Fluoxetine-treated Group Research Articles

Neuroprotective effect of bromelain on BDNF-TRKB signalling pathway in chronic unpredictable stress-induced depression model

BackgroundBromelain is a mixture of protease enzyme extract from the fruit or stem of the pineapple plant. It has a wide range of biological actions, and it is most commonly used as an anti-inflammatory agent. This study was designed to investigate the antidepressant effect of bromelain on chronic unpredictable stress (CUS)-induced depression in rat models by targeting various molecular mechanisms.ResultWe studied the in silico analysis of the antidepressant potential of bromelain by docking with various proteins involved in the pathophysiology of depression. As a result of in silico studies, bromelain showed good binding energy with IL1β, 5-HT, BDNF, CREB, and TrkB. The mRNA expression of BDNF, TrkB, AKT, ERK, and IL-1β was studied by qRT-PCR. Gene expression studies showed a significant decrease in BDNF, TrkB, AKT, and ERK in chronic unpredictable stress, whereas there was a significant increase in the case of the bromelain- and fluoxetine-treated group. Since neuroinflammation is also one of the major concerns in the pathophysiology of depression, pro-inflammatory cytokines were also studied along with apoptotic markers using ELISA. ELISA results showed a significant increase in inflammatory cytokines in CUS, and it was significantly decreased in the case of the bromelain- and fluoxetine-treated group. Similarly, there was an increased concentration of pro-apoptotic protein in the CUS group, whereas it was decreased in the bromelain and fluoxetine groups.ConclusionsFrom the results, it is clear that bromelain exerts an antidepressive effect by preventing neuroinflammation and neurodegeneration and by enhancing neurogenesis and neuroplasticity.Graphical abstract

Modulating gut microbiota improves neurological function and depressive symptoms in rats with post-stroke depression

To evaluate the effect of modulating gut microbiota for improving brain injury in rats with post-stroke depression. Adult SD rats were randomized into normal control, middle cerebral artery occlusion (MCAO), post-stroke depression (PSD), PSD with fecal transplantation, PSD with antibiotics (rifaximin), PSD with probiotics (lactobacilli), and PSD with fluoxetine treatment groups (n=9). Neurological function scores of the rats were determined, and the changes in sugar water preference and immobility time in forced swimming test were observed; plasma levels of trimethylamine N-oxide (TMAO) and hydrogen sulfide (H2S) were detected with ELISA, Occludin, and the expressions of occludin, caudin-5 and IgG proteins Ⅰ the brain tissues were determined using Western blotting. Compared with those in the control group, the rats in MCAO and PSD groups had significantly increased neurological function scores, TMAO level, the ratio of TMAO/H2S, and immobility time in forced swimming test with a lowered level of H2S (P < 0.05). These changes were more obvious in PSD rats, which also exhibited a reduced sugar water preference with increased IgG protein and decreased occluding and caudin-5 expressions in the brain tissue (P < 0.05). TMAO/H2S ratio in PSD rats was positively correlated with neurological function score (R2=0.3235, P=0.0269) and immobility time in swimming (R2=0.6290, P=0.0004) and negatively with sugar water preference (R2=-0.4534, P=0.0059). Treatment with fecal transplantation, antibiotics, probiotics and fluoxetine all significantly reduced neurological function scores, immobility time in forced swimming, TMAO/H2S ratio, and IgG protein expression and increased sugar water preference and brain occludin and caudin-5 expressions of the PSD rats (P < 0.05). In PSD rats, TMAO/H2S ratio is correlated with neurological function score, immobility time in forced swimming and sugar water preference, and modulating intestinal flora can improve neurological function and depressive symptoms and improve the integrity of the blood-brain barrier.

Metabolomic identification of biochemical changes induced by fluoxetine in an insulinoma cell line (MIN6).

The use of fluoxetine raises the risk of pancreatic beta-cell dysfunction. However, the specific mechanism behind its mechanism of action in beta cells is unknown. This study investigated the cellular response of MIN6 cells to fluoxetine using untargeted cell-based metabolomics. Metabolic profiling of MIN6 cells was performed using liquid chromatography-high resolution mass spectrometry (LC-HRMS) analysis on samples prepared under optimized conditions, followed by principal component analysis, partial least squares-discriminant analysis, and pair-wise orthogonal projections to latent structures discriminant analyses. Sixty-six metabolites that had been differentially expressed between the control and fluoxetine-treated groups demonstrated that the citric acid cycle is mainly perturbed by fluoxetine treatment. The current study provides insights into the molecular mechanisms of fluoxetine effects in MIN6 cells.

