Selenium supplementation during pregnancy and lactation promotes metabolic changes in Wistar rats' offspring.

Epidemiological and animal studies have demonstrated a strong association between selenium (Se) supplementation and metabolic disorders, we aimed to evaluate whether maternal Se supplementation was able to change metabolic parameters in rats' offspring. Moreover, as Se is a deiodinase (DIO) cofactor, we decided to investigate how thyroid hormones (THs) would be involved in such metabolic changes. Thereby, two groups (n = 6, ~250 g) of female Wistar rats underwent isotonic saline or sodium selenite (1 mg/kg, p.o.) treatments. Although there were no significant differences in body weight between groups, the Se treatment during pregnancy and lactation increased milk intake and the visceral white adipose tissue (WAT) in offspring. The rats whose mothers were treated with Se also presented an improvement in the glucose tolerance test and in the glucose-stimulated insulin secretion. Regarding the lipid metabolism, the Se group had a reduction of triglycerides in the liver and in WAT. These metabolic changes were accompanied by an increase in serum triiodothyronine (T3 ) and in DIO 2 expression in brown adipose tissue (BAT). We further demonstrate an increased expression of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) and nuclear respiratory factor-1 (NRF-1) mRNA in the liver. In adulthood offspring, Se supplementation programs thyroid function, glucose homeostasis, and feeding behaviour. Taken together, there is no indication that Se programming causes insulin resistance. Moreover, we conjecture that these metabolic responses are induced by increased thyroxine (T4 ) to T3 conversion by DIO2 in BAT and mediated by altered transcription factors expression associated with oxidative metabolism control in the liver.

Social stress-induced hypothyroidism is attenuated by antidepressant treatment in rats.

Although serotonergic system has been classically implicated in mood modulation, there has been relatively little study on the relationship between this system and thyroid hormones (TH) economy in stress models. When TH are studied, the effects of stress on thyroid function seems to be complex and depend on the kind and time of stress which counts for the elusiveness of mechanisms underlying changes in TH economy. Herein, we hypothesized that serum TH are affected in a time-dependent fashion after repeated social stressful stimuli and serotonergic system is implicated in these changes. Therefore, we aimed to investigate the possible alterations in thyroid hormone economy and type 1 (D1) and type 2 (D2) deiodinase activity in a model of social defeat stress. Thereafter, we tested the responsiveness of these changes to fluoxetine treatment. Both short (STS) and a long-term (LTS) stress were performed. Blood samples were drawn just before and 1 (STS) or 4 and 8 weeks (LTS) after the beginning of stress to assess serum T4, T3 and corticosterone. Deiodinases activity was assessed at the end of each protocol. Stress-induced behavior studied in open field arena and hypercorticosteronemia were mainly observed in LTS (week 4). Stress-induced behavior was associated to hypothyroidism which occurred before, since week 1 in stressed group. Serum TH was restored to control levels in week 8, when behavior changes were not observed anymore, and was mainly associated with high brown adipose tissue D2 activity since thyroid and liver D1 activity were low or normal in the STS and LTS respectively in stressed rats compared to control. Antidepressant study revealed that fluoxetine treatment (10mg/kg po during four weeks) fully reversed stress-induced behavior and normalized serum T4, but not T3 levels and hypercorticosteronemia in stressed group compared to control. The current work adds new concepts concerning TH metabolism changes induced by social stress and suggests that serotonergic system impairment may take part in the key events which ultimately lead to hypothyroxinemia and behavioral changes induced by chronic social defeat. This article is part of a Special Issue entitled 'Anxiety and Depression'.

Evaluation of antinociceptive and antiinflammatory effects of Croton pullei var. glabrior Lanj. (Euphorbiaceae) / Avaliação dos efeitos antinociceptivo e antiinflamatório de Croton pullei var. glabrior Lanj. (Euphorbiaceae)

Croton pullei var. glabrior Lanj. (Euphorbiaceae) é uma liana, amplamente distribuída na Floresta Amazônica. Na medicina popular, diversas plantas do gênero Croton têm sido utilizadas com fins terapêuticos em patologias que envolvem dor e inflamação, o que justifica este trabalho. O objetivo deste estudo foi investigar as atividades antinociceptiva e antiinflamatória do extrato metanólico das folhas de C. pullei (MECP). O MECP reduziu, de forma dose-dependente, o número de contorções abdominais (1,2 por cento) em camundongos, sugerindo uma atividade antinociceptiva da planta. Por outro lado, o MECP não alterou significativamente a reatividade ao estímulo térmico no teste da placa quente e a reatividade à estimulação química na primeira fase do teste da formalina, indicando um mecanismo não-opioidérgico. O MECP reduziu a nocicepção na segunda fase do teste da formalina, inibiu o edema de orelha induzido pelo óleo de croton e reduziu a migração leucocitária no teste da peritonite induzida por carragenina, indicando uma atividade antiinflamatória. Apesar dos mecanismos responsáveis pelos efeitos da planta ainda não estarem completamente esclarecidos, estes resultados parecem justificar o uso medicinal potencial de Croton pullei var. glabrior Lanj. em patologias que envolvam dor e inflamação.

