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Serotonin exerts a significant role in the mammalian central nervous system embryogenesis and brain ontogeny. Therefore, we investigate the effect of neonatal treatment of d-fenfluramine (d-FEN), a serotonin (5-HT) releaser, on the behavioral expression of adult male Swiss mice. For this purpose, we divided pregnant female Swiss mice into two groups (n = 6 each and ~35 g). Their offspring were treated with d-FEN (3 mg/kg, s.c.) from postnatal days (PND) 5 to 20. At PND 21, one male puppy of each litter was euthanized; the midbrain and the hippocampus were dissected for RNA analysis. At PND 70, the male offspring underwent a behavioral assessment in the open field, elevated plus-maze, light-dark box, tail suspension, and rotarod test. The programmed animals had a decrease in 5HT1a, serotonin transporter (SERT), and brain-derived neurotrophic factor (BDNF) expression in the mesencephalic raphe region. Alternatively, there was a reduction only in the tryptophan hydroxylase (TPH2) and BDNF expression in the hippocampus. In the light-dark box test, offspring of the treated group had higher latency to light and less time on the light side than the control. Also, it was observed less time of immobility in the tail suspension test. We also observed low motor skill learning in the rotarod test. These findings suggest that programming with d-FEN during the neonatal period alters a mesencephalic and hippocampal serotonergic system, promoting anxiety, antidepressant behavior, low coordination, and motor learning in adults.

Evaluate the anti-inflammatory activity in vivo and in vitro of cis-(±)-acetate of 4-chloro-6-(naphtalene-1-yl)-tetrahydro-2H-pyran-2-yl) methyl 2-(2-(2,6-diclorofenylamine) phenyl (LS19). Male Swiss mice were analyzed in the paw edema, ear edema, and air pouch tests, and in vitro COX inhibition, cytotoxicity evaluation, and cytokine and nitric oxide determination tests. The compound showed effect on the carrageenan- and bradykinin-induced paw edema and capsaicin-induced ear edema tests. In addition, the compound was able to inhibit leukocyte migration to decrease the levels of the pro-inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β) and to increase the levels of the anti-inflammatory cytokine IL-10. The compound was also able to reduce levels of TNF-α, IL-6, and nitric oxide in the RAW 264.7 cell line and to inhibit COX activity. LS19 did not induce any significant changes in the viability of RAW 264.7 cells, demonstrating safety for these cell lines. The compound LS19 did not reduce the production of gastric mucus and induced a smaller increase in the extent of gastric lesions than that developed by the administration of diclofenac. In summary, the new compound proved to be safer and it had additional mechanisms compared to diclofenac.

Pain is responsible for inducing physical and mental stress, interfering negatively in patients' quality of life. Classic analgesic drugs, such as opioids and non-steroidal anti-inflammatory drugs, are known for their wide range of adverse effects, making it important to develop new drugs. Thus, this study aimed to analyze the action of the hybrid compound cis- (±) -acetate of 4-chloro-6- (naphthalene-1-yl) -tetrahydro-2h-pyran -2-yl) methyl2- (2- (2,6-dichlorophenylamine) phenyl (LS19) under acute nociceptive conditions, and deepened the understanding of the responsible mechanisms. Male swiss mice were evaluated in the acetic acid-induced abdominal writhing, formalin, tail-flick, capsaicin- and glutamate-induced nociception, thermal stimulation in animals injected with capsaicin and rotarod tests besides the acute and subchronic toxicological evaluation. The compound showed effect on the acetic acid-induced abdominal writhing, formalin (both phases), tail-flick, thermal stimulation in animals injected with capsaicin and capsaicin-induced nociception tests. In the study of the mechanism of action was observed reversion of the antihyperalgesic effect of the compound from the previous intraperitoneal and intrathecal administration of naloxone, nor-binaltorphimine, naltrindole, methylnaltrexone, 7-nitroindazole, L-NAME, ODQ, glibenclamide on the tail flick test. In the thermal stimulation in animals injected with capsaicin, the compound showed antinociceptive effect by oral and intraplantar routes, besides to reducing the levels of TNF-α, IL-1β and PGE2 in the paws previously administered with capsaicin. There were no signs of acute and subchronic intoxication with the compound. In summary, the compound LS19 presented spinal and local antihyperalgesic effect, demonstrating participation of the opioid/NO/cGMP/K+ ATP pathway and TRPV1 receptors and it demonstrated safety in its use in mice.

