Psidium Exotic and Native Species from Brazil Abolish Depression-like Behavior and Oxidative Stress induced by Corticosterone in Mice.

Depression is a highly prevalent neuropsychiatric disorder worldwide. One currently accepted hypothesis of this pathogenesis is the hypothalamic-pituitary-adrenal axis dysfunction, which involves oxidative stress and brain damage. Therefore, antioxidants, such as phenolic compounds, could be used in depression. In this study, we investigated the antidepressant-like and antioxidant effects of an aqueous extract of the leaves of three species of the genus Psidium, Myrtaceae family, in mice. The exotic Psidium guajava L. and the natives Psidium guineense Sw. and Psidium cattleianum Sabine (10, 1, and 0.1 mg/kg, respectively) and fluoxetine (10 mg/kg) were administered orally (p. o.) once daily for 21 days, with or without corticosterone (20 mg/kg). After behavioral assessments (tail suspension, splash, and open-field tests), the hippocampus, prefrontal cortex, liver, kidneys, and plasma were examined to determine the oxidative stress status. The three extracts and fluoxetine treatment decreased the immobility time and counteracted the oxidative stress induced by corticosterone administration. The phenolic compounds identified as major components of the extracts, quercetin in P. guajava and P. guineense and o-coumaric acid in P. cattleianum, may be involved in the biological activities. Therefore, the aqueous leaf extracts of P. guajava, P. cattleianum, and P. guineense could be potential antidepressants helpful in treating depression and other diseases with elevated nitro-oxidative stress.

Carvacrol alleviates CUMS-induced depressive-like behaviors and cognitive impairment by reducing oxidative stress and neuroinflammation in mice.

The present study aimed to evaluate the protective potential of carvacrol against depressive-like behavior and cognitive impairment prompted by chronic unpredictable mild stress (CUMS) in mice. The animals were divided into six groups: Control (non-stressed), CARV (carvacrol at 50 mg/kg, p.o.), FLU (fluoxetine at 10 mg/kg, p.o.), CUMS (stressed), CUMS + CARV and CUMS + FLU, and the groups with CUMS were subjected to different stressors for 28 days. After treatment, mice underwent behavioral testing (open field, forced swimming, sucrose preference, social interaction, novel object recognition and Y-maze) and brain areas were removed for oxidative stress (MDA, nitrite/nitrate and GSH levels) and cytokine (IL-1ß and TNF-α) content assays. The results revealed that CARV administration reversed depressive-like behavior and significantly ameliorated the cognitive deficit induced by CUMS, as well as was able to attenuate oxidative stress (decreased MDA and nitrite/nitrate levels and increased GSH levels). In addition, a significant reduction in hippocampal IL-1ß and TNF-α levels was observed, demonstrating a potential anti-neuroinflammatory activity. Taken together, the antioxidant and anti-inflammatory activities observed in this study indicate that CARV is a promising drug for antidepressant treatment.

The beneficial effect of fluoxetine on behavioral and cognitive changes in chronic experimental Chagas disease unveils the role of serotonin fueling astrocyte infection by Trypanosoma cruzi.

BACKGROUND: In Chagas disease (CD), a neglected tropical disease caused by the parasite Trypanosoma cruzi, the development of mental disorders such as anxiety, depression, and memory loss may be underpinned by social, psychological, and biological stressors. Here, we investigated biological factors underlying behavioral changes in a preclinical model of CD. METHODOLOGY/PRINCIPAL FINDINGS: In T. cruzi-infected C57BL/6 mice, a kinetic study (5 to 150 days postinfection, dpi) using standardized methods revealed a sequential onset of behavioral changes: reduced innate compulsive behavior, followed by anxiety and depressive-like behavior, ending with progressive memory impairments. Hence, T. cruzi-infected mice were treated (120 to 150 dpi) with 10 mg/Kg/day of the selective serotonin reuptake inhibitor fluoxetine (Fx), an antidepressant that favors neuroplasticity. Fx therapy reversed the innate compulsive behavior loss, anxiety, and depressive-like behavior while preventing or reversing memory deficits. Biochemical, histological, and parasitological analyses of the brain tissue showed increased levels of the neurotransmitters GABA/glutamate and lipid peroxidation products and decreased expression of brain-derived neurotrophic factor in the absence of neuroinflammation at 150 dpi. Fx therapy ameliorated the neurochemical changes and reduced parasite load in the brain tissue. Next, using the human U-87 MG astroglioma cell line, we found no direct effect of Fx on parasite load. Crucially, serotonin/5-HT (Ser/5-HT) promoted parasite uptake, an effect increased by prior stimulation with IFNγ and TNF but abrogated by Fx. Also, Fx blocked the cytokine-driven Ser/5-HT-promoted increase of nitric oxide and glutamate levels in infected cells. CONCLUSION/SIGNIFICANCE: We bring the first evidence of a sequential onset of behavioral changes in T. cruzi-infected mice. Fx therapy improves behavioral and biological changes and parasite control in the brain tissue. Moreover, in the central nervous system, cytokine-driven Ser/5-HT consumption may favor parasite persistence, disrupting neurotransmitter balance and promoting a neurotoxic environment likely contributing to behavioral and cognitive disorders.

