Adapting the in vitro micronucleus assay (OECD Test Guideline No. 487) for testing of manufactured nanomaterials: recommendations for best practices.

The current Organisation for Economic Co-Operation and Development test guideline number 487 (OECD TG No. 487) provides instruction on how to conduct the in vitro micronucleus assay. This assay is one of the gold standard approaches for measuring the mutagenicity of test items; however, it is directed at testing low molecular weight molecules and may not be appropriate for particulate materials (e.g. engineered nanoparticles [ENPs]). This study aimed to adapt the in vitro micronucleus assay for ENP testing and underpins the development of an OECD guidance document. A harmonized, nano-specific protocol was generated and evaluated by two independent laboratories. Cell lines utilized were human lymphoblastoid (TK6) cells, human liver hepatocytes (HepG2) cells, Chinese hamster lung fibroblast (V79) cells, whole blood, and buffy coat cells from healthy human volunteers. These cells were exposed to reference ENPs from the Joint Research Council (JRC): SiO2 (RLS-0102), Au5nm and Au30nm (RLS-03, RLS-010), CeO2 (NM212), and BaSO4 (NM220). Tungsten carbide-cobalt (WC/Co) was used as a trial particulate positive control. The chemical controls were positive in all cell cultures, but WC/Co was only positive in TK6 and buffy coat cells. In TK6 cells, mutagenicity was observed for SiO2- and both Au types. In HepG2 cells, Au5nm and SiO2 showed sub-two-fold increases in micronuclei. In V79 cells, whole blood, and buffy coat cells, no genotoxicity was detected with the test materials. The data confirmed that ENPs could be tested with the harmonized protocol, additionally, concordant data were observed across the two laboratories with V79 cells. WC/Co may be a suitable particulate positive control in the in vitro micronucleus assay when using TK6 and buffy coat cells. Detailed recommendations are therefore provided to adapt OECD TG No. 487 for testing ENP.

Bioactivity of selenium-containing pyridinium salts: Prospecting future pharmaceutical constituents to treat liver diseases involving oxidative stress.

Redox imbalance leads to oxidative stress that causes irreversible cellular damage. The incorporation of the antioxidant element selenium (Se) in the structure of pyridinium salts has been used as a strategy in chemical synthesis and can be useful in drug development. We investigated the antioxidant activity of Se-containing pyridinium salts (named Compounds 3A, 3B, and 3C) through in vitro tests. We focused our study on liver protein carbonylation, liver lipoperoxidation, free radical scavenging activity (1,1-diphenyl-2-picryl-hydrazil [DPPH]; 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid [ABTS]), and enzyme-mimetic activity assays (glutathione S-transferase [GST]-like; superoxide dismutase [SOD]-like). In addition, 2-(4-chlorophenyl)-2-oxoethyl)-2-((phenylselanyl)methyl)pyridin-1-ium bromide (3C) was selected to evaluate the acute oral toxicity in mice due to the best antioxidant profile. The three compounds were effective in reducing the levels of protein carbonylation and lipoperoxidation in the liver in a µM concentration range. All compounds demonstrated scavenger activity of DPPH and ABTS radicals, and GST-like action. No significant effects were detected in the SOD-like assay. Experimental data also showed that the acute oral treatment of mice with Compound 3C (50 and 300 mg/kg) did not cause mortality or change markers of liver and kidney functions. In summary, our findings reveal the antioxidant potential of Se-containing pyridinium salts in liver tissue, which could be related to their radical scavenging ability and mimetic action on the GST enzyme. They also demonstrate a low toxicity potential for Compound 3C. Together, the promising results open space for future studies on the therapeutic application of these molecules.

Critical assessment of the endocrine potential of Linalool and Linalyl acetate: proactive testing strategy assessing estrogenic and androgenic activity of Lavender oil main components.