Alzheimer disease's (AD) is a neurodegenerative disorder characterized by cognitive and behavioral impairment. The central nervous system is an important target of thyroid hormones (TH). An inverse association between serum triiodothyronine (T3) levels and the risk of AD symptoms and progression has been reported. We investigated the effects of T3 treatment on the depression-like behavior in male transgenic 3xTg-AD mice. Animals were divided into 2 groups treated with daily intraperitoneal injections of 20 ng/g of body weight (b.w.) L-T3 (T3 group) or saline (vehicle, control group). The experimental protocol lasted 21 days, and behavioral tests were conducted on days 18-20. At the end of the experiment, the TH profile and hippocampal gene expression were evaluated. The T3-treated group significantly increased serum T3 and decreased thyroxine (T4) levels. When compared to control hippocampal samples, the T3 group exhibited attenuated glycogen synthase kinase-3 (GSK3), metalloproteinase 10 (ADAM10), amyloid-beta precursor-protein (APP), serotonin transporter (SERT), 5HT1A receptor, monocarboxylate transporter 8 (MCT8) and bone morphogenetic protein 7 (BMP-7) gene expression, whereas augmented superoxide dismutase 2 (SOD2) and Hairless gene expression. T3-treated animals also displayed reduced immobility time in both the tail suspension and forced swim tests, and in the latter presented a higher latency time compared to the control group. Therefore, our findings suggest that in an AD mouse model, T3 supplementation promotes improvements in depression-like behavior, through the modulation of the serotonergic related genes involved in the transmission mediated by 5HT1A receptors and serotonin reuptake, and attenuated disease progression.

The potential benefits of treating subclinical hypothyroidism (SCH) are unclear and still controversial. Thus, we surgically induced SCH in rats and evaluated the effects of thyroxine (T4) replacement on the gene expression levels of deiodinases and thyroid hormone (TH) transporters in different tissues. SCH was induced by hemithyroid electrocauterization. The control animals underwent the same surgical procedure but were not subjected to electrocauterization (sham). After 14 days, half of the SCH animals were treated with T4 (SCH + T4). At the end of the experimental protocol, all of the rats were euthanized, serum hormone concentrations were measured, and RNA analyses were performed on different tissues and organs. Consistent with previous studies, we observed increased TSH levels, normal TH levels, and reduced hypothalamic TRH expression in the SCH group. Additionally, Dio2 mRNA expression was downregulated in the hippocampus and pituitary, and Dio1 was upregulated in the kidney and pituitary of the SCH animals. The changes in Dio3 expression were tissue-specific. Concerning TH transporters, Mct10 expression was upregulated in the pituitary, kidney, hypothalamus, and hippocampus, and Mct8 expression was downregulated in the kidney of the SCH group. Crym expression was upregulated in the kidney and pituitary. Notably, T4 replacement significantly attenuated serum TSH levels and reverted Dio1, Dio2, Mct10, and Crym expression in the pituitary, hippocampus, and kidney to levels that were similar to the sham group. Tissue-specific responses were also observed in the liver and hypothalamus. Our results indicate that treatment of SCH should be considered before the appearance of clinical symptoms of hypothyroidism.

The development of analgesic drugs is still a necessity due to the inefficiency of the current treatments for some pathological conditions and also due to the adverse effects produced by these drugs. The aim of this study was to deepen the pharmacological study of two new hybrids NSAIDs tetrahydropyran derivatives, regarding their antinociceptive effects on acute pain in mice. Male swiss mice were evaluated in the acetic acid-induced abdominal writhing, formalin, tail-flick, open-field, glutamate- and capsaicin-induced paw licking tests, and in vitro Cox inhibition assay, besides the acute toxicological evaluation. The compounds had an effect on the acetic acid-induced abdominal writhing, formalin (both phases), and tail-flick tests. In the study of the mechanism of action was observed reversion of the antinociceptive effect of the compounds from the previous administration of naloxone, L-NAME (L-nitro-arginine methyl ester), ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), glibenclamide, and nor-binaltorphimine, by the intrathecal and intraperitoneal routes. The prior administration of MK-801 suggests that the modulation of NMDA receptor contributes to the antinociceptive effect of compounds. In summary, hybrid compounds presented central antinociceptive effect, demonstrating participation of the NO-cGMP-K+ ATP pathway, κ-opioid, and NMDA receptors. In addition, the compounds showed inhibition of cyclo-oxygenase enzymes and adverse effects were not observed with dose 300 times greater than the dose used experimentally.

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.