Croton pullei var. glabrior Lanj. (Euphorbiaceae) is a liana, vastly distributed in the Amazonian Forest. In the folk medicine, several plants of the Croton genus have been used with therapeutic purposes in pathologies that involve painful and inflammatory diseases which justify this work. The aim of this study was to investigate the antinociceptive and antiinflammatory activities of the C. pullei leaves methanol extract (MECP). MECP reduced in a dose-dependent manner the number of acetic acid-induced abdominal writhing (1.2 percent) in mice, suggesting an antinociceptive activity of the plant. On the other hand, MECP did not significantly modify the reactivity to the thermal stimulation in the hot-plate test and the reactivity to the chemical stimulation in the formalin test first phase, indicating a non-opioid mechanism. MECP reduced the formalin-induced nociception in the second phase, inhibited the croton oil-induced ear edema and reduced the leukocytes migration in the test of the carrageenan-induced peritonitis, indicating an antiinflammatory activity. Although the mechanisms that underlie these plant effects are not completely elucidated, these results appear to support the potential medicinal use of Croton pullei var. glabrior Lanj. against painful and inflammatory diseases.

New bisphosphorothioates and bisphosphoroamidates: synthesis, molecular modeling and determination of insecticide and toxicological profile.

A series of new compounds, N,N'-bis(dialkylphosphoryl)diamines and S,S'-bis(dialkylphosphoryl)-1,3-propanedithiols were prepared by a Todd-Atherton like reaction of dialkylphosphites with symmetrical diamines and 1,3-propanedithiols in a biphasic system [F.R. Athertoon, H.T. Howard, A.R. Todd, J. Chem. Soc. (1948) 1106-1111; F.R. Athertoon, H.T. Openshaw, A.R. Todd, J. Chem. Soc. (1945) 660-663]. The structures were characterized by IR, 1H NMR, 13C NMR and mass spectrometry. Compounds with butoxy, isobutoxy and isopropoxy groups linked in the phosphorus atom showed the lowest LD50 values when tested against Musca domestica and Stomoxys calcitrans. The pharmacological and toxicological evaluation of N,N'-bis(diisobutylphosphoryl)-1,3-propylenediamine and S,S'-bis(diisobutylphosphoryl)-1,3-propanedithiol, which were very active against M. domestica and S. calcitrans, demonstrated that these compounds present no toxicological effects against mice in a concentration of 200mg/kg. An explanation for the observed activity profile is presented based on results obtained in a molecular modeling study with insect and mammalian acetylcholinesterase models.

Phytochemical and pharmacological study of Sedum dendroideum leaf juice.

The fresh juice from leaves of Sedum dendroideum Moc & Sessé (Crassulaceae) is used in Brazilian traditional medicine for the treatment of gastric and inflammatory disorders. The present investigation was carried out to evaluate in vivo antinociceptive and anti-inflammatory activities of this plant material. The oral administration (0.1-1g/kg) of the lyophilized Sedum dendroideum juice (L J) caused a significant dose-related reduction of acetic acid-induced writhing response (ID(50)=631 mg/kg) and inhibited croton oil-induced ear oedema formation (66% inhibition at 1g/kg) in mice. In the formalin-induced nociception in mice, L J (1g/kg) only inhibited the second phase of nociception (46%). Phytochemical investigation revealed four known kaempferol glycosides, here, described at the first time for this species. These flavonoids probably explain the antinociceptive and anti-inflammatory effects of the fresh juice of Sedum dendroideum.

A reassessment of the role of serotonergic system in the control of feeding behavior.

The role of serotonergic system in the feeding behavior was appraised by electrolytic lesions in the dorsal raphe nucleus (DRN) and administration of para-chlorophenylalanine (PCPA, 3 mg/5 microl, icv). Chronic evaluations were accomplished through 120 and 360 days in PCPA-injected and DRN-lesioned rats, respectively. Acute food intake was evaluated in fasted rats and submitted to injection of PCPA and hydroxytryptophan (LHTP, 30 mg/kg, ip). DRN-lesioned rats exhibited 22-80% increase in food intake up to sixth month, whereas the obesity was evident and sustained by whole period. In PCPA-injected rats was observed an initial increase in the food intake followed by hypophagy from 25th to 30th day and a transitory increase of body weight from 5th to 60th day. In the acute study, the LHTP reverted partially the PCPA-induced increase in food intake of fasted rats suggesting a sustained capacity of decarboxylation of precursor by serotonergic neurons. Slow restoration of the levels of food intake in DRN-lesioned rats reveals a neuroplasticity in the systems that regulate feeding behavior. A plateau on the body weight curve in lesioned rats possibly represents the establishment of a new and higher set point of energetic balance.