The acyclic linear monoterpenes Linalool (Lin) and Linalyl acetate (LinAc) occur in nature as major constituents of various essential oils such as lavender oils. A potential endocrine activity of these compounds was discussed in literature including premature thelarche and prepubertal gynecomastia due to lavender product use. This study aims to follow-up on these critical findings reported by testing Lin and LinAc in several studies in line with current guidance and regulatory framework. No relevant anti-/ER and AR-mediated activity was observed in recombinant yeast cell-based screening tests and guideline reporter gene in vitro assays in mammalian cells. Findings in the screening test suggested an anti-androgenic activity, which could not be confirmed in the respective mammalian cell guideline assay. Mechanistic guideline in vivo studies (Uterotrophic and Hershberger assays) with Lin did not show significant dose related changes in estrogen or androgen sensitive organ weights and a guideline reproductive toxicity screening study did not reveal evident effects on sex steroid hormone sensitive organ weights, associated histopathological findings and altered sperm parameters. Estrous cycling and mating/fertility indices were not affected and no evident Lin-related steroid hormone dependent effects were found in the offspring. Overall, the initial concerns from literature were not confirmed. Findings in the yeast screening test were aberrant from follow-up guideline in vitro and in vivo studies, which underlines the need to apply careful interpretation of single in vitro test results to support a respective line of evidence and to establish a biologically plausible link to an adverse outcome.

Recent Advances in the Synthesis and Antioxidant Activity of Low Molecular Mass Organoselenium Molecules.

Selenium is an essential trace element in living organisms, and is present in selenoenzymes with antioxidant activity, like glutathione peroxidase (GPx) and thioredoxin reductase (TrxR). The search for small selenium-containing molecules that mimic selenoenzymes is a strong field of research in organic and medicinal chemistry. In this review, we review the synthesis and bioassays of new and known organoselenium compounds with antioxidant activity, covering the last five years. A detailed description of the synthetic procedures and the performed in vitro and in vivo bioassays is presented, highlighting the most active compounds in each series.

The Determinants of Complementary Feeding Introduction Vary According to the Type of Food and Infants' Ages: A Cohort Study-ClaB, Brazil.

INTRODUCTION: Food inadequacies in the first 6 months of life are considered a global problem, with an emphasis on early complementary feeding introduction (CFI). This study aimed to identify the determinants of CFI. METHODS: A birth cohort study (N = 641). Data on infant feeding was collected before 30 days, and at 2, 4, and 6 months of age and, at baseline, data regarding socioeconomic status, demographics, maternal and infant health, obstetric history, and infant care. The hypothesis was that the risk determinants for early CFI vary according to the type of food and the age range of this introduction. Twelve Cox regression models were fit with four outcomes (formula; other types of milk; other beverages; and solid/semi-solid foods) considering three different age ranges of the infant at their introduction (< 2 months, 2-4 months, and 4-6 months). RESULTS: The introduction of the four food groups analyzed was early (median ages of introduction: formulas = 45 days; other milks = 135 days; other beverages = 120 days; solids and semi-solids = 135 days). The determinants that increased the risk of introducing formulas before 2 months were: primiparity, employed without maternity leave, mothers with unsatisfactory prenatal counseling and those who had cesarean sections. Not living with a partner, infant pacifier use at 2 months of age had a higher risk of introducing formula between 2 and 4 months of age. Non-white skin color, more than 35 years old, low maternal education, and lower family income increased the risk of introducing other types of milk between 2 and 4 months of age. Between 4 and 6 months of age, adolescent and low education level mothers had a higher risk of introducing other types of milk, unemployed was a protective factor against the introduction of other foods and beverages in this age group. CONCLUSIONS: The determinants of early CFI varied according to the type of food and the age of introduction.

Consumption of ultra-processed foods in the third gestational trimester and increased weight gain: a Brazilian cohort study.

OBJECTIVE: To investigate whether the consumption of ultra-processed foods (UPF) during pregnancy is associated with gestational weight gain (GWG). DESIGN: Cohort study with collection of two 24-h dietary recalls during each gestational trimester obtained on non-consecutive days and differentiating weekday v. weekend/holiday. The foods were classified according to the NOVA system into fresh or minimally processed foods and their culinary preparations, processed and UPF and subsequently analysed as a percentage contribution to dietary energy. The outcome was average GWG in the second and in the third trimesters, expressed in g/week. SETTING: Botucatu, a medium-sized Brazilian city. PARTICIPANTS: Pregnant women with regular obstetric risk (n 259) undergoing prenatal care in primary healthcare. RESULTS: In a multiple linear regression model, it was found that an increase of 1 percentage point in energy consumption from UPF in the third gestational trimester led to an average increase of 4·17 (95 % CI 0·55; 7·79) g in weekly GWG in this period. There was no association between second-trimester UPF consumption and GWG. CONCLUSIONS: Consumption of UPF in the third gestational trimester is positively associated with average weekly GWG in this period.