Ethnopharmacological relevance Joannesia princeps (SOJP) has been used in folk medicine as anthelmintic treatment and cutaneous wound healing. Aim of the study: The purpose of this study is to evaluate the pharmacological activity of seed oil of Joannesia princeps, administered systemically and topically, on acute pain and inflammation. Materials and methods Male swiss mice were treated orally and topically with seed oil of Joannesia princeps in models of acute pain (acetic acid-induced abdominal writhing, formalin-induced licking behaviour and tail flick tests) and acute inflammation (carrageenan- and histamine-induced paw oedema; arachidonic acid-, capsaicin- and croton oil-induced ear oedema and air pouch tests), besides the open field model in the motor performance evaluation. Results Seed oil of Joannesia princeps showed systemic action against acute pain in abdominal writhing test (37% and 56% inhibition in the number of writhes at doses of 30 and 100 mg/kg, respectively) and in the second phase of formalin-induced licking behaviour test (29%, 47 and 52% inhibition in the licking time at doses of 10, 30 and 100 mg/kg, respectively), as well as reducing croton oil-induced ear oedema by 72%, leukocyte recruitment and production of TNF-α and IL-6 in the air pouch tests. In addition, topical administration of SOJP inhibited carrageenan-induced paw oedema by 39% at dose of 500 μg/paw and inhibited histamine-induced oedema by 43 and 52% at doses of 300 and 500 μg/paw, respectively. SOJP also decreased croton oil-induced ear oedema by 67% at dose of 500 μg/paw and arachidonic acid-induced ear oedema by 63% at dose of 500 μg/paw, reducing the production of TNF-α, IL-1β and MIP2 in both. In addition, no adverse effects were observed at doses up to 2000 mg/kg. Conclusions Seed oil of Joannesia princeps presents antinociceptive and anti-inflammatory actions through its topical and systemic administration, promoted by inhibition of leukocyte recruitment and cytokine production (TNF-α, IL-1β, IL-6 and MIP-2).

Thyroidectomy is a surgical procedure indicated in cases of several maligned or benign thyroid diseases, thus, the aim of our study was to verify how the hypothyroidism induced by thyroidectomy influences behavioral parameters and its relation to thyroid hormones metabolism and neurogenesis at hippocampus. For this purpose, Adult male Wistar rats underwent to thyroidectomy to induce hypothyroidism. Behavioral tests, the thyroid profile and hippocampal gene expression were evaluated in control and in thyroidectomized animals. It was observed that thyroidectomized group had a significant increasing in serum thyroid-stimulating hormone (TSH) and a decreasing in thyroxine (T4) levels as well as in triiodothyronine (T3) serum level. It was also observed reduction of the monocarboxylate transporter 8 (Mct8), thyroid hormone receptor alfa (Trα1), deiodinase type 2 (Dio2), ectonucleotide pyrophosphatase/phosphodiesterase 2 (Enpp2) and brain-derived neurotrophic factor (Bdnf) mRNA expression in hippocampus of thyroidectomized animals. In the forced swimming test, it was verified that thyroidectomy promotes a decrease in time of immobility and climbing when compared with the control group. In summary, we demonstrated that antidepressant behavior in thyroidectomized Wistar rats is induced by hippocampal hypothyroidism. This effect could be associated to an impaired neuronal activity in acute stress response as it is observed in forced swimming paradigm.

In response to the rapid development of genetically engineered glyphosate-tolerant crops, the use of glyphosate-based herbicides (GBHs), in agriculture, has increased substantially. Currently, it is estimated that 747 million kg of GBHs are applied per year. Although several epidemiological studies have demonstrated that there are health risks associated with GBH exposure, the effects these chemicals have on the oxidative and inflammatory response in the brain are still unclear. In fact, alterations in these processes could contribute to the development of neurological diseases, such as Alzheimer’s disease and autism spectrum disorders. The present study exposed pregnant rats to GBH and evaluated changes in the expression of genes related to oxidnte defense and inflammation response and monitored the serum metabolome in the adult male offspring. Pregnant Wistar rats were administered distilled water or Roundup®, at either 5 and 50 mg/kg/day, (p.o.) from gestational day (GD) 18 to postnatal day (PND) 5. There was a significant increase in the gene expression levels of Neuroglobin (Ngb – oxygen storage and tissue protection) (105%, p = 0.031), Glutathione Peroxidase 1 (Gpx1 – oxidative stress) (95%, p = 0.005), Prostaglandin-Endoperoxidase Synthase 1 (Ptgs1 - inflammation) (109%, p = 0.033) and Hypoxia inducible factor 1 subunit alpha (Hif1α – oxygen sensor) (73%, p = 0.017), in the cerebellum of PND90 rats perinatally exposed to 50 mg GBH/kg/day. Moreover, both GBH-exposed groups displayed a significant decrease in the expression of Catalase (Cat – oxidative stress) (49%, p = 0.003; and 31% p = 0.050, respectively) expression, in the cortex. Serum metabolites analyses, from the same animals of each group, demonstrated that there were significant changes in the concentrations of lysophosphatidylcholine and phosphatidylcholine, which have been associated with neurodegenerative diseases. The results of the present study suggest GBH exposure during pregnancy alters the expression of genes associated with oxidant defense, inflammation and lipid metabolism. It is plausible that maternal GBH exposure could have lasting neuronal effects on the offspring later in life.

