Search

ETHNOPHARMACOLOGICAL RELEVANCE: Sonchus oleraceus L. has been used to relieve headaches, general pain, hepatitis, infections, inflammation and rheumatism in Brazilian folk medicine. Nevertheless, scientific information regarding this species is scarce; there are no reports related to its possible anti-inflammatory effects. AIM OF THE STUDY: This study was aimed at evaluating the scientific basis for the traditional use of Sonchus oleraceus using in vivo inflammatory models. MATERIALS AND METHODS: Carrageenan-induced paw edema, peritonitis and febrile response induced by lipopolysaccharide tests, as well as fibrovascular tissue growth induced by s.c. cotton pellet implantation were used to investigate the anti-inflammatory activity of Sonchus oleraceus hydroethanolic extract (SoHE) in rats. RESULTS: The SoHE at test doses of 100-300 mg/kg p.o. clearly demonstrated anti-inflammatory effects by reduced paw edema induced by carragenan, inhibited leukocyte recruitment into the peritoneal cavity and reduced LPS-induced febrile response, and in the model of chronic inflammation using the cotton pellet-induced fibrovascular tissue growth in rats, the SoHE significantly inhibited the formation of granulomatous tissue. The extract administered at 300 mg/kg p.o. had a stronger anti-inflammatory effect than indomethacin (10mg/kg) or dexamethasone (1mg/kg). CONCLUSION: The hydroethanolic extract of Sonchus oleraceus markedly demonstrated anti-inflammatory action in rats, which supports previous claims of its traditional use. [ABSTRACT FROM AUTHOR]

Abstract The aim of the present work is to evaluate the putative antidepressant-like effects of hydroethanolic and dichloromethanic extracts from the aerial parts of Sonchus oleraceus (Family Asteraceae) on the performance of male mice in the forced swimming test (FST) and tail suspension test (TST) models predictive of depression. The hydroethanolic and dichloromethanic extracts, both in doses of 30, 100, and 300 mg/kg, were orally administered 1 hour before carrying out the FST or the TST. The immobility time in both the FST and the TST was significantly reduced by acute oral treatment with the extracts (dose range, 100-300 mg/kg), without accompanying changes in ambulation, as assessed in an open-field test. This excluded the possibility that the effect of the extracts is due to an activation of locomotion. The efficacy of the extracts was found to be comparable to that of amitriptyline (10 mg/kg, p.o.). The present study provides evidence for an antidepressant-like effect of the active principle(s) present in the extracts of S. oleraceus in mice. Therefore, a standardized S. oleraceus extract or its purified constituents could be of potential interest for the treatment of depressive disorders. [ABSTRACT FROM AUTHOR]

Abstract Morus nigra has been used to relieve pain in Brazilian folk medicine. This study was conducted to establish the antinociceptive properties of dichloromethane extract from leaves of M. nigra. The formalin, hot plate, and tail immersion tests as well as acetic acid-induced writhing were used to investigate the antinociceptive activity in mice. The extract at test doses of 100 and 300 mg/kg, p.o. clearly demonstrated antinociceptive activity in all tests. The extract administered at 300 mg/kg, p.o. had a stronger antinociceptive effect than indomethacin (5 mg/kg, p.o.) and morphine (10 mg/kg, p.o.), which supports previous claims for its traditional use. [ABSTRACT FROM AUTHOR]

This study explored the effects of fructose-induced obesity and metabolic disorders on peripheral inflammatory hyperalgesia, employing quantitative sensory testing with the von Frey test and measuring paw edema to assess inflammatory responses. Wistar rats were administered water or 10% fructose solution ad libitum over a period of 5 weeks. After intraplantar administration of inflammatory agents such as carrageenan (1 mg/paw), lipopolysaccharide (LPS; 100 µg/paw), or prostaglandin E2 (PGE2, 100 ng/paw), we conducted mechanical hyperalgesia tests and paw edema evaluations. The fructose diet resulted in dyslipidemia, elevated insulin and leptin plasma levels, insulin resistance, and increased epididymal and retroperitoneal adiposity compared to control animals. In response to inflammatory agents, the fructose group displayed significantly enhanced peripheral hyperalgesia and more pronounced paw edema. Our results demonstrate that fructose not only contributes to the development of obesity and metabolic disorder but also exacerbates peripheral inflammatory pain responses by enhancing prostaglandin sensitivity.

Aims: The present study was developed to investigate how litter reduction-induced obesity promotes early depressive-related behaviors in rodent offspring., Main Methods: We employed a standardized litter size reduction protocol, dividing litters into groups: normal litters (NL), consisting of six males and six females pups and small litters (SL), comprising two males and two females pups. Maternal behavior was monitored during the initial week of lactation. Subsequently, we assessed the pups for weight gain, locomotor activity, social play behavior, and performance in forced swimming test. We further evaluated the weights of retroperitoneal and perigonadal fat tissues, along with the expression of glial fibrillary acidic pprotein (GFAP) in the hippocampus and prefrontal cortex of the offspring., Key Findings: Our results indicated that litter size reduction led to an increased the maternal behavior. In contrast, offspring from the SL group displayed greater weight gain and increased, retroperitoneal and perigonadal fat. Both male and female rodents in the SL group exhibited decreased social play behavior, and male offspring spent more time immobile during the forced swimming test, suggesting a depressive-like phenotype. Notably, we observed an increase in the GFAP expression in the prefrontal cortex of male rodents, with a trend toward increased expression in the hippocampus., Significance: Obesity may facilitate the development of early depressive-like behaviors, potentially associated with elevated GFAP expression in the prefrontal cortex., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To assess the clinical communication characteristics of pharmacy undergraduates, estimate differences in this specific competency, and produce recommendations for further education and training., Methods: Analysis of communication competence between 110 pharmacy students in the last graduation year from each of the 5 Brazilian regions and a simulated patient with complaints of mild allergic rhinitis passive of resolution with non-prescription medicines. The simulated appointment was recorded, and the video was analyzed using the 2 main elements: biomedical/task-focused and socio-emotional exchange of the Roter Interaction Analysis System., Results: The total of utterances/speech from the pharmacist to the patient was 183.4; there was a statistically significant difference according to the Brazilian region. In the consultation, the frequency with which pharmacy students returned to the segment was evaluated, with a total mean clinical history segment 2 of mean 5.60; in segment 4, which is the counseling phase, an average of 4.80. In the task codes and the socio-emotional codes, there was a statistically significant difference between the codes when compared by region. We compare by sex because it is said that women talk more than men. There was a statistically significant difference in socio-emotional code and biomedical/focused and task being higher for women., Conclusion: The level of communication competence of students should be that desired for graduation, in all regions. There seems to be a difference between training and level of competence. Considering gender, although the consultation time is similar, it appears that the quality of communication is higher for women., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Federal University of São João Del-Rei and the Coordination Program of Professional Improvemet of Higher Education (CAPES) for financial assistance and the Minas Gerais State Research Support Foundation (FAPEMIG)., (Copyright © 2024 American Association of Colleges of Pharmacy. Published by Elsevier Inc. All rights reserved.)