Antidepressant evaluation of Andrographis paniculata Nees extract and andrographolide in chronic unpredictable stress zebrafish model

Andrographis paniculata (A. paniculata) showed an anti-depressive effect in rodent models. Zebrafish has recently emerged as a worthy complementary translational model for antidepressant drug discovery study. This study investigates the anti-depressive effect of A. paniculata extract and andrographolide in the chronic unpredictable stress (CUS)- zebrafish model. Four groups of zebrafish (n = 10/group), i.e. control, CUS (stressed, untreated), CUS + A. paniculata (100 mg/L) and CUS + fluoxetine (0.01 mg/L) were assessed in open-field and social interaction tests, 24 h after treatment. After extract screening, behavioural and cortisol analysis of andrographolide (5, 25 and 50 mg/kg, i.p.) and fluoxetine (10 mg/kg, i.p.) were evaluated. Before the behavioural study, acute toxicity and characterization of A. paniculata extract using UHPLC-ESI-MS/MS were performed. A significant reduction in freezing duration was found in A. paniculata- (t-test, p = 0.0234) and fluoxetine-treated groups (t-test, p < 0.0001) compared to the CUS group. A significant increase in total distance travelled, and contact duration was observed only in the fluoxetine-treated group (t-test, p = 0.0007) and (t-test, p = 0.0207), respectively. A significant increase in highly mobile duration was observed in both treatment groups. Andrographolide (50 mg/kg, i.p.) acute treatment showed a significant reduction in freezing duration (p = 0.0042), duration in a dark area (p = 0.0338) and cortisol level (p = 0.0156) and increased total distance travelled (p = 0.0144). Twenty-six compounds were tentatively characterized by LC-MS/MS method, and andrographolide content is 0.042 μg/g. According to cortisol analysis, A. paniculata's LC50 is 627.99 mg/L, while andrographolide's EC50 was determined as 26.915 mg/kg. Further assessment of the cellular and molecular underpinnings of the anti-depressive effect of andrographolide is strongly recommended to evaluate the potential as an antidepressant.

Comparison of LPS and MS-induced depressive mouse model: behavior, inflammation and biochemical changes

Depression is a mental disease involving complex pathophysiological mechanisms, and there are many ways to establish depressive mouse models. The purpose of this study is to comprehensively compare the behavioral changes and its mechanism induced by two different models. This study established two depressive mouse models by maternal separation (MS) or lipopolysaccharide (LPS) administration, and added fluoxetine treatment group respectively for comparison. MS induced more apparent anxiety-like behavior while LPS induced more apparent depressive-like behavior. LPS increased peripheral inflammatory factors more apparent, which were mitigated by fluoxetine. MS inhibited the 5-HT system more obviously and was relieved by fluoxetine. LPS triggered stronger immune response in the hippocampus and prefrontal cortex (PFC). MS significantly reduced the expression of neurotrophic proteins and was alleviated by fluoxetine. Overall, LPS induced stronger system inflammation, while MS impaired the function of HPA axis and 5-HT system. Our results will contribute to a deeper understanding of the pathophysiology of different stress-induced depression and will also help researchers select appropriate models of depression for their own needs.

Effects of SIRT1 in amygdala on chronic restraint stress-induced depression-like behaviors in rats