The proper functioning of the maternal thyroid plays a crucial role in fetal development. Thus, the aim of our study was to verify how maternal hyperthyroidism is able to change behavioral parameters in mice offspring during adulthood. For this purpose, pregnant Swiss mice (n = 24 and ~35 g) were randomly assigned into two groups: a control and a thyroxine (T4)-treatment group. The control was treated with 0.9% saline, while the treatment group received T4 (200 μg/kg, s.c.) once daily during the entire pregnancy period. After completing 70 days of life, a part of male offspring underwent a battery of tests, including open field, dark-light box, elevated plus maze, marble burying, rotarod and tail suspension tests. The other male pups were euthanized, being hippocampus and serum collected for RNA analysis and hormones measurement, respectively. Statistical analysis was performed using Student's t-test, and the means were considered significantly different when p 0.05. In adult offspring, a significant decrease was observed for serum T3 in treated group. It was demonstrated that the T4 group had an increase in total distance traveled in an open field test. In the elevated plus maze test, we observed a higher time in opened arms as well as an increased in percentage of entries in these arms. In the hippocampus, T4 offspring had a higher expression of tryptophan hydroxylase 2 (TPH2), serotonin transporter (SERT) and glutamate decarboxylase 67 (GAD 67) in comparison to controls. These findings suggest that prenatal T4 treatment alters hippocampal serotonergic and GABAergic systems, promoting anxiolysis in male adult offspring.

Piperin is the active compound of black pepper (Piper nigrum). From the piperine was obtained the molecule of the piperic acid (PAC). The objective of this study was to evaluate the antinociceptive and anti-inflammatory of the compound. The antinociceptive effects of PAC were evaluated by abdominal writhing, formalin, capsaicin and tail-flick tests; while the anti-inflammatory effects were evaluated by paw oedema and air pouch tests, and in vitro COX inhibition assay. The possible action mechanism of PAC was evaluated using naloxone, L-NAME, glibenclamide and atropine in tail flick test and by Cholinesterase activity assay and production of TNF-α and IL-1β. PAC significantly reduced the nociceptive effects induced by acetic acid or formalin in mice. PAC also demonstrated an antinociceptive effect in the tail-flick model. The muscarinic receptor antagonist, atropine reduced the antinociceptive effect of PAC in the tail-flick model. PAC was able to inhibit capsaicin-induced nociception, showing involvement of TRPV1. The compound did not alter the motor capacity of the animals, not interfering in the nociceptive response. PAC also showed anti- inflammatory activity by inhibiting the formation of carrageenan-induced paw oedema, leukocyte migration, and cytokine production / release. Atropine reduced the activity of PAC on leukocyte migration, and cytokine production. The compound showed to be able to reduce the cytokine production stimulated by capsaicin. PAC inhibited the COX activity. The results presented suggest that the possible cholinomimetic action and vanilloid agonist of the piperic acid may be responsible by antinociceptive and anti- inflammatory effects; these effects are devoid of toxicity.

The association between caffeine consumption and various psychiatric manifestations has long been observed. The objective was to assess the behavioral profile in offspring of Swiss mice treated during pregnancy and lactation with caffeine. For this purpose, two groups (n = 6 each and BW ~ 35 g) of female mice were treated during pregnancy and lactation by: tap water and caffeine solution at a concentration of 0.3 mg/mL through oral route. The offspring obtained, by completing 70 days of life, was underwent a behavioral battery test. Statistical analysis was performed by student t test and the different significance adopted was p

Based on the relevance of the renin-angiotensin system and the ongoing controversy regarding the role of the sympathetic nervous system in thyroid hormone-induced cardiac hypertrophy, the aim of the present study was to establish whether the putative difference in the degree of cardiac hypertrophy exhibited by males and females might be related to differences in the sympathetic-vagal balance and/or in the cardiac renin-angiotensin system in mice of different genders. Male and female mice (n = 117) were given 0.1 mg kg(-1) of triiodothyronine or normal saline each day for 10 days consecutively. At the end of that period, study of the heart rate variability, spectral analysis and histopathological examination were performed to assess the sympathetic-vagal balance and the diameter of cardiomyocytes. The cardiac levels of angiotensin I and II were also measured. Treatment with triiodothyronine induced a greater degree of cardiac hypertrophy in male (~73%) than in female mice (~42%). This difference was attributed to greater modulation of the sympathetic nervous system and higher levels of angiotensin I and II in male than in female mice. Our data indicate that thyroid hormone-induced cardiac hypertrophy was more intense in male mice due to the synergic effect of the sympathetic nervous system and the cardiac renin-angiotensin system.