Dillenia indica (Linn.) has been reported by several biological activities, including anti-inflammatory, antioxidant, antidiabetic, anti-hyperglycemic, antiproliferative, antimutagenic, anticholinesterase, and antimicrobial. In Brazilian traditional medicine, the fruits of D. indica have been used to treat general topical pain and inflammation, but with no scientific validation. Thus, aiming to study its chemical constitution and antinociceptive properties, the crude extract (CE) and fractions obtained from the fruits of D. indica were submitted to an in vivo pharmacological evaluation and a dereplication study by LC-MS/MS analysis, assisted by the Global Natural Product Social Molecular Networking (GNPS). The oral antinociceptive activity of the fruits of D. indica and the possible participation of the opioid and cannabinoid systems were demonstrated in the formalin-induced nociception model. The chemical dereplication study led us to identify several known chemical constituents, including flavonoids, such as caffeoylmalic acid, naringenin, quercetin, and kaempferol. According to literature data, our results are compatible with significant antinociceptive and anti-inflammatory activities. Therefore, the flavonoid constituents of the fruits of D. indica are probably responsible for its antioxidant, anti-inflammatory, and antinociceptive effects mediated by both opioid and cannabinoid systems, confirming its folk use in the treatment and relief of pain., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

Ring-substituted phenethylamines are believed to induce psychedelic effects primarily by interacting with 5-hydroxytryptamine 2 (5-HT2A) receptors in the brain. We assessed the effect of the psychedelic substances 25H-NBOMe and 25H-NBOH on the depressive-like behavior of male adult rats. Naive Wistar rats were divided into groups to assess the effects of different doses (0.1 mg/kg, 1 mg/kg, and 3 mg/kg) of 25H-NBOMe and 25H-NBOH. The substances were administered intraperitoneally and the hallucinogenic properties were evaluated using the head twitch response test (HTR). Additionally, we assessed their locomotor activity in the open field test (OFT) and depressive-like behavior in the forced swimming test (FST). Our data demonstrated that all doses of synthetic psychedelic substances evaluated exhibited hallucinogenic effects. Interestingly, we observed that both 25H-NBOMe and 25H-NBOH produced a significantly greater motivation to escape in the FST, compared to the control group. Furthermore, we found no significant differences in locomotor activity during the OFT, except for the dose of 3 mg/kg, which induced a reduction in locomotion. This study provides new insights into a potential psychedelic substance, specifically by demonstrating the previously unknown antidepressant properties of a single dose of both 25H-NBOMe and 25H-NBOH. These findings contribute to the ongoing progress of experimental psychiatry toward developing safe and effective clinical practices in the field of psychedelics research., Competing Interests: Declaration of competing interest The authors report no biomedical financial interests or other potential conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Gestational hypothyroidism is a prevalent disorder in pregnant women and also impairs fetal development with relevant outcomes. One of the outcomes of greatest interest has been rodent fear- and anxiety-like behavior. However, the relationship between maternal hypothyroidism and onset of conditioned fear-related responses in offspring remains controversial. Here, we used a well-validated methimazole-induced gestational hypothyroidism to investigate the behavioral consequences in offspring. Dams were treated with methimazole at 0.02% in drinking water up to gestational Day 9. Maternal body weights and maternal behavior were evaluated, and the puppies ware analyzed for weight gain and physical/behavioral development and assigned for the open field and fear conditioning test. Methimazole-induced gestational hypothyroidism induced loss in maternal and litter weight, increases in maternal behavior, and impairs in offspring developmental landmarks in both male and female rodents. Only male offspring enhanced responsiveness to conditioned fear-like behavior in adulthood., (© 2022 International Society for Developmental Neuroscience.)

Glyphosate is the organophosphate pesticide most widely used in the world. Recent studies correlate exposure to glyphosate and the emergence of neurodevelopmental disorders. Therefore, it was objective to propose a rat model of perinatal exposure to glyphosate-based herbicides (GBH) to study associated neurodevelopmental disorders. Behavioral aspects and brain pathways were assessed in the prepubertal phase. For this, maternal treatment occurred throughout the entire gestation period (from GD0) until weaning on postnatal day 22 (PND 22). Control group received oral gavage with 5 mL/kg of saline per day and GBH group received oral gavage with 50 mg/kg of GBH per day (n = 10 per group). Maternal behavior was evaluated in PND 2-6. Offspring were evaluated for quantification of ultrasonic vocalizations (PND 5); homing behavior test (PND 13); and hole board, social play behavior, open field, and object recognition tests (PND 28-32). Prefrontal cortex and hippocampus of the offspring were processed to evaluate oxidative stress. Maternal exposure to GBH impaired early social communication, olfactory discrimination, social play behavior, and the exploration of objects, in addition to increasing repetitive and stereotyped movements. GBH also increased oxidative stress. Therefore, perinatal GBH exposure induced behavioral and oxidative stress impairments in rats associated with neurodevelopmental disorders. The manifestations found in the offspring are in accordance with symptoms of autism spectrum disorder., (© 2022 International Society for Developmental Neuroscience.)

Lipopolysaccharide (LPS) is a potent inducer of inflammation, triggering behavioral changes and fever. The present study aimed to evaluate whether pretreatment with curcumin prevents the behavioral changes and fever induced by LPS through the modulation of nuclear factor-erythroid 2 related factor 2 (Nrf2). Male Wistar rats received either vehicle or LPS and after 2 h, the behavioral responses were assessed through open field test (OFT), social interaction test, forced swim test (FST), and food intake assessment. The febrile response was assessed by telemetry after vehicle or LPS injection to evaluate the effect of curcumin on the thermoregulatory response during the immunological challenge. The pretreatment with curcumin at doses of 50 and 100 mg/kg prevented the reduction of distance traveled on OFT, increased the immobility time of FST, impaired social withdrawal, decreased food intake, and induced fever. In addition, at these doses, it was possible to observe a significant decrease in the plasma levels of cytokines and an increase in Nrf2 translocation to the cell nucleus during the immunological challenge. Our data provide further evidence of curcumin's ability to prevent LPS-induced sickness behavior and fever possibly by a mechanism related to the modulation of Nrf2 translocation., (Copyright © 2022 Elsevier B.V. All rights reserved.)

A new series of eight multifunctional thalidomide-donepezil hybrids were synthesized based on the multi-target-directed ligand strategy and evaluated as potential neuroprotective, cholinesterase inhibitors and anti-neuroinflammatory agents against neurodegenerative diseases. A molecular hybridization approach was used for structural design by combining the N -benzylpiperidine pharmacophore of donepezil and the isoindoline-1,3-dione fragment from the thalidomide structure. The most promising compound, PQM-189 (3g), showed good AChE inhibitory activity with an IC 50 value of 3.15 μM, which was predicted by docking studies as interacting with the enzyme in the same orientation observed in the AChE-donepezil complex and a similar profile of interaction. Additionally, compound 3g significantly decreased iNOS and IL-1β levels by 43% and 39%, respectively, after 24 h of incubation with lipopolysaccharide. In vivo data confirmed the ability of 3g to prevent locomotor impairment and changes in feeding behavior elicited by lipopolysaccharide. Moreover, the PAMPA assay evidenced adequate blood-brain barrier and gastrointestinal tract permeabilities with an Fa value of 69.8%. Altogether, these biological data suggest that compound 3g can treat the inflammatory process and oxidative stress resulting from the overexpression of iNOS and therefore the increase in reactive nitrogen species, and regulate the release of pro-inflammatory cytokines such as IL-1β. In this regard, compound PQM-189 (3g) was revealed to be a promising neuroprotective and anti-neuroinflammatory agent with an innovative thalidomide-donepezil-based hybrid molecular architecture., Competing Interests: The authors declare that there are no conflicts of interest., (This journal is © The Royal Society of Chemistry.)

Aims: During illnesses caused by infectious diseases, a suite of brain-mediated responses called sickness syndrome occurs, triggering behavioral and physiological changes. This study investigated whether ghrelin modulates sickness syndrome induced by systemic administration of lipopolysaccharide (LPS)., Main Methods: Male Wistar rats were pretreated with vehicle or [D-lys3]-GHRP-6, a ghrelin receptor GHS-R1 antagonist (20 nmol, i.c.v), 30 min before injection of LPS (200 μg/kg, i.p.) or sterile saline. We investigated the behavioral effects in male rats after LPS administration by screening for depressive-like behavior, locomotor activity alterations, and corticosterone release. Changes in body temperature were measured using a biotelemetry probe preimplanted in the peritoneal cavity to evaluate the effect of ghrelin on the thermoregulatory response during immunological challenge., Key Findings: Pretreatment with [D-lys3]-GHRP-6 blunted most of the assessed parameters related to sickness syndrome, including social withdrawal, anhedonia, depressive-like behavior, and anorexia, reduced the activation of the HPA axis, but did not alter LPS-induced fever., Significance: Our findings suggest that ghrelin centrally mediates the sickness behavior and activation of HPA, as a ghrelin receptor antagonist attenuates social withdrawal, anhedonia, depressive-like behavior, anorexia, and HPA activation in response to LPS., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Individuals with post-traumatic stress disorder (PTSD) show increased rates of several serious metabolic diseases. However, little is known about pre-existing metabolic diseases and the development of PTSD. Therefore, we aimed to evaluate the course of post-traumatic stress disorder (PTSD) development in rats with preexisting diabetes. In addition, we quantified glial fibrillary acidic protein (GFAP) in the hippocampus of the experimental animals. For this, we used male Wistar rats and divided them into two groups: saline and alloxan (150 mg/Kg, i.p.). The animals were weighed, and plasma glucose was measured after 48 h of diabetes induction by alloxan. The animals were either exposed to inescapable footshocks or not, followed by social isolation. After 14 days, the animals were re-exposed to the box, and the freezing time was evaluated for 10 min. Over the following days, the animals were tested on the open field, social interaction and forced swimming tests. In another group of animals, elevated plus maze and object recognition tests were performed. Our results demonstrated that animals with diabetes had more pronounced PTSD-like symptoms as a reduction in social interaction, an increase in immobility time in forced swimming, a reduction in permanence in the open arms of the elevated plus maze, and a deficit in the object recognition index more accentuated. However, this did not reflect astrocyte activation in the hippocampus. In conclusion, diabetes accentuates post-traumatic stress disorder-like symptoms but not astrocyte activation in the hippocampus., (Copyright © 2021. Published by Elsevier B.V.)

