels. Correlation analysis showed that there are certain correlations between a variety of microorganisms and B12-related factors. These findings suggest that the mechanism of V. jatamansi in treating depression may be through repairing depression-associated intestinal damage. This repair process may affect the intestinal absorption and microbial production of B12. By reversing the reduction of serum B12, V. jatamansi ultimately reduces the infiltration of Hcy into the CNS.

Acute Intermittent Theta-Burst Stimulation Produces Antidepressant-Like Effects by Modulating Neuronal Oscillations and Serotonin Levels of the Medial Prefrontal Cortex in Experimental Parkinson's Disease.

Parkinson's disease (PD)-related depression is associated with aberrant neuronal oscillations and 5-hydroxytryptamine (5-HT) neurotransmission in the medial prefrontal cortex (mPFC). Intermittent theta-burst stimulation (iTBS), an updated pattern of high-frequency repetitive transcranial magnetic stimulation, has possible efficacy in PD-related depression. However, whether iTBS alleviates PD-related depression through modulating neuronal oscillations and 5-HT levels in the mPFC has not been determined. In this study, male Sprague-Dawley rats were used to establish a unilateral 6-hydroxydopamine-induced PD model. Then, acute iTBS was applied to the parkinsonian rats, and behavioral, neurochemical, and electrophysiological experiments were performed. We found that the parkinsonian rats exhibited increased immobility time and decreased sucrose preference accompanied by an increase of δ power and a decrease of θ power in the mPFC compared to sham-operated rats. One block of iTBS (1 block-iTBS, 300 stimuli) alleviated depressive-like behaviors in parkinsonian rats and elevated 5-HT levels in the mPFC compared to sham-iTBS. Additionally, it altered neuronal oscillations in the mPFC in the opposite fashion by suppressing the δ rhythm and enhancing the θ and β rhythms compared to sham-iTBS, suggesting that acute iTBS induces hyperactivity in the mPFC. With this iTBS paradigm, we also observed decreased parvalbumin expression in the mPFC, reflecting reduced cortical inhibition. Finally, correlation analyses showed strong correlation between immobility time and θ power after 1 block-iTBS. These findings suggest that the application of acute iTBS in parkinsonian rats produces antidepressant-like effects, which may be associated with elevated 5-HT levels and normalized neuronal oscillations in the mPFC.

Schisandrol B alleviates depression-like behavior in mice by regulating bile acid homeostasis in the brain-liver-gut axis via the pregnane X receptor.

Depression is a widely recognized neuropsychiatric disorder. Recent studies have shown a potential correlation between bile acid disorders and depression, highlighting the importance of maintaining bile acid balance for effective antidepressant treatment. Schisandrol B (SolB), a primary bioactive compound from Schisandra chinensis (Turcz.) Baill. or Schisandra sphenanthera Rehd.etWils, is pivotal in regulating bile acid homeostasis via pregnane X receptor (PXR) in cholestasis. However, the potential of SolB in alleviating depression-like symptoms, its pharmacological effects, and the underlying mechanisms remain to be fully elucidated. We confirmed the effect of SolB against depression induced by chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS) in mice. The role of SolB in bile acid homeostasis in depression was analyzed using the metabolomic. Gene analyses and 16S rRNA sequencing were employed to investigate the involvement of PXR. Experiments with Pxr-/- mice were conducted to confirm the essential role of the PXR pathway in SolB's antidepressant effects. SolB treatment significantly increased sucrose consumption in the SPT and the locomotor activity in the OFT, while decreasing immobility time in the FST and TST in mice exposed to CRS and CUMS. Additionally, SolB treatment significantly preserved the integrity of the dendritic spine, elevated synaptic protein PSD95 levels, and augmented CREB/BDNF expression. Metabolomic and gene analyses indicated that SolB treatment significantly facilitated bile acid metabolism, promoted intestinal bile acid efflux, decreased hippocampal levels of the secondary bile acids DCA and TLCA, and upregulated expression of the PXR target proteins CYP3A11, SULT2A1, MRP2, and OATP1B1 in the liver, and MRP2 and MDR1 in hippocampus, which are integral to bile acid homeostasis. 16S rRNA sequencing revealed that SolB reduced the abundance of the bile salt hydrolase (BSH)-producing bacteria Lactobacillus johnsonii and Bacteroides fragilis and subsequently decreased the production of TLCA and DCA. Moreover, SolB failed to protect against depression induced by CRS in Pxr-null mice, suggesting that the antidepressant effect of SolB was PXR-dependent. These results provide direct evidence of the antidepressant effect of SolB via activation of PXR to regulate bile acid homeostasis in the brain-liver-gut axis, suggesting that SolB may serve as a novel potential target for preventing and treating depression.