Social-Single Prolonged Stress affects contextual fear conditioning in male and female Wistar rats: Molecular insights in the amygdala.

Stress exposure can lead to post-traumatic stress disorder (PTSD) in male and female rats. Social-Single Prolonged Stress (SPS) protocol has been considered a potential PTSD model. This study aimed to pharmacologically validate the Social-SPS as a PTSD model in male and female rats. Male and female Wistar rats (60-day-old) were exposed to Social-SPS protocol and treated with fluoxetine (10 mg/Kg) or saline solution intraperitoneally 24 h before euthanasia. Two cohorts of animals were used; for cohort 1, male and female rats were still undisturbed until day 7 post-Social-SPS exposure, underwent locomotor and conditioned fear behaviors, and were euthanized on day 9. Animals of cohort 2 were subjected to the same protocol but were re-exposed to contextual fear behavior on day 14. Results showed that fluoxetine-treated rats gained less body weight than control and Social-SPS in both sexes. Social-SPS effectively increased the freezing time in male and female rats on day eight but not on day fourteen. Fluoxetine blocked the increase of freezing in male and female rats on day 8. Different mechanisms for fear behavior were observed in males, such as Social-SPS increased levels of glucocorticoid receptors and Beclin-1 in the amygdala. Social-SPS was shown to increase the levels of NMDA2A, GluR-1, PSD-95, and CAMKII in the amygdala of female rats. No alterations were observed in the amygdala of rats on day fourteen. The study revealed that Social-SPS is a potential PTSD protocol applicable to both male and female rats.

Ecotoxicological effects of ketoprofen and fluoxetine and their mixture in an aquatic microcosm.

The effects of fluoxetine (antidepressant) and ketoprofen (analgesic) on aquatic ecosystems are largely unknown, particularly as a mixture. This work aimed at determining the effect of sublethal concentrations of both compounds individually (0.050 mg/L) and their mixture (0.025 mg/L each) on aquatic communities at a microcosm scale for a period of 14 d. Several physicochemical parameters were monitored to estimate functional alterations in the ecosystem, while model organisms (Daphnia magna, Lemna sp., Raphidocelis subcapitata) and the sequencing of 16S/18S rRNA genes permitted to determine effects on specific populations and changes in community composition, respectively. Disturbances were more clearly observed after 14 d, and overall, the microcosms containing fluoxetine (alone or in combination with ketoprofen) produced larger alterations on most physicochemical and biological variables, compared to the microcosm containing only ketoprofen, which suffered less severe changes. Differences in nitrogen species suggest alterations in the N-cycle due to the presence of fluoxetine; similarly, all pharmaceutical-containing systems decreased the brood rate of D. magna, while individual compounds inhibited the growth of Lemna sp. No clear trends were observed regarding R. subcapitata, as indirectly determined by chlorophyll quantification. The structure of micro-eukaryotic communities was altered in the fluoxetine-containing systems, whereas the structure of bacterial communities was affected to a greater extent by the mixture. The disruptions to the equilibrium of the microcosm demonstrate the ecological risk these compounds pose to aquatic ecosystems.