Maternal infection during pregnancy is an environmental risk factor for neurodevelopmental dysfunction, such as autism spectrum disorder (ASD). This study investigated the effect of maternal immune activation (MIA) on the behavior profile of prepubertal offspring and whether MIA alters the neuronal activation pattern of brain areas related to social play behavior. Pregnant Wistar rats received 500 μg/kg of lipopolysaccharide or saline solution on gestational day 16. Their offspring were tested using behavioral tasks to capture some of the core and associated ASD-like symptoms. Neuronal activation, indexed via c-fos expression after social play behavior, was evaluated in several brain areas. MIA had a number of adverse effects on dams and reduced the number of successful births and litter size. MIA induced sex-specific autistic-like features by a reduction in ultrasonic vocalizations in response to separation from the mother and nest, reduction in discrimination between neutral odors and their nest odor, moderate effect in stereotypies in the hole-board test, impaired risk assessment phenotype, and reduction in social play behavior without changes in locomotor activity only in prepubertal male offspring. A decrease in social play behavior may be associated with a decrease in the number of c-fos-positive cells in the prefrontal cortex and striatum, but hyperactivation of the basolateral and basomedial amygdala. Prenatal immune challenge results in ASD-like symptoms such as impaired risk assessment behavior, communication, and social interactions in male prepubertal offspring. Impaired social play behavior is correlated with neuronal hyperactivation in the amygdala., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Exposure to stress might influence pain sensitivity; however, little is known about whether post-traumatic stress disorder (PTSD)-like symptoms alter pain sensitivity and how it can happen. Male rats were exposed to the inescapable footshock paired with either social isolation or a control condition (not exposed to footshock but subjected to social isolation). After 7, 14, or 21 days, memory retention was evaluated. In the following three days, animals underwent the following tests: open-field, social interaction and formalin tests. Another group of animals were subjected to the object recognition test and to von Frey filaments. In other cohorts of animals, saline, fluoxetine, or desipramine were injected intrathecally and immunohistochemistry was performed to investigate whether PTSD-like symptoms alter the expression of c-Fos in serotonergic and noradrenergic neurons. Inescapable footshock induced the development of PTSD-like symptoms. Animals with PTSD-like symptoms showed an increase in the number of flinches in the formalin test and a reduction in mechanical threshold in the von Frey test at both retention intervals. The social interaction was negatively correlated with the nociceptive response in the formalin test. Fluoxetine or desipramine prevented the nociceptive response to chemical stimulus in the formalin test. In addition, in animals with PTSD-like symptoms, there was a reduction in c-Fos expression in serotonergic and noradrenergic neurons. Our results are important for the association of increased sensitivity to pain as one of the clinical manifestations that are present in the development of PTSD, and a possible treatment for increased pain sensitivity in male individuals with PTSD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aims: We assessed the influence of maternal overweight on the behavioral neurodevelopment of male and female offspring in prepubertal age by reducing the litter size., Main Methods: To reduce litter size in Wistar rats, the offspring of generation 0 (G0) were culled for 12 pups (6 males and 6 females: normal litter, NL-G1) or 4 pups (2 males and 2 females: small litter, SL-G1). In G1 dams, overweight was characterized, maternal behavior and locomotor activity were assessed. At G2, we quantified the ultrasonic vocalizations in post-natal day 5 (PND5); we evaluated olfactory discrimination in the homing behavior test on PND13; and in PND28-32 (prepubertal age), we performed the following tests: social play behavior, hole board, object recognition, and open field. At the end of the experiments, hippocampus and prefrontal cortex were dissected to quantify the synaptophysin by western blotting., Key Findings: Our data demonstrated that a reduction in litter size was able to induce maternal overweight without altering the parameters related to overweight in the offspring. The SL-G2 offspring showed deficits in early social communication, olfactory discrimination, social play behavior, and the exploration of objects, in addition to increasing repetitive and stereotyped movements. There were also changes in the synaptophysin levels in the hippocampus and prefrontal cortex of the offspring from reduced litter dams. In conclusion, maternal overweight caused by litter reduction impairs behavioral neurodevelopment, inducing autism-like symptoms in the offspring., Significance: This study alerts the public about the negative consequences of maternal overweight in the descendants., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Animals subjected to early life maternal separation exhibit increased sensitivity to chemical, thermal, and mechanical stimuli during adulthood. However, the mechanism by which maternal separation can alter pain sensitivity in adulthood has not yet been investigated. Thus, we aimed to evaluate the activity of serotonergic and noradrenergic neurons and the effect of serotonin (5-HT) and noradrenaline (NA) reuptake inhibitors in male and female Wistar rats subjected to maternal separation. This study consisted of two experiments: 1) to confirm whether maternal separation increased pain sensitivity (n = 8 per group) and to evaluate the activity of serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in locus coeruleus in animals subjected to maternal separation in comparison to controls (n = 6 per group); and 2) to evaluate the effect of fluoxetine (a selective 5-HT reuptake inhibitor) and desipramine (a NA reuptake inhibitor) on sensitivity to chemical stimulation using formalin in animals subjected to maternal separation (n = 8 per group). Our findings indicated that maternal separation increases an animal's sensitivity to painful chemical stimulation and reduces the activity of 5-HT and NA neurons. In addition, acute pretreatment with a 5-HT or NA reuptake inhibitor prevented the increased response to painful stimulation induced by maternal separation. In conclusion, maternal separation increases pain sensitivity by reducing the activity of serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in locus coeruleus. This study contributes to possible treatments for pain in individuals exposed to early life stress., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Exposure to stressful environmental events during the perinatal period can increase vulnerability to psychopathologies that cause neuroendocrine changes associated with deficits in emotional behavior that can appear early in life. Post-traumatic stress disorder (PTSD) is a frequent, chronic, and disabling disorder that negatively impacts the emotional, social, and cognitive behaviors of affected individuals. Thus, we induced PTSD in pregnant rats by applying inescapable footshocks and then investigated the behavioral parameters similar to anxiety in offspring at prepubertal age, in addition to the plasma levels of maternal and offspring corticosterone and expression of glucocorticoid receptors (GR) in the offspring's hippocampus. With the dams, maternal behavior, open field, and object recognition tests were performed. With the male and female offspring, we performed the following: quantification of ultrasonic vocalizations, elevated plus-maze test, evaluation of exploratory activity in the open field, and hole board test, as well as plasma corticosterone measurements and Western blotting for GR. Our results showed that gestational PTSD affected maternal behavior, led to anxiety-like symptoms, increased corticosterone levels, and increased GR expression in the offspring's hippocampus. Therefore, our data can contribute to the understanding of the onset of early (childhood and juvenile/pre-pubertal phases) anxiety owing to exposure to a traumatic event during the gestation period., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Overfeeding and rapid weight gain during early life are risk factors for the development of obesity in adulthood. This metabolic malprogramming may be mediated by endocrine disturbances during critical periods of development. Cholecystokinin (CCK) acts on the central nervous system by elevating thermogenesis and the activity of anorectic neurons, modulating overall energy balance. Therefore, we tested the hypothesis that postnatal overfeeding impaired CCK effects. Pups were raised in either a litter of three (neonatal overnutrition/small litter group) or 12 (controls/normal litter group) pups per dam to study the effects of postnatal overfeeding on the central and peripheral CCK systems in adulthood. Rats raised in small litters became overweight during lactation and remained overweight as adults, with increased adiposity and plasma levels of lipids, glucose, insulin, and leptin. Neonatally over-nourished rats showed attenuation of gastric emptying and anorexigenic response to CCK, suggesting that offspring from the SL group may present CCK resistance as adult male rats. Consistent with this idea, overweight rats displayed impaired central response in c-Fos immunoreactivity on the nucleus tractus solitarius, area postrema, paraventricular nucleus, central amygdala, arcuate nucleus, and dorsomedial hypothalamus in response to peripheral CCK at adulthood. The small litter group of adult male rats also exhibited reduced norepinephrine- and CCK-stimulated thermogenesis. Unresponsiveness to the effects of CCK may contribute to overweight and metabolic dysfunctions observed in postnatally over-nourished adult rats. Thus, the involvement of an impaired CCK system, among other neurohormonal failures, may contribute to the development of obesity., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aims: During illnesses caused by infectious disease, a suite of brain-mediated responses called sickness syndrome occurs, triggering behavioral and physiological (fever) changes. Simvastatin is widely used as a lipid-lowering medication that has beneficial immunomodulatory properties. This study investigated the effects of simvastatin in a mouse model of sickness syndrome by systemic administration of lipopolysaccharide (LPS)., Main Methods: Male mice were pretreated with vehicle or simvastatin (40 mg/kg, p.o.) for 7 days and received LPS (200 μg/kg, i.p.) or sterile saline. We investigated the behavioral effects in male mice 2 h after LPS administration using tests screening for depressive-like behavior and locomotor activity alterations. Changes in body temperature were measured by biotelemetry probe preimplanted in the peritoneal cavity to evaluate the effect of simvastatin on the thermoregulatory response during immunological challenge., Key Findings: Pretreatment with simvastatin blunted most of the assessed parameters related to sickness syndrome, including depressive-like behavior and depressed locomotor activity, and attenuated LPS-induced fever. These data are consistent with simvastatin promoting alterations in peripheral febrigenic signaling (plasma levels of TNF-α, IL-1β, and IL-10)., Significance: Our data provide further evidence of the capacity of simvastatin to attenuate sickness behavior and fever induced by immunological challenge through a mechanism related to changes in the profile of cytokine production., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Prenatal ethanol exposure affects brain development and causes neural impairment, leading to both cognitive and behavioral consequences in the offspring. Therefore, the aim of this study was to investigate the impact of prenatal exposure to small amounts of alcohol on social play behavior in adolescent male offspring. Swiss mice were prenatally exposed to ethanol by feeding pregnant dams with a liquid diet containing 25% alcohol-derived calories during gestation (alcohol group). They were then compared to both pair-fed dams that received an isocaloric liquid diet containing 0% alcohol-derived calories (pair-fed group) and dams with ad libitum access to a liquid control diet (control group). Additionally, maternal behavior was evaluated in terms of neural activation indexed via c-fos expression in the prefrontal cortex. Although dams exposed to alcohol during pregnancy did not alter their maternal behavior, the offspring presented a decrease in their social play behavior compared with both control and pair-fed offspring. The decrease in social play behavior may be associated with a decrease in number of c-fos-positive cells in the prefrontal cortex. The exposure to small amounts of alcohol during intrauterine development causes both a deficit in social play behavior and a reduction in the neuronal activity seen in the prefrontal cortex., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Female rats were fed a normal or hypoproteic diet during the phases of gestation and lactation. The male offspring of these rats were grown to adulthood and used to study the effects of maternal protein malnutrition on progeny. The adult male rats were pretreated with either saline or LPS and subjected to behavioral tests 2 and 6 h after administration. Tumor necrosis factor (TNF-α), corticosterone and body temperature were the parameters used for assessment. Two hours after LPS administration, sickness behavior was developed in all the animals, regardless of maternal protein malnutrition. After 6 h of LPS administration, sickness behavior was more pronounced in the rats that had been subjected to maternal protein malnutrition. Only the rats with maternal protein malnutrition expressed an increase in the plasma levels of TNF-α and corticosterone. Maternal protein malnutrition prolongs sickness behaviors in offspring., Competing Interests: Declaration of Competing Interest The authors report no biomedical financial interests or other potential conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