A Comprehensive Evaluation of the Neuropharmacological Potential of Methanolic Leaf Extract of Acanthus ebracteatus (Vahl.) Using Experimental and In Silico Approaches.

This study was undertaken to assess the antioxidant and neuropharmacological potentials of the methanol leaf extract of Acanthus ebracteatus (MAEL) through experimental and in silico methods. The phytochemical screening (PS) and GC-MS (gas chromatography-mass spectrometry) identified 28 phytochemicals with different classes in nature in MAEL. The MAEL revealed better antioxidant activity through various in vitro antioxidant assays. Additionally, in the tail suspension test (TST) and forced swimming test (FST), a dose-dependent reduction in immobility time was observed indicating antidepressant activity. In the elevated plus maze test (EPM), MAEL led to increased time spent and more entries in the open arms. At the same time, the hole board test (HBT) demonstrated an increase in head dipping compared to the control, both indicating anxiolytic activity. Moreover, a dose-dependent reduction in locomotor activities was observed in both the open field test (OFT) and hole cross test (HCT). Molecular docking showed better binding affinities of two compounds, CID-518982 and CID-236641. ADME/T analysis revealed good drug likeliness with no toxicity. Finally, the simulation demonstrated better structural stability with no significant fluctuations of the compounds with the selected receptors. In this study, compounds CID-518982 and CID-236641 might serve as drug candidates for treating anxiety and depression.

Low emotional contagious behavior induces PTSD susceptibility in observers and is related to the regulation of oxytocin receptor in mice.

Post-traumatic stress disorder (PTSD) is a serious psychiatric disorder that occurs after an individual has witnessed or experienced a major traumatic event. Emotional contagion seems to play an important role in witnessing trauma, highlighting the importance of understanding the neurobiological consequences of psychological or emotional stress and its impact on the individual's mental health. Therefore, understanding the relationship between emotional contagion and PTSD susceptibility and the abnormal neurobiological and behavioral changes behind it could help find effective molecular treatment targets. The formalin pain test was used to distinguish the level of emotional contagion in observer mice, dividing them into quartiles according to their pain response. The upper and lower quartiles were the emotional contagion-prone (ECP) and -resistant (ECR) groups, respectively. The vicarious social defeat stress (VSDS) procedure was used to establish PTSD models in mice with various emotional contagion levels when witnessing stress. Open field, elevated plus maze, social interaction test, and forced swimming test were used to examine PTSD-like symptoms. Changes in the medial prefrontal cortex (mPFC) mRNA expression of brain-derived neurotrophic factor (BDNF) and oxytocin receptor (OTR) were detected by qPCR, and their protein levels were analyzed by Western blot and immunofluorescence staining. The formalin pain test induced emotional contagion behaviors in mice between the ECP and ECR levels. The VSDS procedure resulted in PTSD symptoms in mice; mice in the lowest quartile were characterized by high levels of anxiety, depression, and social avoidance behaviors, such as decreased autonomous activity and residence time in the open field test or open arms position and increased immobility time and social avoidance behavior. These were accompanied by reduced OTR and BDNF protein expression levels and fluorescence intensity, as well as reduced OTR and BDNF mRNA levels in the mPFC. Emotional contagion can induce PTSD-like behavior in mice that witnessed stress. Low emotional contagion behavior increased PTSD susceptibility in the observer mice and might be related to the regulation of their oxytocin receptors.