To investigate the effects of silent information regulator 1 (SIRT1) in amygdala on depression-like behaviors in rats using chronic restraint stress (CRS) as a model of depression. Sixty male SD rats were randomly divided into six groups (n=10 per group): control group (Control), chronic restraint stress group (CRS), CRS + fluoxetine-treated group (CRS + FLU), CRS + saline-treated group (CRS + NaCl), CRS + SIRT1-overexpression group (CRS + AAV-SIRT1), and CRS + empty vector group (CRS + AAV-EGFP). Except for the control group, rats from the other groups were exposed to chronic restraint stress for 21 days. After the modeling, rats in fluoxetine-treated group and saline-treated group were, respectively, treated with fluoxetine (10 mg/kg) or saline (10 mg/kg) by gavage every day for 3 weeks; AAV-SIRT1 or AAV-EGFP was, respectively, stereotaxically injected into the amygdala of rats in SIRT1-overexpression group and empty vector group, and the virus was expressed for 3 weeks. Rats in normal control group and CRS model group were not given any drug treatment. The depression-like behaviors of rats in each group were evaluated by sugar preference test (SPT), open field test (OFT) and forced swimming test (FST). SIRT1 expression in amygdala of rats was assessed by using immunoblot blotting. The number of SIRT1-positive cells in amygdala of rats was detected by immunofluorescence technique. Compared with the normal control group, the level of SIRT1 protein and the number of SIRT1+ cells in amygdala of the CRS-exposed rats were decreased significantly (P＜0.01), and CRS-exposed rats showed a significant decrease in sucrose preference (P＜0.01), less total horizontal distance (P＜0.01) and less time entered the center field (P＜0.01) in the OFT, a significant increase in the immobility time of the FST (P＜0.01). Fluoxetine treatment (P＜0.05, P＜0.01) or SIRT1 overexpression (P＜0.01) partially reversed the down-regulation of SIRT1 protein and SIRT1+ cells in amygdala of CRS-exposed rats and significantly improved the depression-like behaviors of CRS rats. Fluoxetine treatment partially reversed the down-regulation of SIRT1 level and the number of SIRT1+ in CRS rats, and significantly improved the depression-like behaviors. The antidepressant effect of fluoxetine treatment may be related to the up-regulation of SIRT1 in the amygdala of CRS-exposed rats.

Effect of Mentone® on depression- and anxiety-like profiles and regional brain neurochemistry in the adolescent Wistar Kyoto rat, a putative model of endogenous depression

Objectives: Antidepressants, when prescribed to treat adolescent depression tend to induce adverse effects, including suicidal tendencies. This is because the adolescent brain circuitry is still maturing and is therefore extremely vulnerable. As such, the search is on for compounds for use in complementary/alternative medicine. Polyherbal formulations are widely used as therapeutic alternatives for the treatment of depression. Such formulations and plant extracts are being studied in adult rodent models using standard pharmacological parameters, but not much emphasis has been given to testing the same in adolescents and endogenous animal models of depression. Therefore, the present study was focused on testing out the effect of the polyherbal formulation Mentone® on depression- and anxiety-like profiles and brain neurochemistry in the adolescent Wistar Kyoto rat (WKY), a putative model of endogenous and treatment-resistant depression (TRD). Materials and Methods: Mentone®, a polyherbal formulation comprising of four different plant species: Centella asiatica (Brahmi), Evolvulus alsinoides (Shankapushpi), Tinospora cordifolia (Guduchi), and Glycyrrhiza glabra (Yashtimadhu) was tested at two (18 and 36 mg/kg body weight) doses from the post-natal day (pnd) 25 to pnd 42 using standard neurobehavioral paradigms. Vehicular controls were intubated with saline and positive controls with 10 mg/kg body weight of conventional antidepressant, Fluoxetine. From pnd 35 onwards, animals were tested on a battery of tests, including sucrose preference, novel open field, elevated plus maze, and forced swim or Porsolt’s learned helplessness test. On pnd 42, animals were sacrificed and brain regional tissues such as the Prefrontal cortex (PFC), Striatum (Str), Nucleus Accumbens (NAc), and Hippocampus were microdissected out and subjected to reverse phase HPLC for the separation and quantification of monoamines: Norepinephrine (NE), dopamine (DA), serotonin (5-HT) and their metabolites, 3,4-Dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) in reference to external standards. Results: Mentone® reversed anhedonia by increasing sucrose consumption in Mentone®-treated as compared to Fluoxetine-treated groups. However, there was no effect on anxiety-related parameters in the novel open field or elevated plus-maze. Mentone® exhibited significant anti-depressant-like effects as indicated by its ability to reduce swim stress-induced immobility in Porsolt’s behavioural despair test with a concomitant increase in climbing or struggling behaviour, signifying reversal of depressive-like symptomatology. HPLC-based separation and quantification of brain regional levels of monoamines and their metabolites revealed increased DA levels in NAc and Str in treated groups with decreased levels of metabolite DOPAC in Mentone®-treated groups indicating increased DA tone. Significantly reduced 5-HT metabolite 5-HIAA levels in both PFC and Str is indicative of increased 5-HT tone in both Mentone®- and Fluoxetine-treated groups. NE was variably affected. Conclusion: While no anxiolytic effects and differential neurochemical effects were observed in brain regional areas in relation to Mentone® and Fluoxetine treatment, anhedonia and forced swim test, which are gold-standard tests for assessing depressive-like profiles indicated an effect of Mentone® that was on par with Fluoxetine. Thus, studies on such Ayurvedic formulations would enable a teasing out or differentiation between anxiolytic-like and depressive-like symptomatology and could constitute a source that holds promise in the development of complementary/alternative therapies for the treatment of depression in general and TRD in particular.