Objective: We tested the correlation between maternal protein malnutrition and autistic-like symptoms using behavioral tests in rodents that measure main behavioral characteristics observed in humans with autism spectrum disorder (ASD). Methods: Pregnant female rats were fed a normal diet or a hypoproteic diet during gestation and lactation periods. The litters were weighed every 3 days during lactation, and the offspring were tested in behavioral tasks during infancy (postnatal day (PND) 5: quantification of ultrasonic vocalizations; PND 13: homing behavior test) and adolescence (PND 30-32: open field, hole-board, play social behavior, and object recognition tests) in order to capture the prevalence of some of the core and associated symptoms of ASD. Results: Litters of the hypoproteic diet group had a lesser weight gain during lactation. In addition, pups of dams fed with a hypoproteic diet vocalized less compared to those fed with a normal diet, and they showed impaired social discrimination abilities in the homing behavior test. In adolescence, both male and female offspring of the hypoproteic diet group showed no impairment in locomotor activity; however, they exhibited stereotypic behavior in the hole-board test and a decrease in social play behaviors. Male offspring showed increased interest in exploring a familiar object rather than a novel object. Conclusion: Our results show that maternal protein malnutrition in rats causes offspring behaviors that resemble core and associated ASD symptoms.

The objective of this study was to investigate the effect of exposure to maternal consumption of a hyperenergetic, highly palatable diet, known as the cafeteria diet, during the gestation period on the development and behavior of offspring. For this, we used pregnant female mice that were fed a normal or a cafeteria diet during the gestation period. The evaluation of maternal behavior in lactating dams was performed from the second to the eighth day postpartum (PND 2-8). Weight gain, feed intake, and energy intake were recorded during the gestation period. In the offspring, reflex parameters and physical development were evaluated during the lactation period and when they reached adolescence. Behavioral performance was evaluated in light-dark, open-field, and play behavior tests. In addition, biochemical parameters of the dams and the adolescent offspring were evaluated. The cafeteria diet during gestation altered maternal behavior and the onset of physical and neurodevelopmental landmarks and had an impact on emotional and play behavior in adolescent offspring. In conclusion, our results demonstrate that exposure to maternal consumption of a cafeteria diet during the gestation period can program developmental and behavioral courses in the offspring., (Copyright © 2018 ISDN. Published by Elsevier Ltd. All rights reserved.)