The association of dietary glycaemic index and glycaemic load with gestational weight gain and newborn birth weight.

Diet during pregnancy is related to several maternal and infant health outcomes; however, the relationship between maternal dietary glycaemic index (GI) and glycaemic load (GL) and gestational weight gain (GWG) or newborn birth weight is controversial. The purpose of the present study was to investigate the relationship between maternal dietary GI and GL and GWG and birth weight. A cohort of adult pregnant women with usual obstetric risk was followed in Botucatu, SP, Brazil. Two 24-h dietary recalls were collected in each gestational trimester (<14, 24-27, 31-34 weeks), one in person and the other by telephone. GI and GL were determined using the software Nutrition Data System for Research. GWG was obtained from medical records and evaluated as the weekly GWG between the second and third gestational trimesters. Newborn birth weight z-score in relation to gestational age was evaluated according to Intergrowth-21st Project recommendations. A multiple linear regression model, adjusted for potential confounders, showed a one-point increase in the GI resulted in a mean decrease of 12·9 (95 % CI -21·48, -4·24) g in weekly GWG; GL was not associated with this outcome. The birth weight z-score was not associated with GI (P = 0·763) or GL (P = 0·317). In conclusion, in a cohort of pregnant women considered at usual risk for obstetric complications, maternal dietary GI was negatively associated with weekly GWG in the second and third gestational trimesters. No association was observed between GL and GWG, and neither GI nor GL was associated with birth weight z-score.

Regioselective Synthesis of 1-Sulfanyl- and 1-Selanylindolizines.

We describe herein a new approach to prepare unprecedented bioactive indolizine motifs decorated with organosulfur and organoselenium groups. A total of 12 1-sulfanylindolizines and 2 1-selanylindolizines were prepared in excellent yields by an intramolecular annulation of easily prepared chalcogen-containing pyridinium salts. The reaction is fast (1 h at 70 °C or 5 min under sonication) and transition-metal-free, using glycerol as a green solvent.

In vitro-to-in vivo extrapolation (IVIVE) by PBTK modeling for animal-free risk assessment approaches of potential endocrine-disrupting compounds.

While in vitro testing is used to identify hazards of chemicals, nominal in vitro assay concentrations may misrepresent potential in vivo effects and do not provide dose-response data which can be used for a risk assessment. We used reverse dosimetry to compare in vitro effect concentrations-to-in vivo doses causing toxic effects related to endocrine disruption. Ten compounds (acetaminophen, bisphenol A, caffeine, 17α-ethinylestradiol, fenarimol, flutamide, genistein, ketoconazole, methyltestosterone, and trenbolone) have been tested in the yeast estrogen screening (YES) or yeast androgen-screening (YAS) assays for estrogen and androgen receptor binding, as well as the H295R assay (OECD test guideline no. 456) for potential interaction with steroidogenesis. With the assumption of comparable concentration-response ratios of these effects in the applied in vitro systems and the in vivo environment, the lowest observed effect concentrations from these assays were extrapolated to oral doses (LOELs) by reverse dosimetry. For extrapolation, an eight-compartment Physiologically Based Toxicokinetic (PBTK) rat model based on in vitro and in silico input data was used. The predicted LOEL was then compared to the LOEL actually observed in corresponding in vivo studies (YES/YAS assay versus uterotrophic or Hershberger assay and steroidogenesis assay versus pubertal assay or generation studies). This evaluation resulted in 6 out of 10 compounds for which the predicted LOELs were in the same order of magnitude as the actual in vivo LOELs. For four compounds, the predicted LOELs differed by more than tenfold from the actual in vivo LOELs. In conclusion, these data demonstrate the applicability of reverse dosimetry using a simple PBTK model to serve in vitro-in silico-based risk assessment, but also identified cases and test substance were the applied methods are insufficient.