Cichorium intybus L. Oligo-Polysaccharides (CIO) Exerts Antianxiety and Antidepressant Effects on Mice Experiencing Behavioral Despair and Chronic Unpredicted Mild Stress.

Cichorium intybus L. oligo-polysaccharides (CIOs), obtained from Cichorium intybus L., is a mixture of oligosaccharides and polysaccharides. This study explores the antianxiety and antidepressant effects and mechanisms of CIOs by using acute behavioral despair and chronic unpredictable mild stress mice models and measuring the levels of 5-HT and the expression of proteins related to the BDNF/ERK and PI3K/Akt/mTOR pathways. Moreover, 56 male C57BL/6N mice were used to test behavioral despair. They were randomized into seven groups (Control, Citalopram, CIO 12.5 mg/kg, CIO 25 mg/kg, CIO 100 mg/kg, and CIO 200 mg/kg) based on body weight; they were administered with the corresponding medication daily for 7 days; and behavioral tests were conducted on them (forced swimming test (FST) and tail suspension test (TST)) after 7 days. Seventy male C57BL/6N mice were adopted in the next part of the experiment and randomly divided into seven groups (Control, CUMS, Fluoxetine, MOO, CIO 25 mg/kg, and CIO 100 mg/kg) based on the sucrose preference index. Except for the control group, the other groups were subjected to 6 weeks of CUMS. From the fifth week of stress, the corresponding drugs were administered by gavage until the end of the behavioral tests. In the behavioral despair tests, the immobility time was significantly reduced in the FST and TST after the CIO (25 and 100 mg/kg) treatment of 7 days. After 6 weeks of chronic unpredicted mild stress (CUMS) treatment, CIO (25, 50, and 100 mg/kg) administration significantly reduced the number of buried beads in the marble burying test (MBT), decreased the latency in the novelty-suppressed feeding test (NSFT), and shortened the immobility time in the FST and TST. CIO administration significantly increased the sucrose preference index in the sucrose preference test (SPT). Additionally, CIO treatment increased hippocampal 5-HT levels while upregulating the expression of BDNF, P-PI3K/PI3K, P-ERK/ERK, P-Akt/Akt, and P-mTOR/mTOR. In summary, CIO exerted promising antidepressant effects in behavioral despair and antianxiety and antidepressant effects in CUMS-induced depressive mice. Moreover, CIO therapy was facilitated by increasing the 5-HT content, alleviating the damage of hippocampal neurons, and upregulating the BDNF/ERK and PI3K/AKT/mTOR cascade. Thus, CIO is a substance with the potential to treat anxiety and depression.

L-type calcium channel blockade attenuates the anxiogenic-like effects of cocaine abstinence in female and male rats.

Cocaine abstinence and withdrawal are linked to relapse and heightened anxiety. While L-type calcium channels (LTCCs) have been associated with cocaine use disorders in humans and drug-seeking in rodents, their role in mood-related symptoms during cocaine abstinence remains unclear. We addressed this by investigating the ability of LTCC blockade with isradipine to alter the mood-related behavioral phenotypes induced by cocaine abstinence. Female and male Sprague-Dawley rats were trained to self-administer cocaine or saline, followed by a 14-day period of abstinence. Subsequently, behavioral responses were examined using the sucrose preference test (SPT), elevated plus maze (EPM), and forced swim test (FST). Cocaine-abstinent rats showed decreased open arm time in the EPM and increased immobility time in the FST with no changes in the SPT. Isradipine (0.4mg/kg or 1.2mg/kg, i.p.), reversed the anxiogenic-like EPM behavior in female cocaine-abstinent rats, whereas only the higher dose (1.2mg/kg, i.p.) was effective in male cocaine-abstinent rats. In the FST, the lower dose (0.4mg/kg, i.p.) of isradipine reversed the increased immobility time observed in cocaine-abstinent female and male rats, with no isradipine effect in saline-abstinent rats. In contrast 1.2mg/kg, i.p. isradipine decreased immobility time in both cocaine and saline abstinent female and male rats. In summary, isradipine administration reversed the anxiogenic and increased the FST immobility time associated with cocaine abstinence in a dose and sex-dependent manner. The data underscore the importance of further investigation of LTCC mechanisms and their therapeutic potential for mood disorders associated with cocaine use disorder.