A new series of sixteen multifunctional N-benzyl-piperidine-aryl-acylhydrazones hybrid derivatives was synthesized and evaluated for multi-target activities related to Alzheimer's disease (AD). The molecular hybridization approach was based on the combination, in a single molecule, of the pharmacophoric N-benzyl-piperidine subunit of donepezil, the substituted hydroxy-piperidine fragment of the AChE inhibitor LASSBio-767, and an acylhydrazone linker, a privileged structure present in a number of synthetic aryl- and aryl-acylhydrazone derivatives with significant AChE and anti-inflammatory activities. Among them, compounds 4c, 4d, 4g and 4j presented the best AChE inhibitory activities, but only compounds 4c and 4g exhibited concurrent anti-inflammatory activity in vitro and in vivo, against amyloid beta oligomer (AβO) induced neuroinflammation. Compound 4c also showed the best in vitro and in vivo neuroprotective effects against AβO-induced neurodegeneration. In addition, compound 4c showed a similar binding mode to donepezil in both acetylated and free forms of AChE enzyme in molecular docking studies and did not show relevant toxic effects on in vitro and in vivo assays, with good predicted ADME parameters in silico. Overall, all these results highlighted compound 4c as a promising and innovative multi-target drug prototype candidate for AD treatment., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Here in, we report the preparation and evaluation of four 3-hydroxy-piperidine-N-benzyl-aryl-acylhydrazone derivatives (6a-d) for their potential antinociceptive activity. In the tail flick test, compounds 6a and 6d exhibited a significant increase in the latency time of the animals, in comparison to the control group. These two compounds also showed a significant increase in the nociceptive threshold from 1 to 6 h after treatment in the CCI neuropathic pain model. In both cases, the antinociceptive activity was blocked by naloxone, suggesting an opioid mechanism of action, but without sedative or motor coordination effects., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Previous studies have demonstrated that zymosan, a cell wall component of the yeast Saccharomyces cerevisiae, induces inflammation in experimental models. However, few studies have evaluated the potential of zymosan to induce sickness behavior, a central motivational state that allows an organism to cope with infection. To determine whether zymosan administration results in sickness behavior, mice were submitted to the forced swim (FST) and open field (OFT) tests 2, 6, and 24 h after treatment with zymosan (1, 10, or 100 mg/kg). Additionally, to evaluate the possible relationship between zymosan-induced sickness behavior and prostaglandin synthesis, mice were pretreated with the cyclooxygenase inhibitors indomethacin (10 mg/kg) and nimesulide (5 mg/kg) and the glucocorticoid drug dexamethasone (1 mg/kg). Zymosan induced time-dependent decreases in locomotor activity in the OFT, and an increase in immobility in the FST, and increased plasma levels of corticosterone at 2 h. Pretreatment with indomethacin, nimesulide, or dexamethasone blocked zymosan-induced behavioral changes in both the FST and OFT at 2 h post administration. These findings confirm previous observations that zymosan induces sickness behavior. Furthermore, our results provide new evidence that prostaglandin synthesis is necessary for this effect, as anti-inflammatory drugs that inhibit prostaglandin synthesis attenuated zymosan-induced behavioral changes.

Maternal separation is a widely accepted model for studying long-term behavioral changes produced by events during early life and its association with changes in pain sensitivity. Thus, our objective was to evaluate sensitivity to pain, under different stimuli in adult male and female rats that had undergone early life maternal separation. Animals were subjected to maternal separation from postnatal day (PND) 2-15. Maternal behavior and litter weight were evaluated during this period. Sensitivity to pain was assessed in offsprings during adulthood by exposing them to stimuli, including formalin (5%; 20μl), a hot plate, and the electronic von Frey test, 4, 7, 10, and 24h after the administration of saline or Freund's complete adjuvant (CFA) injection. Maternal separation did not affect maternal behavior or litter weight during PND 2-15. However, experiencing maternal separation increased pain sensitivity in the rats subjected to formalin by increasing number of flinches and licking time Further, females appeared more sensitive than males to thermal stimuli, as they showed a decrease in latency in the hot plate test. In this test, male and female offsprings that were exposed to early life maternal separation and received the CFA injection also showed a reduction in latency to react to the painful stimuli. In the von Frey test, there was a reduction in withdrawal threshold in maternal separation animals injected with CFA, thus demonstrating a greater sensitivity to the mechanical stimuli. In conclusion, experiencing early life maternal separation increased pain sensitivity in adult offsprings. Thus, our data are important to understand the impact of environmental influences, such as stressful life events during critical developmental periods, on pain vulnerability., (Copyright © 2017 ISDN. Published by Elsevier Ltd. All rights reserved.)

Objective: The aim of this study was to evaluate the effects of protein malnutrition during pregnancy on maternal behavior, on the early behavior in pups by ultrasonic vocalizations (USVs) emission, and on the behavior of offspring in adulthood in an elevated T-maze., Methods: Pregnant female rats were fed a normal protein-powdered diet (22% casein; control) or a low-protein (hypoproteic) diet (6% casein; protein restriction) during the first 2 weeks of pregnancy. On the fifth postpartum day (PND5), the number of USV was rated. On PND7, maternal behavior was assessed. Male offspring in adulthood were evaluated for behavioral performance in an elevated T-maze., Results: Our results demonstrated that a hypoproteic diet during early pregnancy increased the maternal behavior, increased the number of USV by pups, and reduced the inhibitory avoidance responses in an elevated T-maze during adulthood. In addition, there was a reduction in weight gain of rats during pregnancy and of offspring during lactation., Conclusion: In conclusion, the data found in our study suggest that the increase in USV emitted by pups due to hypoproteic diet during pregnancy accentuated maternal behavior. In addition, an increase in maternal care promoted the reduction in anxiety-like behavior in adult male offspring.

The involvement of purinergic signaling in several brain functions has been recognized, but the modulation on maternal behavior by the purinergic system is not established, even though there are functional interactions between the purinergic and oxytocinergic systems. Therefore, the aim of our study was to investigate whether central administration of P2 receptor antagonists affected the maternal behavior of lactating rats and c-Fos immunoreactivity in the forebrain. On day 7 of lactation, female rats were treated with vehicle (5μL; i.c.v.), suramin (9.4-75.0μg/5μL; i.c.v.) or PPADS (9.4-75.0μg/5μL; i.c.v.) 30min before the experiment began. The maternal behavior was evaluated during the 30min following suramin or PPADS administration. In addition, c-Fos-positive nuclei were counted in the medial preoptic area (MPOA) and in the bed nucleus of the stria terminalis (BNST), and neurons that were double-labeled for c-Fos/OT were counted in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus of lactating rats. The results show that P2 receptor antagonists decreased maternal care and decreased neuronal activation in the MPOA and BNST and activation of oxytocinergic neurons in hypothalamic nuclei. Our results indicate that the purinergic system modulates maternal behavior and neuronal activation induced by suckling during lactation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Dipyrone (metamizole), a powerful drug, is widely used as an analgesic and antipyretic; however, the safety of its use during lactation and the potential impact on the offspring are not well established. This study aimed to determine the effect of maternal dipyrone treatment during lactation on offspring development and emotional behavior and on the dam's maternal behavior. Hence, on postnatal day (PND) 2, drinking water only or drinking water containing dipyrone at doses of 100, 300, and 500mg/kg/day, were offered to lactating mothers up to PND9. Thereafter, all mice were provided regular drinking water. On PND2, all litters were culled to 8 pups (4 males and 4 females). Maternal behavior was evaluated at PND3, 6, 9, and 12, and at PND7 we evaluated locomotor activity in the open field. Reflex parameters and physical development of offspring were evaluated during lactation. At PND7, analysis of ultrasonic vocalization (USV) was performed. When the animals reached adolescence, we evaluated their performance in the open field, elevated plus maze (EPM), and marble burying. Our data demonstrated that maternal dipyrone treatment during lactation not only altered maternal behavior and the onset of physical and neurodevelopmental landmarks but also had an impact on anxiety-like behavior in offspring., (Copyright © 2017 ISDN. Published by Elsevier Ltd. All rights reserved.)

Several studies have investigated the effects of artificial litter size adjustment on offspring development. Social play behavior is important for neurobehavioral development and is impaired in several developmental psychiatric disorders. This study therefore investigated the effect of litter size on play behavior in adolescent rats. On postnatal day (PND) 2, litters were adjusted to a small litter (SL) size of 3 pups per dam or normal litter (NL) size of 12 pups per dam. Maternal behaviors scored daily during the first week of lactation (PND2-8) revealed that arched nursing and pup licking behaviors were increased in dams with SLs versus those with NLs. SL offspring exhibited accelerated weight gain and advanced development of physical landmarks and reflexes, possibly due to overnutrition. Social isolation lasting 3.5h prior to social play behavioral testing produced a higher frequency and duration of pouncing, pinning, sniffing, and grooming in both male and female offspring. However, male SL offspring exhibited a lower frequency of pouncing and pinning when compared with male NL offspring, while no litter size-dependent differences were observed in social behaviors unrelated to play (sniffing and grooming). These findings identify a possible sexually dimorphic influence of litter size in the development of social behavior. Given that social behaviors such as play behavior are vital for normal cognitive and social development, these findings have important implications for developmental and neuropsychiatric research., (Copyright © 2016 ISDN. Published by Elsevier Ltd. All rights reserved.)