Psychoactive substance consumption after the Fundão dam mine tailing disaster in Minas Gerais State, Brazil.

Disasters cause changes in morbidity, mortality, and medicine use. Brazil is one of the main producers of mineral ores at great environmental cost. Mine tailings are stored in dams and ruptures have led to major disasters. We investigated the consumption of psychoactive medicines in the municipalities affected by the Fundão dam disaster in Minas Gerais State. An ecological study was carried out on drug consumption, estimated using public purchases in Minas Gerais and dispensing data from private retail pharmacies. Consumption (in number of defined daily doses/100,000 inhabitants per day) was analyzed descriptively in eight municipalities, stratified according to consumption level during a 25-month period. Six comparisons of mean consumption values for both data sets were done for pre- and post-disaster periods. The means of medicine consumption before and after the event were plotted and linear trends were added. Public purchase data evinced high consumption levels. Only pharmaceutical retail showed significant differences between the strata in the pre-disaster versus two post-disaster periods. Smaller municipalities showed an increase in consumption 15 months after the disaster. Clonazepam led the way in pharmaceutical retail consumption, followed by fluoxetine. Medicines showed an upward trend after the disaster. The high public provision may have stifled significant consumption patterns of psychoactive drugs; however, peak consumption were observed in private retail, suggesting a modification in use patterns after the disaster. The decrease in consumption immediately after the event was probably related to lower care-seeking behavior on the part of the population, and significant peaks after the disaster may reflect economic consequences of it.

Involvement of the GABAA Receptor in the Antidepressant-Like Effects Produced by Low and High Doses of the Flavonoid Chrysin in the Rat: A Longitudinal Study.

BACKGROUND: The flavonoid chrysin produces rapid and long-lasting anxiolytic- and antidepressant-like effects in rats. However, it is not known whether low and high doses of chrysin produce differential anti-immobility effects through the Gamma-Aminobutyric Acid sub-type A (GABAA) receptor. The goal of this work was therefore to compare low and high doses of chrysin for their effects on depression-like behavior in a longitudinal study. Moreover, chrysin was compared with the serotonergic fluoxetine and Gamma-Aminobutyric Acid (GABA)ergic allopregnanolone, and its involvement with the GABAA receptor after chronic treatment was also investigated. METHODS: Male Wistar rats were assigned to five groups (n = 8 each): vehicle, 1 mg/kg chrysin, 5 mg/kg chrysin, 1 mg/kg fluoxetine, and 1 mg/kg allopregnanolone. In the first experiment, treatments were injected daily and the effects on locomotor activity and the forced swim test were evaluated at 0, 1, 14, and 28 days of treatment, and 48 h after the final treatment. In the second experiment, similar groups were treated for 28 days with injection of 1 mg/kg picrotoxin to investigate the role of the GABAA receptor. Depending on the experimental design, one- and two-way analysis of variance (ANOVA) tests were used for statistical analysis, with p < 0.05 set as the criteria for significance. RESULTS: In both experiments, the treatments did not alter locomotor activity. However, low and high doses of chrysin, allopregnanolone, and fluoxetine gradually produced antidepressant-like effects in the forced swim test, and maintained this effect for 48 h post-treatment, except with low dose chrysin. Picrotoxin blocked the antidepressant-like effects produced by low dose chrysin, but did not affect those produced by high dose chrysin, allopregnanolone, or fluoxetine. CONCLUSIONS: The differential antidepressant-like effects caused by low and high doses of chrysin are time-dependent. Low dose chrysin produces a rapid antidepressant-like effect, whereas high dose chrysin produces a delayed but sustained the effect, even 48 h after withdrawal. The effect with high dose chrysin was similar to that observed with allopregnanolone and fluoxetine. The mechanism for the antidepressant-like effect of low chrysin appears to be GABAergic, whereas the effect of high dose chrysin may involve other neurotransmission and neuromodulation systems related to the serotonergic system.

The involvement of neuroinflammation in an animal model of dementia and depression.