Preventive and Therapeutic Effects of Intracerebroventricular Administration of Maresin-1 on Lipopolysaccharide-Induced Depression-Like Behaviors in Mice

Enhanced inflammatory and immune responses have been observed in patients with major depressive disorder, pointing to anti-inflammatory substances as potential seeds for developing novel antidepressants. Omega-3 polyunsaturated fatty acid metabolites, such as resolvin D and E series, maresins, and protectins (collectively known as specialized pro-resolving mediators) demonstrate anti-inflammatory effects. This study examined the antidepressant-like effects of maresin-1 (MaR1) on lipopolysaccharide (LPS)-induced depression-like behaviors in mice. Using the tail suspension test (TST) and the forced swim test (FST), we assessed depression-like behaviors 26 and 28 h after intraperitoneal injection of LPS (0.8 mg/kg), respectively. An open field test (OFT) was also conducted to evaluate locomotor activity 24 h after LPS injection. Intracerebroventricular (i.c.v.) injection of MaR1 (10 ng/mouse) immediately after the LPS challenge mitigated the increased immobility time in the TST and FST, without affecting locomotor activity in the OFT, indicating the preventive effects of MaR1 on LPS-induced depression-like behaviors. Furthermore, i.c.v. injection of MaR1 23 h after the LPS challenge reduced the immobility time in both tests, underscoring its therapeutic potential. These findings suggest that MaR1 could be a promising seed for developing novel antidepressants.

Cordycepin Extracted from Cordyceps militaris mitigated CUMS-induced depression of rats via targeting GSK3β/β-catenin signaling pathway.

Cordycepin, the main active component of Cordyceps militaris, exhibits various pharmacological activities, including anti-tumor and antioxidant effects. However, its antidepressant effect and the underlying mechanisms remain unclear. This study aimed to explore the antidepressant effect of cordycepin and elucidate the potential molecular mechanisms. Chronic unpredictable mild stress (CUMS) rat model was established to assess antidepressant effect of cordycepin. Gas chromatography-mass spectrometry (GC-MS) metabolomics with integrated network pharmacology were used to find differential metabolites in serum, brain, and cerebrospinal fluid of rats and identify potential target by cordycepin. Western blot and Real-time PCR were applied to validate the signaling pathway. Cordycepin alleviated CUMS-induced depression-like behaviors by weight gain, sucrose preference increment, immobility time reduction, total travelling distance extension and serum corticosterone levels reduction. Metabolomics showed that cordycepin reversed CUMS-induced metabolic disturbances through alanine and TCA cycle metabolism pathways. Network pharmacology identified GSK3β as a potential target. Cordycepin increased protein levels of p-GSK3β, β-catenin and nuclear β-catenin, and enhanced transcription of downstream genes PKM, LDHA, Cyclin D1 and C-myc in brains of CUMS-induced rats. This study indicated that cordycepin exerted antidepressant effect by modulating GSK3β/β-catenin pathway, suggesting its potential as a candidate agent for depression.

Repeated high-dose esketamine in early postnatal rats leads to behavioural deficits with long-term modifications in white matter microstructural integrity