Abstract 5285: Antitumor and mechanism of selective serotonin reuptake inhibitor fluoxetine on muscle invasive bladder cancer

Abstract Purpose/Introduction: Bladder cancer can be broadly divided into two type, including non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC). Among them, MIBC has been recognized as hard to treatment type of cancer for many decades. Therefore, to develop a new treatment strategy for MIBC is urgently needed. Transcription factor nuclear factor-kappaB (NF-κB) plays important role in various cancer progression, including hepatocellular carcinoma (HCC), lung adenocarcinoma (LUAD), and MIBC. Thus, NF-κB may be a potential target to suppress the progression of MIBC. Fluoxetine is FDA approval antidepressant agent, belongs to selective serotonin reuptake inhibitor (SSRI). Interestingly, recent study indicated that Fluoxetine inhibited NF-κB and induced apoptosis in the HCC both in vivo and in vitro. However, whether Fluoxetine may regulate NF-κB and inhibit MIBC tumor progression is remaining unknown. Therefore, the aim of present study is to verify the treatment efficacy and underlying mechanism of fluoxetine on MIBC. Methods: Human MIBC cells TSGH8301 and T24 cells and mice bearing with MIBC MB49 cells was used in this study. Cytotoxicity, apoptosis, and metastasis ability of cells after fluoxetine treatment was validated through MTT assay, cleaved caspase-3, -8, -9 activation using flow cytometry and transwell migration/invasion assay, respectively. In in vivo study murine MB49 cells were subcutaneous inoculated into right flank of C57B6/J mice and treated with fluoxetine for 15 days. Result: Fluoxetine markedly induced cytotoxicity, cleaved caspase-3, -8, -9 expression, and inhibited migration and invasion in both TSGH8301 and T24 cells. Western blotting and reporter gene assay indicated that fluoxetine may suppress the phosphorylation and activity of NF-κB. In in vivo results, fluoxetine inhibited tumor growth and the expression of NF-κB within tumor. Tumor immunohistochemistry (IHC) staining results proved that the apoptosis marker such as Caspase-3, -8, -9 were all increased by fluoxetine. AST and ALT value that represent as liver function showed no significant difference between vehicle group and fluoxetine treatment group. Body weight and H&amp;E results also proved the safety of fluoxetine usage. Conclusion: Fluoxetine induced cytotoxicity via both extrinsic/intrinsic apoptotic pathway and inhibited metastasis ability as well. Fluoxetine may also suppress the phosphorylation and activity NF-κB in vitro and in vivo. In sum, we suggested that fluoxetine may effectively suppress tumor progression via inactivate NF-κB signaling pathway. Citation Format: Zhao-Lin Tan, Yuan Chang, I-Tsang Chiang, Fei-Ting Hsu, Fei-Ting Hsu. Antitumor and mechanism of selective serotonin reuptake inhibitor fluoxetine on muscle invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5285.

Electron microscopic study on the effect of chronic fluoxetine treatment on pituitary gland and the possible therapeutic effect of adipose-derived mesenchymal stem cells in adult male albino rats

ABSTRACT Background: Adipose-derived mesenchymal stem cells (ADSCs) have therapeutic potential for the treatment of a variety of disorders due to their self-renewal and multipotential differentiation capabilities. Aim of the work: This study was planned to demonstrate the electron microscopic structure of the pituitary gland after chronic fluoxetine treatment and the possible therapeutic effect of ADSCs. Materials and methods:Thirty healthy male adult albino rats were classified into Control group (Group I). Fluoxetine treated (Group II) received 24 mg/kg/day of fluoxetine dissolved in 1.0 mL of tap water once a day. Fluoxetine group treated with ADSCs (Group III) received fluoxetine as group (II) for 30 days and then was injected once by ADSCs at a dose of 1 × 106 cells/rat in the tail vein suspended in 0.5 ml of phosphate-buffered saline (PBS). Recovery group (Group IV) received fluoxetine for 30 days and then received no treatment till the end of the experiment. Results: The ultrastructural observations of the fluoxetine-treated group revealed major histological changes in both the pars distalis and nervosa. Pars distalis revealed cells with different shapes, sizes, nuclei, and variable profiles of the cytoplasm. Pars nervosa, on the other hand, revealed pituicytes with electron-lucent cytoplasm and small apoptotic nuclei. Administration of ADSCs greatly improved the microscopic appearance of cells, while the recovery group showed similar histological changes as the fluoxetine group. Conclusion: Fluoxetine caused various deleterious changes in the pituitary gland of albino rats, as evidenced by electron microscopy. These changes were almost corrected by the ADSCs treatment. .