Alzheimer's disease (AD) and depression are inflammatory pathologies, leading to increased inflammatory response and neurotoxicity. Therefore, this study aimed to evaluate the effect of the treatment with fluoxetine and/or galantamine and/or donepezil on the levels of proinflammatory and anti-inflammatory cytokines in a mixed animal model of depression and dementia. Adult male Wistar rats underwent chronic mild stress (CMS) protocol for 40 days and were subjected to stereotaxic surgery for intra-hippocampal administration of amyloid-beta (Aꞵ) peptide or artificial cerebrospinal fluid (ACSF) to mimic the dementia animal model. On the 42nd day, animals were treated with water, galantamine, donepezil, and/or fluoxetine, orally for 17 days. On the 57th and 58th days, the Splash and Y-maze tests for behavior analysis were performed. The frontal cortex and hippocampus were used to analyze the tumor necrosis factor alfa (TNF-α), interleukin 1 beta (IL-1ꞵ), IL-6, and IL-10 levels. The results of this study show that animals subjected to CMS and administration of Aꞵ had anhedonia, cognitive impairment, increased TNF-α and IL-1ꞵ levels in the frontal cortex, and reduced IL-10 levels in the hippocampus. All treatment groups were able to reverse the cognitive impairment. Only donepezil did not decrease the TNF-α levels in the hippocampus. Fluoxetine + galantamine and fluoxetine + donepezil reversed the anhedonia. Fluoxetine reversed the anhedonia and IL-1ꞵ levels in the frontal cortex. In addition, fluoxetine + donepezil reversed the reduction of IL-10 levels in the hippocampus. The results indicate a pathophysiological interaction between AD and depression, and the association of medications in the future may be a possible therapeutic strategy to reduce inflammation, especially the fluoxetine-associated treatments.

In vitro effects of selective serotonin reuptake inhibitors on Cryptococcus gattii capsule and biofilm.

Infections caused by Cryptococcus gattii mainly affect immunocompetent individuals and the treatment presents important limitations. This study aimed to validate the efficacy of selective serotonin reuptake inhibitors (SSRI), fluoxetine hydrochloride (FLH), and paroxetine hydrochloride (PAH) in vitro against C. gattii. The antifungal activity of SSRI using the microdilution method revealed a minimal inhibitory concentration (MIC) of 31.25 µg/ml. The combination of FLH or PAH with amphotericin B (AmB) was analyzed using the checkerboard assay and the synergistic effect of SSRI in combination with AmB was able to reduce the SSRI or AmB MIC values 4-8-fold. When examining the effect of SSRI on the induced capsules, we observed that FLH and PAH significantly decreased the size of C. gattii capsules. In addition, the effects of FLH and PAH were evaluated in biofilm biomass and viability. The SSRI were able to reduce biofilm biomass and biofilm viability. In conclusion, our results indicate the use of FLH and PAH exhibited in vitro anticryptococcal activity, representing a possible future alternative for the cryptococcosis treatment.

Hollow-fiber liquid phase microextraction for determination of fluoxetine in human serum by nano-liquid chromatography coupled to high resolution mass spectrometry.

Therapeutic drug monitoring (TDM) is a personalized care tool based on the determination of a target drug concentration in human serum. An antidepressant drug of interest for such investigations is fluoxetine (FXT), due to a severe impact of genetic polymorphisms on its metabolism. A bioanalytical method employed for TDM purposes must exhibit satisfactory selectivity and detectability, which becomes more difficult due to highly complex biological matrices. In this study, a highly selective bioanalytical method for the determination of FXT in human serum is proposed, which provides excellent clean-up efficiency based on a low cost hollow fiber liquid-phase microextraction (HF-LPME) sample preparation step and nano-liquid chromatography coupled to high-resolution mass spectrometry (nano-LC-HRMS). HF-LPME was performed using a two-phase "U" configuration, with 6 cm fiber, 20 µL of 1-octanol acting as supported liquid membrane, and ammonium hydroxide (pH 10) as the donor phase with NaCl (10 % m/v) and methanol (5 % v/v) as additives, requiring only 250 µL of the sample. The procedure was conducted for 30 min under a 750 rpm stirring rate. Gradient elution was carried out employing an acetonitrile-water as mobile phase, the composition of 30:70 to 100:00 (v/v) for 15 min, using formic acid 0.1 % (v/v) as an additive. MS1 was acquired in an Orbitrap mass analyzer, while MS2 was acquired in a linear trap quadrupole. Satisfactory linearity (Pearson's r = 0.99709) was obtained for a concentration range of 0.02 to 2.5 µg mL-1, which is compatible with the therapeutic and toxic range for FXT. The developed method presents adequate precision (1.61 to 7.45 %) and accuracy (95 to 114 %) and allows the dilution of high concentration samples in a 1:4 ratio (v/v), enabling its application for forensic serum samples. To our knowledge, this is the first study reporting a method based on HF-LPME and nano-LC-HRMS with any analytical purpose, especially with a TDM focus.