Esketamine is commonly used for sedation or general anaesthesia in infants and young children. However, repeated esketamine administration during periods of rapid brain growth and development may result in various pathophysiological and cognitive changes. Therefore, this study aimed to investigate the influence of recurrent esketamine exposure on long-term behavioural and white matter consequences. Seven-day-old (P7) male rats were allocated to control, high-, and low-dose groups. Behavioural paradigm assessment was conducted at P25–29. Diffusion tensor imaging revealed long-term effects on water diffusivity in the splenium and cingulum white matter of the corpus callosum at P30. Subsequent two-dimensional structure-tensor analysis of brain tissue sections stained with Luxol fast blue (LFB) showed marked changes in the white matter microstructure in rats after multiple exposures to varying esketamine doses. High-dose esketamine significantly reduced activity time and total distance in the open-field experiment. High-dose esketamine exposure might lead to impaired short-term memory in rats. Additionally, the high-dose group showed prolonged immobility time during the forced swimming test. On the balance beam, the high-dose group displayed more right turns and right-foot slips and lower time spent on the rotating bar, indicating motor defects, than did the other groups. Diffusion tensor imaging demonstrated a decreased water molecule diffusion ability in the corpus callosum in the high-dose group. LFB staining indicated microstructural differences in the white matter of animals in the high-dose group. These findings suggest that behavioural deficits in high-dose esketamine-treated rats are at least partially attributed to changes in the white matter microstructure.

Exploring the therapeutic potential of α-(Phenylselanyl) acetophenone in tumor necrosis Factor-α-Induced depressive-like and hyperalgesic behavior in mice.

Chronic pain and depression exhibit a high comorbidity, are challenging to manage, and their pathophysiology mechanisms are intricated and closely related to the up-regulation of pro-inflammatory response and oxidative stress. Chronic pain and depression often coexist and present significant management challenges. Their underlying pathophysiological mechanisms are complex and closely linked to the up-regulation of pro-inflammatory responses and oxidative stress. α-(Phenylselanyl) acetophenone (PSAP), an organoselenium compound, has shown antioxidant, antidepressant-like and antinociceptive effects in animal models. This study aimed to evaluate the effects of acute PSAP administration in a comorbid pain-depression model induced by intracerebroventricular (i.c.v.) injection of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) in male Swiss mice. TNF-α (0.1 ƒg/5 µL, i.c.v.) was injected 1h before the behavioral tests, followed by acute PSAP treatment (10mg/kg, intragastrically [i.g.]) 30min post-TNF-α injection. TNF-α decreased the latency time to first immobility episode and increased the total immobility time of mice in the forced swimming test (FST), effects prevented by PSAP treatment. PSAP also reversed TNF-α-induced nociceptive responses in mice, assessed by the hot plate test. These behavioral improvements may be attributed, at least in part, to the capacity of PSAP treatment reverse the TNF-α-induced increase on reactive species and lipoperoxidation levels, as well as modulate altered activities of antioxidant enzymes catalase and superoxide dismutase in the cerebral cortex and hippocampus. Furthermore, PSAP decreased circulating corticosterone levels elevated by TNF-α injection. In conclusion, PSAP emerges as a promising candidate for the development of innovative therapeutic strategies to address the comorbidity of pain and depression.

Dorsal bed nucleus of the stria terminalis GABA neurons are necessary for chronic unpredictable stress-induced depressive behaviors in adolescent male mice.

Previous studies have shown that neurons in the Bed Nucleus of the Stria Terminalis (BNST) respond to stress and play a key role in mental health. However, the cellular bases of BNST in adolescent depression remain elusive. Male C57BL/6 mice were randomly assigned to the control (Ctrl) or chronic unpredictable stress (CUS) groups. The CUS mice, aged 28 days, were subjected to diverse stressors at various times of the day for 12 days. Depression-like behaviors were assessed through the sucrose preference test (SPT) and tail suspension test (TST). Immunostaining was used to investigate the neural activity and subtypes in the brain. A chemogenetic tool was conducted to examine the role of specific neural activity in CUS-induced depression-like behaviors. CUS led to a significant decrease in preference for sucrose solution in the SPT and increased immobility time in the TST. C-Fos immunostaining showed hyperactivity of the GABAergic neurons within the dorsal BNST (dBNSTGABA). Chemogenetic activation of dBNSTGABA neurons increased depression-like behaviors. Conversely, chemogenetic inhibition of dBNSTGABA neurons led to a decrease in CUS-induced depression. These results suggest that adolescent CUS induces hyperactivity of dBNSTGABA neurons, subsequently giving rise to depression-like behaviors and that reducing dBNSTGABA neuronal activity might constitute a novel and efficacious therapeutic approach for adolescent depression.