Antidepressant-Like Effect of Traditional Medicinal Plant Carthamus Tinctorius in Mice Model through Neuro-Behavioral Tests and Transcriptomic Approach

Major depression disorder (MDD) has become a common life-threatening disorder. Despite the number of studies and the introduced antidepressants, MDD remains a major global health issue. Carthamus tinctorius (safflower) is traditionally used for food and medical purposes. This study investigated the chemical profile and the antidepressant-like effect of the Carthamus tincto-rius hot water extract in male mice and its mechanism using a transcriptomic analysis. The antidepressant effect of hot water extract (50 mg/kg and 150 mg/kg) was investigated in mice versus the untreated group (saline) and positive control group (fluoxetine 10 mg/kg). Hippocampus transcriptome changes were investigated to understand the Carthamus tinctorius mechanism of action. The GC-MS analysis of Carthamus tinctorius showed that hot water extract yielded the highest amount of oleamide as the most active ingredient. Neuro-behavioral tests demonstrated that the safflower treatment significantly reduced immobility time in TST and FST and improved performance in the YMSAT compared to the control group. RNA-seq analysis revealed a significant differential gene expression pattern in several genes such as Ube2j2, Ncor1, Tuba1c, Grik1, Msmo1, and Casp9 related to MDD regulation in 50 mg/kg safflower treatment as compared to untreated and fluoxetine-treated groups. Our findings demonstrated the antidepressant-like effect of safflower hot water extract and its bioactive ingredient oleamide on mice, validated by a significantly shortened immobility time in TST and FST and an increase in the percentage of spontaneous alternation.

Study of the effect of fluoxetine on liver enzymes in the blood serum of pregnant albino rats

The current study examined the effect of fluoxetine on liver enzymes in pregnant female rats. 42 rats, including ten males, were used for inoculation only, while the number of females was 32 rats. Female rats were divided into two groups, the control group consisted of 8 rats. The fluoxetine-treated group of 24 females was divided into three groups. The first group included 8 pregnant female rats injected with fluoxetine at a concentration of 20 mg/kg of body weight from day 0 of gestation until day 7 or 18, and the second group also included 8 pregnant females injected with fluoxetine at a concentration of 40 mg/kg. of body weight from day day 0 of gestation until day 7 or 18, and the third group included 8 pregnant females injected with fluoxetine at a concentration of 60 mg/kg of body weight from day 0 of gestation until day 7 or 18, blood samples were collected on the 7 or 18 days From pregnancy from all animal groups to measure the following parameters: ALT, alkaline phosphatase, ALP, and aspartate aminotransferase (AST).

Therapeutic efficacy of adipose-derived mesenchymal stem cells after chronic fluoxetine treatment on pars distalis in adult male albino rats

BackgroundFluoxetine hydrochloride is one of the most commonly used antidepressants in the selective serotonin reuptake inhibitor class. The aim of work: The study was conducted to detect the effect of chronic fluoxetine treatment on pars distalis and the possible therapeutic effect of adipose-derived mesenchymal stem cells (ADSCs). Material and methodThirty healthy male adult albino rats were classified into four groups. Control group (Group I) included fifteen rats. Fluoxetine treated (Group II) included five rats that received 24 mg/kg/day of fluoxetine dissolved in 1.0 ml of tap water once a day for 30 days. Fluoxetine group treated with ADSCs (Group III) included five rats that received fluoxetine as group (II) for 30 days, then supplied once by ADSCs at a dose of 1 × 106 cells/rat in the tail vein suspended in 0.5 ml of phosphate-buffered saline (PBS). Recovery group (Group IV) included five rats that received fluoxetine as the group (II) then received no treatment till the end of the experiment. Samples from pars distalis were processed for light, electron microscopic examination, morphometrical and statistical analyses. ResultsIn the fluoxetine-treated group, there was a disruption in cellular architecture, size, shape, and staining characteristics of pars distalis cells. The administration of ADSCs significantly improved the microscopic appearance of cells, while the recovery group showed some histological changes similar to the fluoxetine group. ConclusionFluoxetine induced various deleterious changes in the pars distalis of albino rats. These changes were almost corrected by the ADSCs treatment.