Arjunolic acid reverses fluoxetine-induced alterations in testicular steroidogenic enzymes and membrane bound ionic pump imbalance through suppression of oxido-inflammatory stress and apoptosis.

OBJECTIVE: The impact of the anti-depressant therapy on gonadal function has been recognized and discussed over the years. However, data to supplement our understanding of the impact of arjunolic acid (AA) therapies in protecting against FXT-induced gonadal dysfunction is lacking clear scientific evidence. Hence, this study aimed to investigate the possible effect of AA on fluoxetine-induced altered testicular function in rats. METHODS: After 14 days acclimatization, Thirty-six (36) adult male rats were randomly divided into 6 groups (n=6). Rats in groups 1 received normal saline (10mL/kg); groups 2 & 3 were given AA (1.0mg/kg body weight) and AA (2.0mg/kg body weight), respectively; whereas, rats in group 4 were given FXT (10mg/kg/p.o/day), and groups 5 & 6 were given a combination of FXT (10mg/kg) + AA (1.0mg/kg body weight); and FXT (10mg/kg) + AA (2.0mg/kg body weight), respectively. RESULTS: The results shows that FXT significantly altered testicular steroidogenic enzymes (3ß-HSD and 17ß-HSD) and proton pump ATPase (Na+/K+ ATPase, Ca2+ ATPase and H+ ATPase) activities, as well as testicular architecture when compared with controls. More so, FXT caused oxido-inflammation and apoptosis, as evidence by increases in MDA, MPO, TNF-α, IL-1ß, Caspase 3 and p53. However, AA at a different dose significantly ameliorated the destructive impacts of FXT on steroidogenic enzymes, proton pump ATPase as well as increased Bcl-2, SOD, CAT, GSH and improved testicular architecture in rats. CONCLUSIONS: AA reverses fluoxetine-induced alterations in testicular steroidogenic enzymes and membrane-bound ionic pump through suppression of oxido-inflammatory stress and apoptosis.

A comparative analysis of depressive-like behavior: Exploring sex-related differences and insights.

Profiling the variability related to the estrous cycle is essential for assessing depressive-like behavior and screening drugs. This study compares circulating plasma corticosterone levels [CORT] and behavioral alterations in mice exposed to sucrose preference, forced swimming, and tail suspension tests (SPT, FST, and TST, respectively). While SPT exposure did not significantly alter [CORT], FST and TST showed notable changes. Mice in the TST exhibited increased movement and decreased immobility time compared to FST, suggesting a lower likelihood of depressive-like behavior in male mice. Notably, during the proestrus phase, female mice displayed the highest tendency for depressive-like behavior and elevated [CORT], but similar response to antidepressants (imipramine and fluoxetine). The inherent stress of the FST and TST tasks appears to influence [CORT] as well as depressant and antidepressant effects. These comparisons provide valuable insights for further behavioral phenotyping, model sensitivity assessment, and deepen our neurobiological understanding of depression in the context of drug screening.

ANTIDEPRESSANT MEDICATIONS ARE ASSOCIATED WITH INCREASED RISK OF HOSPITAL-ACQUIRED CLOSTRIDIOIDES DIFFICILE INFECTION: A POPULATION-BASED STUDY.