Antidepressant Activity of Ethanol Extract of Cassava Leaves (Manihot esculenta C.) in Male White Mice Using the Forced Swimming Test Method

Depression is a disorder characterized by changes in one's mood and activity patterns that are different than usual. Depression is experienced by teenagers to old age. One of the ways to overcome people's depression is to consume drugs made from herbal ingredients. Cassava leaves are thought to have efficacy as an antidepressant. This study aims to determine the antidepressant effect of cassava leaf extract given orally to male white mice. The extraction was carried out by soxhletation method. The extract obtained was tested for phytochemical content. The antidepressant effect test of cassava leaf extract was carried out using the forced swimming test method with the immobility time parameter. The test animals were divided into 5 groups each consisting of 5 mice. Group 1 was drug control (amitriptyline), group 2 was depression control (CMC Na 0.5%), groups 3, 4, 5 were given ethanol extract of cassava leaves at doses of 125, 250 and 500 mg/KgBb. The result showed that the extract contained flavonoid, alkaloid, saponin and steroid. The results showed that the ethanol extract of cassava leaves at doses of 125 mg/KgBb, 250 mg/KgBb, 500 mg/KgBb had an antidepressant effect, as indicated by the immobility time scores of each group of 28.76%, 35.14% and 44.94%. The ethanol extract of cassava leaf has an optimal effect as an antidepressant in male white mice at a dose of 500 mg/KgBb, equivalent to the control drug amitriptyline.

Mechanism of electroacupuncture on hippocampal neuron regeneration in depression rats based on Wnt/β-catenin and Notch signaling pathway

To observe the effect of electroacupuncture (EA) on the proliferation of hippocampal neurons and Wnt/β-catenin and Notch signaling pathways in depression like behavior rats, so as to explore its mechanism underlying improvement of depression. SD rats were randomly divided into blank, model, medication and EA groups, with 12 rats in each group. The depression model was established by chronic unpredictable mild stimulation combined with solitary raising for 35 consecutive days. After 14 days modeling, EA was applied to "Baihui"(GV20) and "Taichong"(LR3) for 15 min once daily for 3 weeks. For rats of the medication group, clomipramine (2.5 mg/kg) was given (i.p.) once a day for 3 weeks. The depression-like behavior was evaluated by open field test and forced swimming test. The ultrastructure of hippocampal neurons was observed by transmission electron microscope (TEM). The positive expression of 5-bromo-2'-deoxyuridine/neuron-specific nucleoprotein (BrdU/NeuN) in hippocampal dentate gyrus of rats was detected by immunofluorescence double labeling method. Western blot was used to detect the relative expression of Wnt/β-catenin and Notch pathway key proteins β-catenin, G1/S-specific cyclin-D1 (Cyclin D1), NICD and Hes1 in hippocampus of rats. Compared with the blank group, the total distance and average speed of open field movement were decreased (P<0.01), and the immobility time of forced swimming was increased (P<0.01). The positive expression of BrdU/NeuN in hippocampal dentate gyrus was decreased (P<0.01). The relative expression of β-catenin and Cyclin D1 protein in hippocampus were decreased (P<0.01), while the relative expression of NICD and Hes1 protein increased (P<0.01) in the model group. Following the treatment and compared with the model group, the total distance and average speed of movement in the open field were increased (P<0.05), and the immobility time of forced swimming was decreased (P<0.05) in both medication and EA groups. The positive expression of BrdU/NeuN in hippocampal dentate gyrus was increased (P<0.01). The relative expression of β-catenin and Cyclin D1 protein in hippocampus were increased (P<0.01), while the relative expression of NICD and Hes1 protein were decreased (P<0.01, P<0.05) in both medication and EA groups. TEM microscope observation showed irregularity of hippocampal neurons, rupture of nuclear membranes, disruption of mitochondrial structure, and dilation of endoplasmic reticulum in the model group, which was relatively milder in both medication and EA groups. EA can improve the depressive state of depression model rats, which may be associated with its functions in regulating Wnt and Notch signaling pathways, thereby promoting the regeneration of hippocampal neurons.