Ultra-processed Food Consumption by Pregnant Women: The Effect of an Educational Intervention with Health Professionals.

Objectives Nutrition during pregnancy is related with many maternal and child outcomes. To investigate the consumption of ultra-processed foods is one of the newest methods to evaluate food consumption, but these studies in pregnant women are rare. Methods We conducted a non-randomized controlled educational intervention on healthy eating and physical activity during pregnancy in primary health care units of Botucatu, São Paulo, Brazil. The sample comprised two groups of pregnant women with low obstetric risk, an intervention group (n = 181) and a control group (n = 172). The health professionals that assisted the pregnant women from the intervention group were trained to promote five healthy food practices during the prenatal care appointments: consumption of three fruits; two portions of vegetables; two portions of beans, at least 5 days per week; and restriction of soft drinks and industrially processed cookies. All pregnant women answered two 24-h dietary recalls per trimester, one face-to-face, another by telephone. The foods consumed by pregnant women were classified according Nova. The impact of the intervention on the ultra-processed food consumption was evaluated by multilevel linear regression analysis. Results A quarter of the energy consumed by the pregnant women provided from ultra-processed foods. The intervention reduced these percentage of energy between the first and second trimester of pregnancy by 4.6 points (p = 0.015). This effect was not observed in the third trimester of pregnancy. Conclusions for Practice Training health care professionals to promote healthy food practices is a viable and sustainable alternative to reduce ultra-processed foods during pregnancy.

Glass Microbeads in Analog Models of Thrust Wedges.

Glass microbeads are frequently used in analog physical modeling to simulate weak detachment zones but have been neglected in models of thrust wedges. Microbeads differ from quartz sand in grain shape and in low angle of internal friction. In this study, we compared the structural characteristics of microbeads and sand wedges. To obtain a better picture of their mechanical behavior, we determined the physical and frictional properties of microbeads using polarizing and scanning electron microscopy and ring-shear tests, respectively. We built shortening experiments with different basal frictions and measured the thickness, slope and length of the wedges and also the fault spacings. All the microbeads experiments revealed wedge geometries that were consistent with previous studies that have been performed with sand. However, the deformation features in the microbeads shortened over low to intermediate basal frictions were slightly different. Microbeads produced different fault geometries than sand as well as a different grain flow. In addition, they produced slip on minor faults, which was associated with distributed deformation and gave the microbeads wedges the appearance of disharmonic folds. We concluded that the glass microbeads may be used to simulate relatively competent rocks, like carbonates, which may be characterized by small-scale deformation features.

Analog Models of Flanking Structures and a Natural Example in the Quadrilátero Ferrífero, Minas Gerais.

The aim of this study is to present analog models of flanking structures and to analyze the Fábrica Nova synform, Quadrilátero Ferrífero, Minas Gerais, from a geometric point of view. We set up seven models using a linear viscous silicone and produced flanking structures with a shear velocity of 2 cm h-1. At different initial orientations with respect to the shear zone boundary, a rigid cross-cutting element with lubricated boundaries was deformed via sinistral bulk flow at a shear strain of γ = 1.28. The most interesting features of our experiments are the geometries of the different marker lines, which are heterogeneous and resulted from thickening and thinning of the silicone at the cross-cutting element terminations. To compare our analog models and the Fábrica Nova synform, we analyzed the outermost marker line of the analog models and the top surface of the Cauê Formation in the Paleoproterozoic metasediments. The best comparisons between the experiments and the natural example were obtained by our CIS90 model in terms of the flexure shape near the cross-cutting element and the cross-cutting element orientation. Thus, we suggest that the cross-cutting elements in both situations act as obstacles and consequently produce local perturbations in laminar flow.

Testing the influence of a sand mica mixture on basin fill in extension and inversion experiments.