WHAT IS ALREADY KNOWN: •The rate and severity of Clostridioides difficile infection (CDI) has increased throughout North America, the United Kingdom, and Europe. •Scattered evidence about the association of CDI with antidepressant medications use exists in the literature so far. What are the new findings: •The risk of Clostridioides difficile infection is higher in patients who are on mirtazapine, nortriptyline, or trazodone. •The prevalence rate of Clostridioides difficile infection in patients who were using antidepressant medications and the ones who did not, increased with age. Background - During the past decade, Clostridioides difficile infection (CDI) has become the most common cause of antibiotic-associated diarrhea. Several risk factors have been implicated. Scattered evidence about the association of CDI with antidepressant medications use exists in the literature so far. Therefore, we aim to investigate whether the risk of developing CDI is increased in hospitalized patients using antidepressant medications.Methods - Patients who were hospitalized were included in our cohort. We excluded individuals aged less than 18 years. A multivariate regression analysis was performed to calculate the risk of CDI accounting for potential confounders. Results - The risk of CDI in hospitalized patients was increased in individuals diagnosed with inflammatory bowel disease (OR: 4.44; 95%CI: 4.35-4.52), and in patients using clindamycin (OR: 1.55; 95%CI: 1.53-1.57), beta-lactam antibiotics (OR: 1.62; 95%CI: 1.60-1.64), PPI (OR: 3.27; 95%CI: 3.23-3.30), trazodone (OR: 1.31; 95%CI: 1.29-1.33), nortriptyline (OR: 1.25; 95%CI: 1.21-1.28), and mirtazapine (OR: 2.50; 95%CI: 2.46-2.54). After controlling for covariates, the risk of CDI was not increased in patients who were taking fluoxetine (OR: 0.94; 95%CI: 0.92-0.96). Conclusion - In contrary to fluoxetine; mirtazapine, nortriptyline, and trazodone were associated with increased risk of CDI in hospitalized patients.

Acute exposure to fluoxetine leads to oxidative stress and hematological disorder in Danio rerio adults.

Fluoxetine (FLX), a selective serotonin reuptake inhibitor (SSRI), is consistently introduced into the environment due to its ongoing consumption and inadequate removal by wastewater treatment plants. As a result, the scientific community has displayed a keen interest in investigating the potential toxicological effects associated with this medication. Nevertheless, there is a scarcity of available data regarding the impact of FLX on blood parameters. With this in mind, this study aimed to evaluate the potential toxicological consequences of FLX at environmentally significant concentrations (5, 16, and 40 ng/L) following a 96-hour acute exposure blood parameters in Danio rerio fish. Moreover, the investigation encompassed an assessment of oxidative stress parameters to determine whether the drug could induce disruptions in the REDOX status of the fish. The findings unveiled that FLX prompted the induction of oxidative stress in various organs of the fish, encompassing the liver, gut, brain, and gills. Notably, the gills and brain exhibited heightened susceptibility to the drug's effects compared to other organs. Furthermore, following acute exposure to FLX, there was an upregulation of antioxidant-related genes (sod, cat, gpx, nrf1, and nrf2), thereby providing additional evidence supporting the induction of oxidative stress in the organs of the fish. Lastly, FLX significantly impacted the customary values of various blood parameters, including glucose, blood urea nitrogen, alanine aminotransferase, alkaline phosphatase, red blood cell count, hemoglobin, and hematocrit. Thus, it can be inferred that FLX harmed the overall health status of the fish, resulting in the development of liver disease, anemia, and other associated illnesses.

Determination of Fluoxetine in Weight Loss Herbal Medicine Using an Electrochemical Sensor Based on rGO-CuNPs.

The rising popularity of herbal medicine as a weight loss remedy, fueled by misleading propaganda, raises concerns about the manufacturing processes and potential inclusion of controlled substances such as fluoxetine (FLU). The objective of this work is to develop and evaluate the performance of an electrochemical device by modifying a glassy carbon electrode (GC) with a nanocomposite based on reduced graphene oxide (rGO) and copper nanoparticles (CuNPs) for detecting FLU in manipulated herbal medicines. Scanning electron microscopy (FEG-SEM) and cyclic voltammetry (CV) were applied for morphological and electrochemical characterization and analysis of the composite's electrochemical behavior. Under optimized conditions, the proposed sensor successfully detected FLU within the range of 0.6 to 1.6 µmol L-1, showing a limit of detection (LOD) of 0.14 µmol L-1. To determine the presence of FLU in herbal samples, known amounts of the analytical standard were added to the sample, and the analyses were performed using the standard addition method, yielding recoveries between -2.13 and 2.0%.