GC-MS Analysis, Neuropharmacological, and Antidiarrheal Activities of the Acetone Extract of Najas gracillima Seaweed: In Vivo and In Silico Study.

Najas gracillima, a marine seaweed found in North America and Asia, was investigated for its neuropharmacological and antidiarrheal properties. Acetone extracts of N. gracillima (ANG) were analyzed using both in vivo and in silico methods. Gas chromatography-mass spectrometry (GC-MS) analysis was conducted to identify bioactive compounds present in the extract. In vivo assessments, including the elevated plus maze, light-dark box, and hole board tests, showed that ANG at doses of 200 and 400mg/kg exhibited significant (p<0.001) anxiolytic effects. Both doses also demonstrated antidepressant effects in the forced swimming and tail suspension tests by significantly (p<0.001) reducing immobility time, with the 200mg/kg dose showing more pronounced effects. Sedative activity was confirmed through open field and hole cross tests, where both doses exhibited significant (p<0.001) sedative effects. ANG also demonstrated significant antidiarrheal effects at 400mg/kg in castor oil-induced diarrhea (p<0.05) and gastrointestinal motility tests (p<0.01). Molecular docking simulations revealed that compounds from ANG had strong binding affinities to critical drug targets involved in anxiety, depression, sleep disorders, and diarrhea. These findings suggest that N. gracillima holds potential for therapeutic use in treating neuropharmacological disorders and diarrhea, warranting further investigation.

The Dark Side of Acid Suppression: Exploring Mood Changes in Omeprazole treated Mice

Depression is considered as one of the most common major health obstacles in the communities, according to World Health Organization (WHO) about 3.8% of population are suffering from depression. The prevalence of depression in Libya is 23.68%, excluding other mental and psychiatric disorders. Few studies and experiments bay attention about the significance of pharmacological cause of depression. The researchers have turned their focus to the association between Proton pump inhibitors (PPIs) and depression and suicidal attempts, which are considered as one of the most common prescribed drugs and can be sold without prescriptions in some nations. The aim of Study is assessment omeprazole's possible depressive-like effects on experimental animals. Behavioral tests: the tail suspension test (TST), forced swim test (FST), and sucrose preference test (SPT) were used to evaluate different behavioral changes in male Swiss albino mice after they were given omeprazole (40 mg/kg) for 15 days. According to our findings, the omeprazole (40 mg/kg) had a significant effect (p &lt; 0.01) on the tail suspension test and the forced swim test, and both tests had longer immobility times. An indicator of anhedonia, sucrose preference, was dramatically reduced by omeprazole (p value &lt; 0.01). A one-way ANOVA of the body weight data showed that it was not significant (p &gt; 0.05). Concerns about the long-term use of omeprazole are raised by the depressive-like effects seen in this study, especially in patients who may be taking the drug for longer periods of time. However, the supporting evidence remains limited, necessitating further research to comprehensively understand the implications of these drugs on mental health.

Transcriptomic Alterations in the Hippocampus and Prefrontal Cortex of Rats with Chronic Unpredictable Stress Induced by Low-Intensity Pulsed Ultrasound.

In our previous study, low-intensity pulsed ultrasound stimulation (LIPUS), a novel noninvasive neuromodulation tool, effectively alleviated depression-like behaviors in a rat model of depression. However, the underlying mechanisms remain unclear. The present study aimed to elucidate the relevant mechanisms through transcriptomic research. To induce depression-like phenotypes, rats were subjected to chronic unpredictable stress (CUS) for six weeks. Following this initial stress period, LIPUS was administered daily for an additional four weeks while the rats were continuously exposed to CUS, which was previously determined to significantly reduce immobility time in forced swimming test. The transcriptome expression profiles in the hippocampus and prefrontal cortex (PFC) were subsequently analyzed by RNA sequencing techniques. Overall, LIPUS reversed the abnormal expression of genes in the brain of model rats, especially the expression of genes linked to glucose and lipid metabolism. Specifically, we found that the CUS rats exhibited 3464 differentially expressed genes (DEGs) in the hippocampus and 1781 DEGs in the PFC compared to the control group. LIPUS reversed the expression of 592 genes in the hippocampus and 254 genes in the PFC. Functional analysis revealed a significant enrichment of DEGs related to oxygen carrier activity and sugar metabolism. Subsequently, the alterations in the top ten genes were validated using real-time PCR. The significant changes in the expression of hemoglobin subunit beta, growth hormone 1, and glucokinase were confirmed. The results suggest that LIPUS may alleviate depression-related manifestations by regulating cerebral oxygenation and sugar metabolism processes in the brain.