We compare the deformation patterns produced by sand and a sand mica mixture (14:1 ratio of sand to mica by weight) while simulating basin fill in extension and inversion models to analyze the potential of the sand mica mixture for applications that require a strong elasto-frictional plastic analogue material in physical models. Sand and the sand mica mixture have nearly equal angles of internal friction, but the sand mica mixture deforms at a significantly lower level of peak shear stress. In extension, the sand mica mixture basin fill experiments show fewer normal faults. During inversion, the most striking difference between the sand and the sand mica mixture basin fill experiments is related to the internal deformation in fault-propagation folds, which increases with an increase in the basal friction. We conclude that our strongly elasto-frictional plastic sand mica mixture may be used to simulate folds in experiments that focus on mild inversion in the brittle crust.

Monensin poisoning outbreak in free-ranging and captive birds.

Monensin poisoning is uncommon and has been rarely reported in birds. This work aimed to described clinical-pathological aspects of an outbreak of monensin poisoning in captive and free-ranging birds. Thirty-seven of 600 captive birds fed a diet containing 893.19 mg/kg of monensin died within 10 days (mortality 6.17%). There was no ionophore antibiotics on the feed label supplied to captive birds, which established an error in feed production. Necropsies were performed on twelve animals: Muscovy duck (Cairina moschata) (2/12), greater rhea (Rhea americana) (2/12), black-necked swan (Cygnus melancoryphus) (2/12), garganey (Anas querquedula) (1/12), ostrich (Struthio camelus) (1/12), and common pigeon (Columbus livia) (4/12). These four common pigeons were free-ranging birds and died after eating the same contaminated feed. Birds were mainly found dead, however in animals which clinical signs were observed (Columba livia, Rhea americana, Cairina moschata, Anas querquedula, and Struthio camelus), they included incoordination, inability to stand, and intense prostration, that ranged from 24 to 72 h until death. Grossly, five birds had focally extensive pale firm areas in the myocardium and two had in the skeletal muscles, one being concomitant lesions. Histologically, muscle necrosis and degeneration were observed in striated musculature (skeletal and/or heart) in all birds analyzed. Monensin poisoning outbreaks can affect free-ranging birds that are fed on external feeders, as well as captive birds, due to an error in the feed formulation.

1-(Phenylselanyl)-2-(p-tolyl)indolizine: A selenoindolizine with potential antidepressant-like activity in mice mediated by the modulation of dopaminergic and noradrenergic systems.

1-(Phenylselanyl)-2-(p-tolyl)indolizine (MeSeI) is a selenoindolizine with an antidepressant-like effect in mice by regulation of the serotonergic system. This study investigated the involvement of dopaminergic and noradrenergic systems in the antidepressant-like action of MeSeI. For this purpose, Swiss male mice were pretreated with different antagonists, after 15 min, the MeSeI was administrated by intragastric (i.g.) via; after 30 min, the mouse behavior was assessed in the forced swimming test (FST). The action of MeSeI on the activity of monoamine oxidase (MAO) was determined. The pretreatment of mice with haloperidol (0.05 mg/kg, intraperitoneally, i.p.; non-selective dopamine receptor antagonist), sulpiride (50 mg/kg, i.p.; D2 receptor antagonist), yohimbine (1 mg/kg, i.p.; α2 receptor antagonist), and propranolol (2 mg/kg, i.p.; non-selective ß receptor antagonist), inhibited the anti-immobility action of MeSeI (50 mg/kg, i.g.) in the FST. This blocking effect was not observed when SCH23390 (0.01 mg/kg, i.p.; D1 receptor antagonist), and prazosin (1 mg/kg, i.p.; α1 receptor antagonist) were administered. The coadministration of subeffective doses of bupropion (3 mg/kg. i.g.; dopamine and noradrenaline reuptake inhibitor) and MeSeI (0.5 mg/kg. i.g.) reduced the immobility time in the FST. Furthermore, MeSeI inhibited MAO-A and B activities in vitro and ex vivo tests. These results suggest that MeSeI exerts its antidepressant-like effect via regulation of the D2, α2, and ß1 receptors and the inhibition of MAO-A and B activities. Molecular docking investigations corroborated these results. This study provides comprehensive insights into the antidepressant-like mechanism of MeSeI in mice, suggesting its potential as a novel antidepressant candidate.