Maternal alcohol use during pregnancy adversely affects prenatal and postnatal growth and increases the risk of behavioral deficits. The aim of the present study was to evaluate the effect of prenatal exposure to a moderate dose of alcohol on sexual motivation during adulthood. Rats were prenatally exposed to ethanol by feeding pregnant dams a liquid diet containing 25% ethanol-derived calories on days 6 through 19 of gestation. The controls consisted of pair-fed dams (receiving an isocaloric liquid diet containing 0% ethanol-derived calories) and dams with ad libitum access to a liquid control diet. The sexual motivation of offspring was evaluated during adulthood. The results revealed that the male and female pups of dams treated with alcohol exhibited reduced weight gain, which persisted until adulthood. Both male and female adult animals from dams that were exposed to alcohol showed a reduction in the preference score in the sexual motivation test. Taken together, these results provide evidence of the damaging effects of prenatal alcohol exposure on sexual motivation responses in adulthood., (Copyright © 2016 Elsevier Inc. All rights reserved.)

This study investigated behavioral responses to an immune challenge among animals with fructose-induced metabolic disorders. Adult male Wistar rats were provided either water or a fructose solution (10%) for 5 weeks. Sickness behaviors were assessed 2h following the injection of either a lipopolysaccharide (LPS) or vehicle. The rats were subjected to an open field test, a social interaction test, a food intake test and a fever evaluation. Cytokine expression was assessed in both adipose tissue and hypothalamus samples. The neural response was assessed in the forebrain immunohistochemistry for c-Fos. Compared with the control group, the fructose diet induced dyslipidemia and significantly higher plasma total cholesterol, HDL-cholesterol, triglyceride, and glucose levels as well as both epididymal and retroperitoneal adiposity. Furthermore, in response to LPS (1 mg/kg), the rats subjected to a fructose diet exhibited exacerbated sickness behaviors and accentuated febrile responses. LPS induced Fos protein expression in several areas of the brains of the control rats; however, higher numbers of Fos-positive cells were observed in the brains of the rats that were fed a fructose diet. Moreover, larger increases in cytokine expression were observed in both the hypothalamus and the adipose tissue of the obese rats compared with the control rats in response to LPS. In this study, fructose diets played an important role in both the induction of metabolic disorders and the modulation of sickness behaviors in response to an immunological challenge, most likely through the induction of cytokines in the hypothalamus., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Administration of a high dose of chronic peripheral corticosterone during the postpartum period has been shown to lead to reduced maternal care, but the interference of acute corticosterone, mimicking a situation of acute stress, on maternal behavior has not been well established. Therefore, the aim of our study was to investigate the influence of acute central corticosterone on behavioral and neuroendocrine responses during lactation. On day 7 of lactation, female rats were treated with vehicle (5 μL; i.c.v.) or corticosterone (10 ng/5 μL; i.c.v.) 30 min before the start of the experiment. To evaluate maternal behavior, the pups were returned to the side of their home cages opposite the previous nest, and the resulting behavior of the lactating rats was filmed for the next 30 min. Plasma levels of oxytocin and the amount of milk consumed by the pups were evaluated 15 min after the onset of suckling. In addition, the double-labeled c-Fos/oxytocin neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) and c-Fos immunoreactivity in medial preoptic area (MPOA) neurons were quantified for each lactating rat. Corticosterone decreased maternal care, plasma oxytocin levels, milk consumption by the pups, the activation of oxytocinergic neurons in hypothalamic nuclei, and c-Fos immunoreactivity in MPOA neurons. Our results indicate that changes in the behavioral responses of lactating rats treated with corticosterone may be related to disruption of the neuroendocrine control of oxytocin secretion., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Dipyrone is a non-steroidal anti-inflammatory drug used primarily as an analgesic and antipyretic. Some hypothesize that dipyrone activity can modulate other pathways, including endocannabinoid signalling. Thus, the aim of the present study was to evaluate the possible role of endocannabinoids in mediating dipyrone activity. This study is based on the tetrad effects of cannabinoids, namely an antinociceptive and cataleptic state, hypolocomotion and hypothermia. Dipyrone (500 mg/kg, i.p.) treatment decreased locomotor activity, increased the latency to a thermal analgesic response and induced a cataleptic and hypothermic state. These reactions are similar to the tetrad effects caused by the cannabinoid agonist WIN 55,212-2 (3 mg/kg, i.p.). The cannabinoid CB1 receptor antagonist AM251 (10 mg/kg, i.p.) reversed the effects of dipyrone on locomotor activity, the cataleptic response and thermal analgesia. Both AM251 (10 mg/kg, i.p.) and the transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine (10 mg/kg, i.p.) accentuated the reduction in body temperature caused by dipyrone. However, the CB2 receptor antagonist AM630 did not alter the hypothermic response to dipyrone. These results indicate involvement of the endocannabinoid system, especially CB1 receptors, in the analgesic and cataleptic effects of dipyrone, as well as hypolocomotion. However, cannabinoid receptors and TRPV1 were not involved in the hypothermic effects of dipyrone. We hypothesize that the mechanism of action of dipyrone may involve inhibition of cyclo-oxygenase and fatty acid amide hydrolase, which together provide additional arachidonic acid as substrate for endocannabinoid synthesis or other related molecules. This increase in endocannabinoid availability enhances CB1 receptor stimulation, contributing to the observed effects., (© 2014 Wiley Publishing Asia Pty Ltd.)

It has been shown that the endocannabinoid system is involved in the neurohypophyseal hormone secretion produced by exposure to several different stimuli; however, the influence of this system on neuroendocrine responses during lactation is unclear. Therefore, the aim of our study was to investigate the influence of an acute peripheral administration of WIN55,212-2 (cannabinoid receptor agonist) on behavioral and neuroendocrine responses during lactation. On day 6 of lactation, female rats were treated with vehicle or WIN55,212-2 30 min before the start of our experiments. To evaluate maternal behavior, the pups were returned to their home cages to the side of the cage opposite the previous nest, and the resulting behavior of the lactating rats was recorded for the next 30 min. Aggressive behavior was evaluated for 10 min following the placement of an intruder male rat in the home cage. The plasma level of oxytocin and the amount of milk consumption by the pups were evaluated 15 min after the onset of suckling. In addition, double-labelled c-Fos/oxytocin neurons in the medial magnocellular subdivision of the paraventricular nucleus and in the supraoptic nucleus were quantified for each lactating rat. The results show that WIN decreased maternal care, decreased aggressive behaviors, suppressed maternal anxiolysis, decreased plasma oxytocin levels and milk consumption by pups and decreased activation of oxytocinergic neurons in hypothalamic nuclei. Our results indicate that the changes in the behavioral responses of lactating rats treated with WIN maybe can be related to disruption in the neuroendocrine control of oxytocin secretion., (Copyright © 2014 Elsevier B.V. All rights reserved.)

In lactating rats, maternal behavior consists of several integrated elements designed to promote care and nutrition of the offspring to ensure their survival. Given previous studies showing the role of the brain endocannabinoid system in maternal behavior, the objective of this work was to determine which changes in maternal care occur during continuous intracerebroventricular infusion of a cannabinoid receptor agonist (WIN 55,212-2). Maternal behavior was scored daily in 4 sessions of 72 min each (3 during the light phase and 1 during the dark phase). During drug infusion, the results indicated decreased time spent by the mother licking pups and an increase in feeding time. To determine the extent to which variations in maternal care during the neonatal period affect offspring later in life, we evaluated possible changes in the fear response of offspring once they reached adulthood. Offspring of mothers treated with a cannabinoid agonist presented a lower latency for freezing behavior and increased time spent freezing in a fear test. These results show that treatment with a cannabinoid agonist decreases maternal care, mainly licking, in lactating rats and is associated with increased fear responses in offspring later in life., (Copyright © 2013 Elsevier B.V. All rights reserved.)