Chronic Antidepressant Use

Background: Chronic use of antidepressant drugs often results in drug-induced organ damage, which is mostly undetected and under-reported. The study aimed at evaluating the effect of selected antidepressants on organs and blood cell counts in adult albino rats. Materials and Methods: Adult rats were divided into four groups (n = 5): Group 1 (5 mL/kg of body weight/day normal saline), Group 2 (1 mg/kg of body weight/day risperidone), Group 3 (5 mg/kg of body weight/day fluoxetine), and Group 4 (15 mg/kg of body weight/day imipramine) for 14 days. The animals experienced different stressors during the treatment period to simulate physiological state of depression. On the 14th day, the animals were exposed to the forced swimming test 1 h after the respective treatments. On the 15th day, the animals were sacrificed under halothane anesthesia. Blood sample was collected. Liver and kidney were excised for histological examination. Results were analyzed using one-way analysis of variance. Results: Kidney histology was normal for all groups. Risperidone-exposed rats presented with hepatotoxicity with areas of zonal necrosis and partial central vein congestion. Neutrophil (%) was significantly reduced (P &lt; 0.01) in all treatment groups when compared with controls. White blood cell count was significantly increased (P &lt; 0.01) in the imipramine and risperidone treatment groups but significantly reduced (P &lt; 0.01) in the fluoxetine treatment group when compared with controls. Also, the platelet count was significantly increased (P &lt; 0.01) in the fluoxetine group but decreased in imipramine-and risperidone-treated groups. Conclusion: Chronic antidepressant use can cause changes in blood cell counts and drug-induced organ damage; hence, frequent organ function tests and blood count are required in patients undergoing chronic antidepressant therapy.

Efficacy of Fluoxetine for Post-Ischemic Stroke Depression in Tanzania

ObjectivePost-stroke fluoxetine trials are primarily conducted in high-income countries. We characterize post-ischemic stroke depression in fluoxetine-treated and -untreated study participants in urban Tanzania. MethodsAdults (>18 years old) within 14 days of CT-confirmed acute ischemic stroke onset were enrolled at Muhimbili National Hospital, Tanzania. The fluoxetine-treated group took 20mg fluoxetine daily for 90 days in a phase II trial and were compared to fluoxetine-untreated historical controls. The primary outcome was depression at 90 days, measured by the Patient Health Questionnaire-9 (PHQ-9). PHQ-9 scores were compared between fluoxetine-treated and -untreated groups. A score >=9 points was considered to reflect depression. A multivariable linear regression model assessed associations with post-stroke PHQ-9 scores. ResultsOf the fluoxetine-treated (n=27) and -untreated (n=32) participants, the average age was 56.8 years old (39% women, 100% Black/African). The average presentation NIHSS score was 12.1 points and modified Rankin Scale (mRS) score was 3.5. The average mRS score at 90-day follow-up was 2.3. There was no significant difference between 90-day PHQ-9 scores in the fluoxetine-treated (mean=4.1 points, standard deviation=3.2; 11% depression) and untreated (mean=4.4, standard deviation=4.8; 19% depression) groups, p=.69. In the multivariable analysis, older age (β=0.08, p=.03) and higher NIHSS score (β=0.15, p=.04), but neither fluoxetine (β=0.57, p=.59) nor sex (β=-0.51, p=.63), were significantly associated with more depressive symptoms. ConclusionsOur findings parallel results from trials from higher income settings that fluoxetine does not significantly improve post-ischemic stroke depression, although our sample size was small. More work is needed to depict the longitudinal nature and treatment of post-stroke depression in Sub-Saharan Africa.

Effect of Regular Physical Exercise on Gut Microbiota and Depressive Behaviors in Rats