Exploring the antioxidant potential of chalcogen-indolizines throughout in vitro assays.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are highly reactive molecules produced naturally by the body and by external factors. When these species are generated in excessive amounts, they can lead to oxidative stress, which in turn can cause cellular and tissue damage. This damage is known to contribute to the aging process and is associated with age-related conditions, including cardiovascular and neurodegenerative diseases. In recent years, there has been an increased interest in the development of compounds with antioxidant potential to assist in the treatment of disorders related to oxidative stress. In this way, compounds containing sulfur (S) and/or selenium (Se) have been considered promising due to the relevant role of these elements in the biosynthesis of antioxidant enzymes and essential proteins with physiological functions. In this context, studies involving heterocyclic nuclei have significantly increased, notably highlighting the indolizine nucleus, given that compounds containing this nucleus have been demonstrating considerable pharmacological properties. Thus, the objective of this research was to evaluate the in vitro antioxidant activity of eight S- and Se-derivatives containing indolizine nucleus and different substituents. The in vitro assays 1,1-diphenyl-2-picryl-hydrazil (DPPH) scavenger activity, ferric ion (Fe3+) reducing antioxidant power (FRAP), thiobarbituric acid reactive species (TBARS), and protein carbonylation (PC) were used to access the antioxidant profile of the compounds. Our findings demonstrated that all the compounds showed FRAP activity and reduced the levels of TBARS and PC in mouse brains homogenates. Some compounds were also capable of acting as DPPH scavengers. In conclusion, the present study demonstrated that eight novel organochalcogen compounds exhibit antioxidant activity.

Pulmonary acinar adenocarcinoma in a captive lioness (Panthera leo).

Neoplasms in wild felids are more frequently observed in captive animals, of which clinicopathological features of pulmonary tumors are not commonly described. This study aimed to describe the clinical and pathological aspects of a case of diffuse pulmonary acinar adenocarcinoma in a 23-year-old, captive lioness with clinical history of dyspnea, progressive weight loss and inappetence. At necropsy, the lungs were mildly pale, moderately firm, and the pleural surface was diffusely irregular with multifocal to coalescent, grey to white areas. No masses or superficial nodules were detected, but, on the cut surface, there were numerous, spherical, firm, white to yellow areas up to 0.5 cm in diameter affecting all pulmonary lobes. Histologically, in the lungs, there were extensive, non-delineated areas of neoplastic proliferation of columnar, ciliated epithelial cells arranged in irregular tubuloacinar structures. Immunohistochemical analysis revealed immunolabeling of neoplastic cells for pan-cytokeratin and thyroid transcription factor-1. Napsin-A exhibited only scarce and scattered immunolabeling in the neoplastic cells. The gross, histologic and immunohistochemical findings confirmed the final diagnosis of primary diffuse pulmonary adenocarcinoma.

Depression during pregnancy and gestational weight gain: A study of Brazilian pregnant women.

OBJECTIVES: The relationship between psychosocial factors/mental health/depressive symptoms and inadequate gestational weight (GW) change remains poorly understood. Thus, the aim of this study was to evaluate the association between depressive symptoms and inadequate GW change according to the criteria established by the Institute of Medicine in 2009. METHODS: This cross-sectional study was part of a prospective cohort, and conducted in Botucatu, São Paulo, Brazil. Pregnant women who received prenatal care at basic health care units in the city participated in the study (n = 297). The Edinburgh Postnatal Depression Scale was used to assess depressive symptoms during pregnancy, and the cutoff point used for the positive screening of depressive symptoms was ≥13. The association between depressive symptoms and two outcomes (insufficient and excessive weight change during second and third trimesters) was investigated using logistic regression models with adjustment for potential confounders. Crude and adjusted effect measures (odds ratios) and their relevant 95% confidence intervals were estimated. RESULTS: There was an association between a positive score for depression during pregnancy and insufficient GW gain. No association was observed between depressive symptoms and excessive GW gain. CONCLUSIONS: The presence of depressive symptoms significantly increased the chance of insufficient GW change. This finding enhances the need for screening for depression in prenatal care.