Chronic stress induces behavioural changes through increased kynurenic acid by downregulation of kynurenine-3-monooxygenase with microglial decline.

Alterations in tryptophan-kynurenine (TRP-KYN) pathway are implicated in major depressive disorder (MDD). α7 nicotinic acetylcholine (α7nACh) receptor regulates the hypothalamic-pituitary-adrenal (HPA) axis. We have shown that deficiency of kynurenine 3-monooxygenase (KMO) induces depression-like behaviour via kynurenic acid (KYNA; α7nACh antagonist). In this study, we investigated the involvement of the TRP-KYN pathway in stress-induced behavioural changes and the regulation of the HPA axis. Mice were exposed to chronic unpredictable mild stress (CUMS) and subjected to behavioural tests. We measured TRP-KYN metabolites and the expression of their enzymes in the hippocampus. KMO heterozygous mice were used to investigate stress vulnerability. We also evaluated the effect of nicotine (s.c.) on CUMS-induced behavioural changes and an increase in serum corticosterone (CORT) concentration. CUMS decreased social interaction time but increased immobility time under tail suspension associated with increased serum corticosterone concentration. CUMS increased KYNA levels via KMO suppression with microglial decline in the hippocampus. Kmo+/- mice were vulnerable to stress: they exhibited social impairment and increased serum corticosterone concentration even after short-term CUMS. Nicotine attenuated CUMS-induced behavioural changes and increased serum corticosterone concentration by inhibiting the increase in corticotropin-releasing hormone. Methyllycaconitine (α7nACh antagonist) inhibited the attenuating effect of nicotine. CUMS-induced behavioural changes and the HPA axis dysregulation could be induced by the increased levels of KYNA via KMO suppression. KYNA plays an important role in the pathophysiology of MDD as an α7nACh antagonist. Therefore, α7nACh receptor is an attractive therapeutic target for MDD.

Potential Effects of Clitoria ternatea on Rotenone-Induced Rat Model of Parkinson Disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterised by motor dysfunction due to the loss of dopaminergic neurons in the substantia nigra. Clitoria ternatea (CT), a medicinal plant used in Ayurvedic medicine, has shown promising neuroprotective properties that may be beneficial in the context of PD. This study investigates the potential effects of CT on a rotenone-induced rat model of Parkinson's disease. Sixty adult male Sprague Dawley rats were divided into six groups: the normal control group, the positive control group treated with Levodopa, the negative control group, and three experimental groups treated with CT extract at doses of 150 mg/kg, 250 mg/kg, and 500 mg/kg, respectively, for 28 days. Behavioural analyses, including motor and cognitive assessments, and histological examinations were performed. The group treated with the highest dose (500 mg/kg) showed the most significant reduction in immobility time from day 1 to day 28. Anxiety-like behaviour was assessed using the open field test, and motor impairment was evaluated with the beam walking test. The highest dose group showed a significant increase in total distance travelled, from 72.3% to 95.4% over the treatment period, compared to the control groups. Histological analysis revealed that the 500 mg/kg treatment group had the most substantial reduction in Lewy bodies. Overall, the administration of CT extract at 500 mg/kg improved motor deficits, neurobehavioral performance, and reduced neurodegeneration. These findings suggest that CT could be a promising natural therapeutic agent for the treatment and management of PD.