Objective. The gut microbiota, as the critical mediator of the gut-brain axis, can produce and transport neuroactive substances, thus playing a significant role in the pathogenesis of depression. Although regular physical exercise is an important nondrug antidepressant, its specific effector mechanism is still unclear. Methods. Rats were randomly divided into four different groups (n = 10 for each group) as follows: normal group (G1), depression group (G2), fluoxetine treatment group (G3), and regular exercise treatment group (G4). All rats underwent forced swimming tests, tail suspension tests, open field tests, and elevated plus-maze tests to detect behavioristics. Then, corticosterone levels were detected by ELISA. Additionally, taxonomic analysis of the gut microbiota in all rats was performed after they were exercised regularly for 60 days. Results. Compared with the G1 group, the rats in the G2 group showed significant depression-like behaviors, with increased serum corticosterone levels. The proportions of Bacteroides, Actinomycetes, Proteobacteria, Saccharomyces, and Cyanobacteria in rats of the G2 group were lower than those in the G1 group, while the proportions of Firmicutes, Tenicotte, Deferrobacteria, and Fusobacteria were increased. Furthermore, after regular exercise treatment, the gut microbiota of rats was effectively improved, almost returning to the level of the G1 group, and depressive behavior and corticosterone levels were also restored, which was almost the same as the effect of fluoxetine treatment. Conclusion. Regular physical exercise could alleviate depressive-like behaviors by modulating the species and function of the gut microbiota.

A probiotic supplement, Lactobacillus rhamnosus GG, and kefir separately can improve mood and exhibit potential anti-depressant-like activities in mice

AbstractDepression is a common psychiatric disorder that can be continuous or recurrent. It has been previously reported that intestine probiotics play an essential role in the bidirectional communication of the intestine and brain. This study aims to investigate the antidepressant effects of kefir, a probiotic supplement, and Lactobacillus rhamnosus GG and their potentials in depression-like behaviour treatment in two-week and four-week treatments. In the present study, BALB/c mice were used for this purpose. The saline- and fluoxetine-treated groups were designed as negative and positive control groups, respectively. The forced swimming and tail suspension tests have been performed to assess the level of depression-like activity. We have observed that two-week treatment reduces the duration of depression-like activities, and four-week treatment enhances the antidepressant properties. Overall, our results suggest that kefir, L. rhamnosus GG, and the investigated probiotic supplement have antidepressant-like properties.

Vascular sympathetic neurotransmission and its serotonergic regulation are modified by chronic fluoxetine treatment

Given the interconnection between depressive and cardiovascular disorders, we investigated whether antidepressant treatment (fluoxetine) modifies the serotonergic influence on rat vascular noradrenergic outflow. Twelve-week-old male Wistar rats received fluoxetine treatment (10 mg/kg/day; p.o.) for 14 days; then, they were pithed and prepared for sympathetic stimulation. Vasopressor responses were obtained by electrical stimulation of the sympathetic outflow (0.1, 0.5, 1, and 5 Hz) or i.v. noradrenaline (NA; 0.01, 0.05, 0.1, and 0.5 μg/kg). In fluoxetine-treated group, the electrical-induced vasoconstrictions were lower compared to non-treated rats. Intravenous infusion of 5-HT (10 μg/kg/min) inhibited the sympathetically-induced vasoconstrictions. Only 5-CT, 8-OH-DPAT and L-694,247 (5-HT1/7, 5-HT1A and 5-HT1D agonists, respectively) mimicked 5-HT-induced inhibition, while α-methyl-5-HT (5-HT2 agonist) increased the vasopressor responses. The inhibitory effect of 5-HT was: a) no modified by SB269970 (5-HT7 antagonist); b) abolished by WAY-100,635 (5-HT1A antagonist) plus LY310762 (5-HT1D antagonist); and c) potentiated by ritanserin (5-HT2A receptor antagonist). The vasoconstrictions induced by exogenous NA were not modified by 5-CT but were increased by α-methyl-5-HT. Our results suggest that fluoxetine treatment decreases NA release at vascular level and changes 5-HT modulation on rat vascular noradrenergic neurotransmission, inducing sympatho-inhibition via prejunctional 5-HT1A/1D receptors, and sympatho-potentiation via pre and/or postjunctional 5-HT2A receptors.

Does the Initiation of Fluoxetine Postacute Stroke Result in Improved Functional Recovery?: A Critically Appraised Topic.