Involvement of the serotonergic system in the antidepressant-like effect of 1-(phenylselanyl)-2-(p-tolyl)indolizine in mice.

RATIONALE: Depression is a mental disorder that affects approximately 280 million people worldwide. In the search for new treatments for mood disorders, compounds containing selenium and indolizine derivatives show promising results. OBJECTIVES AND METHODS: To evaluate the antidepressant-like effect of 1-(phenylselanyl)-2-(p-tolyl)indolizine (MeSeI) (0.5-50 mg/kg, intragastric-i.g.) on the tail suspension test (TST) and the forced swim test (FST) in adult male Swiss mice and to elucidate the role of the serotonergic system in this effect through pharmacological and in silico approaches, as well to evaluate acute oral toxicity at a high dose (300 mg/kg). RESULTS: MeSeI administered 30 min before the FST and the TST reduced immobility time at doses from 1 mg/kg and at 50 mg/kg and increased the latency time for the first episode of immobility, demonstrating an antidepressant-like effect. In the open field test (OFT), MeSeI did not change the locomotor activity. The antidepressant-like effect of MeSeI (50 mg/kg, i.g.) was prevented by the pre-treatment with p-chlorophenylalanine (p-CPA), a selective tryptophan hydroxylase inhibitor (100 mg/kg, intraperitoneally-i.p. for 4 days), with ketanserin, a 5-HT2A/2C receptor antagonist (1 mg/kg, i.p.), and with GR113808, a 5-HT4 receptor antagonist (0.1 mg/kg, i.p.), but not with WAY100635, a selective 5-HT1A receptor antagonist (0.1 mg/kg, subcutaneous-s.c.) and ondansetron, a 5-HT3 receptor antagonist (1 mg/kg, i.p.). MeSeI showed a binding affinity with 5-HT2A, 5 -HT2C, and 5-HT4 receptors by molecular docking. MeSeI (300 mg/kg, i.g.) demonstrated low potential to cause acute toxicity in adult female Swiss mice. CONCLUSION: In summary, MeSeI exhibits an antidepressant-like effect mediated by the serotonergic system and could be considered for the development of new treatment strategies for depression.

Antidepressant-Like Effect of a Selenoindolizine in Mice: In Vivo and In Silico Evidence for the Involvement of the Serotonergic 5-HT2A/C Receptors.

The monoaminergic dysfunction plays a central role in major depressive disorder (MDD), a mental disturbance associated with constant feeling of sadness and lack of interest. The available treatments do not present a desirable efficacy and some of them provoke several adverse effects. In this context, organoselenium compounds and molecules containing the indolizine nucleus have demonstrated interesting pharmacological properties, including antidepressant-like effects. In this study, the antidepressant-like effect of 2-phenyl-1-(phenylselanyl)indolizine (SeI), a selenium-containing indolizine derivative, was investigated on the forced swimming test (FST) and on the tail suspension test (TST) in male Swiss mice. The involvement of the serotonergic system in this effect was also accessed. The selenium compound SeI (10-100 mg/kg, intragastrical (i.g.)) was administered 0.5 h before the behavioral tests, and it diminished the immobility on both FST and TST experiments, which is an indication of antidepressant-like effect. No changing in the locomotor motion was observed in the open-field test (OFT). The anti-immobility effect of SeI was not altered by the preadministration of the selective serotonergic receptor antagonists ondansetron (1 mg/kg, intraperitoneally (i.p.), antagonist of 5-HT3 receptor) and WAY100635 (0.1 mg/kg, subcutaneous route (s.c.), antagonist of 5-HT1A receptor). In contrast, the preadministration of ketanserin (1 mg/kg, i.p., antagonist of 5-HT2A/C receptor) blocked this effect, demonstrating that the antidepressant-like effect of SeI involves 5-HT2A/C. In addition, molecular docking studies showed a strong interaction between SeI and the receptors of 5-HT2A and 5-HT2C. The toxicological results demonstrated that SeI has low potential to cause adverse effects in mice. It was found that the antidepressant-like effect of SeI is related to modulation of the serotonergic system, and this selenium compound could be included in new treatment approaches for MDD.