A reassessment of the role of serotonergic system in the control of feeding behavior

O papel do sistema serotonérgico no comportamento alimentar foi avaliado através de lesões eletrolíticas do núcleo dorsal da rafe (L-NDR) e da administração de para-clorofenilalanina (PCPA, 3 mg/5 µl, icv). Avaliações crônicas foram realizadas durante 120 e 360 dias em ratos injetados com PCPA e L-NDR, respectivamente. Avaliações agudas foram realizadas em ratos em jejum e injetados com PCPA e l-triptofano (LHTP, 30 mg/kg, ip). Ratos lesionados apresentaram um aumento de 22-80% na ingestão de alimento até o sexto mês enquanto a obesidade foi evidenciada e mantida por todo o período. Ratos injetados com PCPA apresentaram um aumento da ingestão alimentar seguido de uma hipofagia do 25º ao 30º dia e um aumento transitório do peso corporal do 5º ao 60º. Agudamente, o LHTP reverteu parcialmente o aumento da ingestão de alimento em ratos tratados com PCPA e jejuados, sugerindo a preservação da capacidade de descarboxilação do precursor pelos neurônios serotonérgicos. A lenta recuperação dos níveis de ingestão alimentar em ratos lesionados revela um mecanismo de neuroplasticidade dos sistemas de regulação do comportamento alimentar. Estabelecimento de platô na curva de peso corporal dos ratos lesionados representaria o estabelecimento de um novo e mais elevado ponto de calibração do balanço energético.

Brain serotonin depletion enhances the sodium appetite induced by sodium depletion or beta-adrenergic stimulation.

We investigate the influence of brain serotonin depletion on the sodium appetite. Rats depleted of serotonin through the systemic administration of p-chlorophenylalanine (300 mg/kg, ip, for 2 days) showed an intense natriorexigenic response induced by sodium depletion (furosemide, 20 mg/kg, sc, 24 h before water and 1.8% NaCl presentation). Intake of 1.8% NaCl was always higher than that observed for the control group (12.9 +/- 1.4 and 21.4 +/- 3.0 mL vs 5.7 +/- 1.2 and 12.7 +/- 1.6 mL, 30 and 300 min after water and saline presentation). After 24 h, the natriorexigenic response continued to be significantly higher compared to control (33.6+/-5.1 vs 21.9+/-3.6 mL,P <0.05). Fourteen days after p-chlorophenylalanine administration, 1.8% NaCl intake did not differ from controls. Serotonin-depleted rats expressed an early natriorexigenic response after isoproterenol administration on the third day after the first injection of p-chlorophenylalanine. An increase in 1.8% NaCl intake was first observed at 120 min (1.9 +/- 0.2 vs 0.45 +/- 0.3 mL,P <0.05) and remained high up to the end of the 24-h observation period (17.3+/-3.2 vs 1.1+/-0.5 mL,P <0.05). After 7 and 14 days, the natriorexigenic response became comparable to that of control animals. Present results show that brain serotonin depletion exaggerates the sodium appetite induced by the paradigm of sodium depletion or after beta-adrenergic stimulation.

Brain serotonin depletion enhances the sodium appetite induced by sodium depletion or beta-adrenergic stimulation

We investigate the influence of brain serotonin depletion on the sodium appetite. Rats depleted of serotonin through the systemic administration of p-chlorophenylalanine (300 mg/kg, ip, for 2 days) showed an intense natriorexigenic response induced by sodium depletion (furosemide, 20 mg/kg, sc, 24 h before water and 1.8 percent NaCl presentation). Intake of 1.8 percent NaCl was always higher than that observed for the control group (12.9 ± 1.4 and 21.4 ± 3.0 mL vs 5.7 ± 1.2 and 12.7 ± 1.6 mL, 30 and 300 min after water and saline presentation). After 24 h, the natriorexigenic response continued to be significantly higher compared to control (33.6±5.1 vs 21.9±3.6 mL,P <0.05). Fourteen days after p-chlorophenylalanine administration, 1.8 percent NaCl intake did not differ from controls. Serotonin-depleted rats expressed an early natriorexigenic response after isoproterenol administration on the third day after the first injection of p-chlorophenylalanine. An increase in 1.8 percent NaCl intake was first observed at 120 min (1.9 ± 0.2 vs 0.45 ± 0.3 mL,P <0.05) and remained high up to the end of the 24-h observation period (17.3±3.2 vs 1.1±0.5 mL,P <0.05). After 7 and 14 days, the natriorexigenic response became comparable to that of control animals. Present results show that brain serotonin depletion exaggerates the sodium appetite induced by the paradigm of sodium depletion or after beta-adrenergic stimulation.