Stroke is a leading cause of disability worldwide. Selective serotonin reuptake inhibitors are often prescribed following stroke due to high rates of depression. Interest in selective serotonin reuptake inhibitor use for poststroke motor and functional recovery was generated after the publication of the Fluoxetine for motor recovery after acute ischemic stroke (FLAME) trial in 2011, which showed improved motor recovery in ischemic stroke patients with moderate to severe motor deficits. The objective of this study was to critically assess current evidence regarding the use of fluoxetine compared with placebo for poststroke functional recovery. The objective was addressed through the development of a structured critically appraised topic. This included a clinical scenario and question, literature search, critical appraisal, results, evidence summary, commentary, and clinical bottom line conclusions. Participants included consultant and resident neurologists, medical librarian, clinical epidemiologists, and content experts in the field of cerebrovascular neurology and physical medicine and rehabilitation. A randomized, placebo-controlled clinical trial was selected for critical appraisal. This trial compared the functional outcomes of subjects poststroke receiving fluoxetine versus placebo. There was no significant difference in functional outcome measured by the Modified Rankin Scale between the 2 groups. Prespecified secondary analysis showed significantly decreased rates of depression in the fluoxetine group, but significantly increased rates of bone fracture. Among patients with stroke, early initiation of fluoxetine did not result in improved functional recovery. Lower rates of depression were observed in the fluoxetine-treated group; however these patients experienced higher rates of bone fracture.

Effect of fluoxetine on the MAPK-ERK1/2 signaling pathway and expression of associated factors in human conjunctival epithelial cells in culture.

The aim of the present study was to evaluate the effect of fluoxetine on activation of the mitogen-activated protein kinase (MAPK) signaling pathway and the expression of apoptosis-associated factors in human conjunctival epithelial cells (HConEpiCs) in culture. HConEpiCs were isolated, cultured and characterized by immunostaining. HConEpiC cells at passage 3-4 were cultured with fluoxetine at different dosages (0, 1, 2.5, 5, 10, 20 and 40 µM) and proliferation rates were determined using a Cell Counting Kit-8 assay. Subsequently, Transwell assays were performed to evaluate the effect of fluoxetine (5 µM) on the invasion and migration capacities of HConEpiCs. ERK1/2 and phosphorylated (p-)ERK1/2 levels were also evaluated in control and fluoxetine-treated groups of HConEpiCs via immunostaining. Finally, western blot assays were performed to evaluate the intracellular protein levels of ERK, p-ERK, Bcl-2, Bax and matrix metalloproteinases (MMPs) in HConEpiCs. It was identified that, as the fluoxetine concentration increased, proliferation rates of HConEpiCs gradually decreased and 5 µΜ fluoxetine was selected for further evaluation. The results of Transwell assays indicated that fluoxetine treatment significantly repressed cell migration and invasion. Immunostaining suggested that there was no significant difference in fluorescence intensity of ERK1/2 between the control and fluoxetine-treated groups, while p-ERK1/2 was significantly enhanced in the fluoxetine-treated group. This result indicated that fluoxetine promoted ERK1/2 activation without affecting its expression. Similarly, western blot analysis revealed no significant difference in ERK1/2 and MMP levels between fluoxetine-treated and control groups, but p-ERK1/2 and Bax were upregulated and Bcl-2 was decreased in the fluoxetine-treated group. In conclusion, fluoxetine induces apoptosis of HConEpiCs in culture via activating the MAPK-ERK1/2 signaling pathway.

Effect of fluoxetine on HIF-1α- Netrin/VEGF cascade, angiogenesis and neuroprotection in a rat model of transient middle cerebral artery occlusion

Fluoxetine is one of the most promising drugs for improving clinical outcome in patients with ischemic stroke. This in vivo study investigated the hypothesis that fluoxetine may affect HIF-1α-Netrin/VEGF cascade, angiogenesis and neuroprotection using a rat model of transient middle cerebral artery occlusion (tMCAO). The rats were given fluoxetine or saline after tMCAO for 4 weeks. Then, protein expression of HIF-1α-Netrin/VEGF cascade was examined at 1, 2, 4 weeks after tMCAO. In vivo synchrotron radiation were performed to observe microangiography of ischemic brain after 4 weeks of tMCAO. The infarct size and neurobehavioral test were carried out 1 to 4 weeks after tMCAO. Results revealed that HIF-1α expression was upregulated in fluoxetine-treated group. Similarly, fluoxetine increased protein expression of Netrin and its receptor DCC, VEGF and its receptor VEGFR. Synchrotron radiation angiography revealed more branches in fluoxetine-treated rats. We found no difference of infarct volume between fluoxetine and saline treated rats after 1 week of tMCAO, and ischemia-induced brain atrophy volume in fluoxetine-treated group was attenuated after 4 weeks of tMCAO. Neurological deficits were improved in fluoxetine-treated rats at 3 and 4 weeks after tMCAO. Our results indicated that fluoxetine could upregulate protein expression of HIF-1α-Netrin/VEGF cascade, promote angiogenesis, and improve long-term functional recovery after ischemic stroke.