It has been shown that glucocorticoids can modulate oxytocin (OT) secretion and disrupt maternal behaviour. Because the CB1 receptor (CB1R) has been implicated in some rapid glucocorticoid-induced actions, the present study aimed to evaluate the possible involvement of CB1Rs in maternal behaviour and neuronal activation during lactation. For this purpose, lactating female rats were pre-treated with dexamethasone (DEX) or saline, followed by treatment with AM251, a CB1R antagonist, or vehicle 90 min later. All of the experiments were performed 30 min after the administration of AM251 or vehicle. To evaluate maternal behaviour, the pups were returned to their home cages to the side of the cage opposite the previous nest after 12 h of separation and were filmed for the next 30 min. Aggressive behaviour was evaluated for 10 min following the placement of a male rat in the home cage. For the evaluation of behavioural performance, lactating rats were subjected to a T-maze and open-field tests. The amount of weight gained by the pups was evaluated 15 min after the onset of suckling to determine the amount of milk that they had obtained from the dam. In the central nervous system of lactating rats, c-Fos-positive nuclei were counted in the medial preoptic area, in both the ventral (v) and dorsal (d) parts of the median preoptic nucleus and in the bed nucleus of the stria terminalis (BNST). The number of neurons that were double-labelled for c-Fos/OT was counted in the medial magnocellular subdivision of the paraventricular nucleus, in the periventricular hypothalamic nucleus and in the supraoptic nucleus of the lactating rats. The results show that DEX had the following effects: (1) decreased the amount time the dam spent licking the pups, the amount of time the dam spent in an arched-nursing position and full maternal behaviour; (2) increased the latency to the first attack and decreased front attacks; (3) increased anxiety-like behaviour; and (4) decreased weight gain in the pups. In addition, DEX decreased neuronal activation in all of the investigated hypothalamic and forebrain areas. AM251 administration reversed these parameters, indicating that the behavioural effects and neuronal responses produced by DEX in lactating rats are likely to be mediated by CB1Rs.

Sickness behavior appears to be the expression of a central motivational state that reorganizes an organism's priorities to cope with infectious pathogens. To evaluate the possible participation of nitric oxide (NO) in lipopolysaccharide-induced sickness behaviors, mice were submitted to the forced swim test (FST), open field test and dark-light box test. Food intake and corticosterone plasma levels were evaluated. Lipopolysaccharide (LPS, 100 μg/kg; i.p.) administration increased the time spent floating in the FST and decreased locomotor activity in the open field. Indeed, treatment with LPS decreased the total number of transitions between the dark and light compartments of the apparatus. In addition, LPS reduced food intake and increased corticosterone levels. Pretreatment with L-NAME (30 mg/kg; i.p.) or aminoguanidine (50mg/kg; i.p.) accentuated the behavioral changes induced by LPS in the FST, open field and light-dark box tests as well as induced an increment in hypophagia and in corticosterone levels. These findings confirm previous observations that have reported LPS-induced sickness behaviors. In addition, they provide evidence that the synthesis of NO modulates changes in depressive-like and exploratory behaviors in mice, which is supported by the fact that NO synthase inhibitors also attenuate LPS-induced behavioral changes. In addition, the present study suggests that NO may have a protective role, acting in an inhibitory feedback manner to limit LPS-induced sickness behavior., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Lactation is associated with profound behavioral and physiological adaptations in the mother that support reproductive success. These include neuroendocrine adaptation to stress that reduces anxiety-related behavior and emotional responsiveness. However, the way in which endogenous glucocorticoids secreted during immunological challenge influence the neuroendocrine system and behavior of lactating rats is not well understood. To evaluate the effects of glucocorticoids on the neuroendocrine response to suckling, maternal behavior and maternal anxiolysis, lactating female rats were treated with vehicle or metyrapone prior to the administration of a saline solution or a lipopolysaccharide (LPS) solution. LPS treatment reduced oxytocin and prolactin secretion during suckling and affected a variety of maternal behaviors, such as increasing the latency of retrieval a new nest, decreasing the number of pups gathered to the nest, increasing the latency of retrieving the first pup and decreasing the percentage of time spent in the arched-nursing position. In addition, the LPS treatment increased the baseline and avoidance latencies in an elevated T-maze. Pretreatment with metyrapone counteracted effects produced by LPS, including hormonal and behavioral responses in lactating rats. Taken together, our results indicate that stress induced by LPS treatment attenuates the neuroendocrine response to suckling, followed by disruption of maternal behavior and maternal anxiolysis in lactating female rats. These changes may be due to corticosterone release, as evidenced by the reversal of behavioral and neuroendocrine responses after immunological challenge in lactating rats that had been pretreated with metyrapone., (Copyright © 2013 S. Karger AG, Basel.)

Lactating female rats show a maternal anxiolysis signal, which is part of the behavioral pattern that develops post-partum and seems to be related to hormonal changes during lactation. Assuming that glucocorticoids modulate prolactin and oxytocin secretion, we evaluated the effect of dexamethasone on behavior responses of fear and anxiety in lactating rats. For this study, the non-lactating and lactating rats were submitted to an elevated T-maze and open field tests. In the elevated T-maze, the lactating rats showed a decrease in inhibitory avoidance and an increase in the escape time when compared with the non-lactating group. The lactating rats that had been treated with dexamethasone showed increased initial avoidance latency when compared with lactating rats treated with vehicle. The same result was found in the subsequent repetitions (avoidance 1 and 2). In addition, there was a reduction in one-way escape time for the lactating rats that were treated with dexamethasone. The lactating rats treated with vehicle had increase of number central entries, and consequently, the anti-thigmotactic effect increased relative to non-lactating rats. Thus, lactating rats showed a reduced emotional responsiveness as evaluated by elevated T-maze and open field tests, which characterizes maternal anxiolysis. In addition, it could be concluded that the dexamethasone impairs maternal anxiolysis in lactating female rats., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

The influence of glucocorticoids on the neuroendocrine system and behavior of lactating rats is not well known. To evaluate the effects of glucocorticoids on the neuroendocrine system and maternal and aggressive behavior, lactating female rats were treated with dexamethasone or vehicle for 2 h before experiments. Blood samples were collected 15 min after the beginning of suckling to evaluate hormonal changes. To evaluate the maternal behavior of lactating rats, eight pups were placed in their home cages on the side opposite the location of the previous nest, and the resulting behavior of the lactating rat was filmed for 30 min. Aggressive behavior was evaluated by placing a male rat (intruder) in the home cage. Dexamethasone treatment reduced oxytocin and prolactin secretion during lactation and reduced pup weight gain. Relative to control treatment, dexamethasone treatment also adversely affected a variety of maternal behaviors; it increased the latency to build a new nest, decreased the number of pups gathered to the nest, increased the latency to retrieve the first pup, and decreased the percentage of time spent in the arched-nursing position. Dexamethasone treatment, compared with control, also reduced aggressive behavior, as evidenced by an increase in the latency to the first attack, a reduction in the number of front and side attacks, and a decrease in lateral threat and biting. Taken together, our results suggest dexamethasone treatment in lactating rats disrupts prolactin and oxytocin secretion, and this is followed by an attenuation of maternal and aggressive behavior.