Antifungal activity of selective serotonin reuptake inhibitors against Cryptococcus spp. and their possible mechanism of action.

Fungal infections caused by Cryptococcus spp. pose a threat to health, especially in immunocompromised individuals. The available arsenal of drugs against cryptococcosis is limited, due to their toxicity and/or lack of accessibility in low-income countries, requiring more therapeutic alternatives. Selective serotonin reuptake inhibitors (SSRIs), through drug repositioning, are a promising alternative to broaden the range of new antifungals against Cryptococcus spp. This study evaluates the antifungal activity of three SSRIs, sertraline, paroxetine, and fluoxetine, against Cryptococcus spp. strains, as well as assesses their possible mechanism of action. Seven strains of Cryptococcus spp. were used. Sensitivity to SSRIs, fluconazole, and itraconazole was evaluated using the broth microdilution assay. The interactions resulting from combinations of SSRIs and azoles were investigated using the checkerboard assay. The possible action mechanism of SSRIs against Cryptococcus spp. was evaluated through flow cytometry assays. The SSRIs exhibited in vitro antifungal activity against Cryptococcus spp. strains, with minimum inhibitory concentrations ranging from 2 to 32 µg/mL, and had synergistic and additive interactions with azoles. The mechanism of action of SSRIs against Cryptococcus spp. involved damage to the mitochondrial membrane and increasing the production of reactive oxygen species, resulting in loss of cellular viability and apoptotic cell death. Fluoxetine also was able to cause significant damage to yeast DNA. These findings demonstrate the in vitro antifungal potential of SSRIs against Cryptococcus spp. strains.

Low doses of fluoxetine for the treatment of emotional premenstrual syndrome: a randomized double-blind, placebo-controlled, pilot study.

INTRODUCTION: The neuroactive metabolite of progesterone, allopregnanolone (ALLO), has been implicated in premenstrual syndrome (PMS) physiopathology and preclinical studies suggested that low doses of fluoxetine increase the ALLO brain concentration. OBJECTIVES: To assess which low dose of fluoxetine (2 mg/d, 5 mg/d or 10 mg/d), administered exclusively during the luteal phase of menstrual cycle, has a potential effect for preventing or mitigating emotional PMS symptoms. METHODS: In this randomized, double-blind, placebo-controlled pilot study, we followed 40 women (mean age = 29.7 +/- 7.4 years) with emotional PMS, during two menstrual cycles: cycle 1, without pharmacological intervention; and cycle 2, with pharmacological intervention. Participants took capsules, on average, seven days preceding the likely date of menses. We assessed the severity of PMS symptoms in both cycles using the Daily Record of Severity of Problems scale (DRSP). RESULTS: There was an increase in the DRSP scores during the late luteal phase of cycle 1, confirming the diagnosis of emotional PMS. Low doses of fluoxetine (5 mg/d: 33.5%; 10 mg/d: 48.4%) reduced DRSP total score in the day before menses (day-1) at cycle 2 compared with day-1 at cycle 1. Fluoxetine 10 mg/d had the most consistent decline in emotional PMS symptoms; 70% of the participants reported a reduction greater than 40% in the DRSP score. CONCLUSIONS: Low doses of fluoxetine, which may have no or few effect on the serotonergic system, but may interfere in the progesterone metabolization, seem to have some potential to mitigate emotional PMS symptoms. While the 10 mg/d of fluoxetine had the best performance on reducing emotional PMS symptoms, the 5 mg/d dose also seems to have some effect on emotional PMS symptoms. Further larger studies will help establish the lowest effective dose of flouxetine for PMS treatment.

Environmental enrichment affects behavioral and pharmacological response to antidepressants in CF1 mice.

It has been described that environmental enrichment (EE) exerts beneficial effects on cognitive and emotional performances, dendritic branching, synaptic density, neurogenesis and modulation of neurotrophic systems and neurotransmitters in rodents. However, the influence of EE on pharmacological and behavioral responses in animal models of psychiatric disorders has not been fully established. In this context, the aim of this study was to evaluate the influence of exposure to EE on mice behavior in the open field test (OFT) and forced swimming tests (FST), as well as the response to antidepressant drugs (fluoxetine 30 mg/kg and bupropion 30 mg/kg, p.o.). CF1 mice were exposed to an enriched housing condition at different developmental stages: from mating to postnatal day (PND) 55 (lifelong enrichment), from mating to PND21 (perinatal enrichment) and from PND21 to PND55 (post-weaning enrichment). At PND58 the male offspring were evaluated in the OFT and FST. BDNF gene expression in the hippocampus was determined through qPCR. Mice exposed to perinatal enrichment remained longer in the peripheral zone of the OFT and performed fewer grooming than mice housed under standard condition, and these effects were independent of drug treatment. Post-weaning and lifelong enrichment increased grooming behavior. Bupropion reduced grooming in all groups except in perinatal enriched. In turn, fluoxetine decreased grooming only in post-weaning enriched group. None of the enriched housing conditions altered the immobility time in the FST, which indicates that EE had no antidepressant-like effect. However, all enriched housing conditions abolished the anti-immobility effect of bupropion. None of the EE protocols affected BDNF hippocampal expression. The main conclusion is that mice behavior in the OFT is sensitive to alterations in the housing environment and depends on the developmental stage of exposure. Bupropion and fluoxetine yielded divergent responses depending on the housing condition, which suggests that EE modulates monoaminergic neurotransmission pathways.

Effect of fluoxetine on planktonic and biofilm growth and the antimicrobial susceptibility of Burkholderia pseudomallei.

Aim: This study evaluated the effect of fluoxetine (FLU) on planktonic and biofilm growth and the antimicrobial susceptibility of Burkholderia pseudomallei. Materials & methods: The minimum inhibitory concentrations (MICs) for FLU were determined by broth microdilution. Its effect on growing and mature biofilms and its interaction with antibacterial drugs were evaluated by assessing biofilm metabolic activity, biomass and structure through confocal microscopy. Results: The FLU MIC range was 19.53-312.5 µg/ml. FLU eradicated growing and mature biofilms of B. pseudomallei at 19.53-312.5 µg/ml and 1250-2500 µg/ml, respectively, with no structural alterations and enhanced the antibiofilm activity of antimicrobial drugs. Conclusion: These results bring perspectives for the use of FLU in the treatment of melioidosis, requiring further studies to evaluate its applicability.

Guanosine treatment prevents lipopolysaccharide-induced depressive-like behavior in mice.

Guanosine is a purinergic nucleoside that has been shown to have neuroprotective effects, mainly through its ability to modulate the glutamatergic system. An increase in pro-inflammatory cytokine levels triggers the activation of the enzyme indoleamine 2,3-dioxygenase 1 (IDO-1), leading to glutamatergic excitotoxicity, which has important roles in the pathophysiology of depression. The aim of this study was to investigate the possible antidepressant-like effects and underlying mechanisms of action of guanosine against lipopolysaccharide (LPS)-induced depression in a mouse model. Mice were orally pre-treated with saline (0.9% NaCl), guanosine (8 or 16 mg/kg), or fluoxetine (30 mg/kg) for 7 days before LPS (0.5 mg/kg, intraperitoneal) injection. One day after LPS injection, mice were subjected to the forced swim test (FST), tail suspension test (TST), and open field test (OFT). After the behavioral tests, mice were euthanized and the levels of tumor necrosis factor-α (TNF-α), IDO-1, glutathione, and malondialdehyde in the hippocampus were measured. Pretreatment with guanosine was able to prevent LPS- induced depressive-like behaviors in the TST and FST. In the OFT, no locomotor changes were observed with any treatment. Both guanosine (8 and 16 mg/kg/day) and fluoxetine treatment prevented the LPS-induced increase in TNF-α and IDO expression and lipid peroxidation as well as decrease of reduced glutathione levels in the hippocampus. Taken together, our findings suggest that guanosine may have neuroprotective effects against LPS-induced depressive-like behavior through preventing oxidative stress and the expression of IDO-1 and TNF-α in the hippocampus.