Aim of the Study: Byrsonima intermedia is commonly used for its antiseptic, antimicrobial, and anti-inflammatory properties in the treatment of diarrhea and dysentery in Brazilian folk medicine. The purpose of this study was to examine the anti-inflammatory activity of the aqueous extract and fractions of Byrsonima intermedia leaves., Materials and Methods: Rats with carrageenan-induced paw edema and fibrovascular tissue growth, which was induced by subcutaneous implantation of a cotton pellet, were used as acute and chronic animal models of inflammation to investigate the anti-inflammatory effects of the aqueous extract and the individual ethyl acetate (EtOAc) and aqueous fractions of Byrsonima intermedia and catechin. High-performance liquid chromatography (HPLC) was used to determine the fingerprint chromatogram of the aqueous extract and fractions of Byrsonima intermedia., Results: The crude aqueous extract at test doses of 30-300 mg/kg p.o. clearly demonstrated anti-inflammatory effects by reducing carrageenan-induced paw edema, as did the ethyl acetate (100mg/kg) and aqueous fractions (30-100mg/kg). In the chronic inflammation rat animal model with fibrovascular tissue growth, the aqueous extract of Byrsonima intermedia (BiAE) at doses of 30-300 mg/kg and the individual EtOAc and aqueous fractions at doses of 30-100mg/kg and catechin significantly reduced the formation of granulomatous tissue. The presence of catechin and phenolic compounds in the extract and fractions of Byrsonima intermedia was confirmed using HPLC., Conclusion: BiAE and the individual EtOAc and aqueous fractions of Byrsonima intermedia exhibited chronic and acute anti-inflammatory efficacy in rats, which supports previous claims of its use in traditional medicine., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

7-Epiclusianone, a natural prenylated benzophenone, was extracted from Garcinia brasiliensis Planch. & Triana (Clusiaceae), a native plant commonly known as bacupari and used in traditional Brazilian medicine for the treatment of inflammatory diseases. As a result of the wide spectrum of biological activities attributed to polyisoprenylated benzophenones, the aim of this study was to evaluate the analgesic and anti-inflammatory effects of 7-epiclusianone using two animal models. Carrageenan-induced paw oedema and peritonitis were used to investigate the anti-inflammatory activity of 7-epiclusianone in rats. The acetic acid-induced writhing, formalin and hot-plate tests were used to investigate its antinociceptive activity in mice. At test doses of 5, 10 and 15 mg/kg p.o., 7-epiclusianone had an anti-inflammatory effect as demonstrated by the reduction of paw oedema induced by carrageenan and the inhibition of leukocyte recruitment into the peritoneal cavity. At the same doses, 7-epiclusianone inhibited nociception induced by an intraperitoneal injection of acetic acid, observed by the decrease in the number of writhing episodes. Additionally, 7-epiclusianone decreased licking time caused by a subplantar injection of formalin. Moreover, the hot plate test produced a significant increase in latency reaction, demonstrating an antinociceptive effect. The experimental data demonstrated that the polyisoprenylated benzophenone 7-epiclusianone has remarkable anti-inflammatory and antinociceptive activities., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Byrsonima intermedia A. Juss. is popularly known as "murici pequeno" and is native to the Brazilian Cerrado. This species has been used as an antimicrobial, anti-hemorrhagic, anti-diarrheal and anti-inflammatory. Nevertheless, scientific information regarding Byrsonima intermedia is limited; there are no reports related to its possible anti inflammatory and antinociceptive effects. This study employed in vivo inflammatory and nociceptive models to evaluate the scientific basis for the traditional use of Byrsonima intermedia., Materials and Methods: Carrageenan-induced paw edema, peritonitis and fibrovascular tissue growth induced by s.c. cotton pellet implantation tests were used to investigate the anti-inflammatory activity of Byrsonima intermedia aqueous extract (BiAE) in rats. Mechanical nociceptive paw, formalin and hot plate tests were used to evaluate the antinociceptive activity in mice. High-performance liquid chromatography (HPLC), phytochemistry screening and determination of total phenolics and flavonoids were used to determine the chemical profile of the BiAE., Results: BiAE at test doses of 30-300 mg/kg p.o. clearly demonstrated anti-inflammatory effects by reduced carrageenan-induced paw edema, by inhibited leukocyte recruitment into the peritoneal cavity and, in the model of chronic inflammation, by using the cotton pellet-induced fibrovascular tissue growth in rats. The extracts at test doses of 30-300 mg/kg p.o. clearly demonstrated antinociceptive activity in all tests. Administration of the opioid receptor antagonist naloxone completely inhibited the antinociceptive effect induced by BiAE (100 mg/kg)., Conclusion: BiAE markedly exhibits anti-inflammatory action in rats and antinociceptive activity in mice. Thus, it may be useful in the treatment of inflammatory hyperalgesic disorders, which supports previous claims of its traditional use., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Aim of the Study: Emilia sonchifolia (L.) DC. (Asteraceae) is a medicinal plant traditionally used in Brazilian folk medicine to treat asthma, fever, cuts, wounds and rheumatism. This study was conducted to establish the antinociceptive properties of hydroethanolic extract from aerial parts of Emilia sonchifolia in mice using chemical and thermal models of nociception., Materials and Methods: To evaluate the antinociceptive effect of Emilia sonchifolia hydroethanolic extract (EsHE) administered by oral route, peripheral (acetic acid-induced abdominal writhing and formalin), spinal (tail flick) and supra-spinal (hot plate) behavioral models of acute pain were used. High-performance liquid chromatography (HPLC) was used to determine the fingerprint chromatogram of the EsHE., Results: The EsHE at test doses of 100 and 300 mg/kg, p.o. clearly demonstrated antinociceptive activity in all tests. The extract had a stronger antinociceptive effect than morphine. Administration of the opioid receptor antagonist, naloxone, completely inhibited the antinociceptive effect induced by EsHE (100mg/kg). The presence of phenolic compounds in the extract of Emilia sonchifolia was confirmed using HPLC., Conclusion: The extract of Emilia sonchifolia markedly exhibits opioid-mediated anti-nociceptive activity action in mice. Thus, may be useful in the treatment of inflammatory hyperalgesic disorders, which supports previous claims of its traditional use., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Aim of the Study: Arrabidaea brachypoda (DC.) Bureau has been used to relieve general pain, painful joints and kidney stones in Brazilian folk medicine. Nevertheless, scientific information regarding this species is scarce; there are no reports related to its possible analgesic and anti-inflammatory effects. This study was aimed at evaluating the traditional use of Arrabidaea brachypoda root using in vivo inflammatory and nociceptive models., Materials and Methods: Carrageenan-induced paw edema, peritonitis and fibrovascular tissue growth induced by s.c. cotton pellet implantation were used to investigate the anti-inflammatory activity of Arrabidaea brachypoda roots ethanolic extract (AbEE) in rats. Formalin and acetic acid-induced writhing tests were used to investigate the antinociceptive activity in mice. High-performance liquid chromatography (HPLC) was used to determine the fingerprint chromatogram of AbEE., Results: The AbEE at test doses of 30-300 mg/kg p.o. demonstrated anti-inflammatory effects. AbEE reduced paw edema induced by carrageenan, inhibited leukocyte recruitment into the peritoneal cavity and, in the model of chronic inflammation using the cotton pellet-induced fibrovascular tissue growth in rats, significantly inhibited the formation of granulomatous tissue. The extracts at test doses of 30-300 mg/kg p.o. clearly demonstrated antinociceptive activity, except during the first phase of the formalin test. The presence of quercetin and phenolic compounds in the extract Arrabidaea brachypoda was confirmed using HPLC., Conclusion: Arrabidaea brachypoda ethanol extract markedly demonstrated anti-inflammatory action in rats and antinociceptive activity in mice, which supports the previous claims of traditional use., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Aim of the Study: In Brazilian folk medicine, the leaves of Garcinia brasiliensis are used to treat tumors, inflammation of the urinary tract and arthritis as well as to relieve pain. Nevertheless, scientific information regarding Garcinia brasiliensis is limited; there are no reports related to its possible anti-inflammatory and antinociceptive effects. This study employed in vivo inflammatory and nociceptive models to evaluate the scientific basis for the traditional use of Garcinia brasiliensis., Materials and Methods: Carrageenan-induced paw edema, peritonitis and fibrovascular tissue growth induced by s.c. cotton pellet implantation were used to investigate the anti-inflammatory activity of Garcinia brasiliensis ethanolic extract (GbEE) in rats. Formalin and acetic acid-induced writhing tests were used to investigate the antinociceptive activity in mice., Results: GbEE at test doses of 30-300 mg/kg p.o. clearly demonstrated anti-inflammatory effects by reduced paw edema induced by carrageenan, inhibited leukocyte recruitment into the peritoneal cavity, and in the model of chronic inflammation using the cotton pellet-induced fibrovascular tissue growth in rats, the GbEE significantly inhibited the formation of granulomatous tissue. The extracts at test doses of 30-300 mg/kg, p.o., clearly demonstrated antinociceptive activity, except for the first phase of the formalin test., Conclusion: GbEE markedly demonstrated anti-inflammatory action in rats and antinociceptive activity in mice, which supports previous claims of the traditional use of species of the Garcinia genus for inflammation and pain., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)