Creatine supplementation increases postnatal growth and strength and prevents overexpression of pro-inflammatory interleukin 6 in the hippocampus in an experimental model of cerebral palsy.

ABSTRACTObjectives: The aim of this study was thus to evaluate the effect of Cr supplementation on morphological changes and expression of pro-inflammatory cytokines in the hippocampus and on developmental parameters. Methods: Male Wistar rat pups were submitted to an experimental model of CP. Cr was administered via gavage from the 21st to the 28th postnatal day, and in water after the 28th, until the end of the experiment. Body weight (BW), food consumption (FC), muscle strength, and locomotion were evaluated. Expression of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α) were assessed in the hippocampus by quantitative real-time polymerase chain reaction. Iba1 immunoreactivity was assessed by immunocytochemistry in the hippocampal hilus. Results: Experimental CP caused increased density and activation of microglial cells, and overexpression of IL-6. The rats with CP also presented abnormal BW development and impairment of strength and locomotion. Cr supplementation was able to reverse the overexpression of IL-6 in the hippocampus and mitigate the impairments observed in BW, strength, and locomotion. Discussion: Future studies should evaluate other neurobiological characteristics, including changes in neural precursor cells and other cytokines, both pro- and anti-inflammatory.

Resveratrol Reduces Neuroinflammation and Hippocampal Microglia Activation and Protects Against Impairment of Memory and Anxiety-Like Behavior in Experimental Cerebral Palsy.

Cerebral palsy (CP) is a neurodevelopmental disorder characterized by motor and postural impairments. However, early brain injury can promote deleterious effects on the hippocampus, impairing memory. This study aims to investigate the effects of resveratrol treatment on memory, anxiety-like behavior, and neuroinflammation markers in rats with CP. Male Wistar rats were subjected to perinatal anoxia (P0-P1) and sensory-motor restriction (P2-P28). They were treated with resveratrol (10 mg/kg, 0.1 ml/100 g) or saline from P3-P21, being divided into four experimental groups: CS (n = 15), CR (n = 15), CPS (n = 15), and CPR (n = 15). They were evaluated in the tests of novel object recognition (NORT), T-Maze, Light-Dark Box (LDB), and Elevated Plus Maze (EPM). Compared to the CS group, the CPS group has demonstrated a reduced discrimination index on the NORT (p < 0.0001) and alternation on the T-Maze (p < 0.01). In addition, the CPS group showed an increase in permanence time on the dark side in LDB (p < 0.0001) and on the close arms of the EPM (p < 0.001). The CPR group demonstrated an increase in the object discrimination index (p < 0.001), on the alternation (p < 0.001), on the permanence time on the light side (p < 0.0001), and on the open arms (p < 0.001). The CPR group showed a reduction in gene expression of IL-6 (p = 0.0175) and TNF-α (p = 0.0007) and an increase in Creb-1 levels (p = 0.0020). The CPS group showed an increase in the activated microglia and a reduction in cell proliferation in the hippocampus, while CPR animals showed a reduction of activated microglia and an increase in cell proliferation. These results demonstrate promising effects of resveratrol in cerebral palsy behavior impairment through reduced neuroinflammation in the hippocampus.

Effectiveness of Polyphenols on Perinatal Brain Damage: A Systematic Review of Preclinical Studies.

Polyphenol supplementation during early life has been associated with a reduction of oxidative stress and neuroinflammation in diseases caused by oxygen deprivation, including cerebral palsy, hydrocephaly, blindness, and deafness. Evidence has shown that perinatal polyphenols supplementation may alleviate brain injury in embryonic, fetal, neonatal, and offspring subjects, highlighting its role in modulating adaptative responses involving phenotypical plasticity. Therefore, it is reasonable to infer that the administration of polyphenols during the early life period may be considered a potential intervention to modulate the inflammatory and oxidative stress that cause impairments in locomotion, cognitive, and behavioral functions throughout life. The beneficial effects of polyphenols are linked with several mechanisms, including epigenetic alterations, involving the AMP-activated protein kinase (AMPK), nuclear factor kappa B (NF-κB), and phosphoinositide 3-kinase (PI3K) pathways. To highlight these new perspectives, the objective of this systematic review was to summarize the understanding emerging from preclinical studies about polyphenol supplementation, its capacity to minimize brain injury caused by hypoxia-ischemia in terms of morphological, inflammatory, and oxidative parameters and its repercussions for motor and behavioral functions.

Dietary flavonoid kaempferol reduces obesity-associated hypothalamic microglia activation and promotes body weight loss in mice with obesity.

BACKGROUND: Obesity results from an unbalance in the ingested and burned calories. Energy balance (EB) is critically regulated by the hypothalamic arcuate nucleus (ARC) by promoting appetite or anorectic actions. Hypothalamic inflammation, driven by high activation of the microglia, has been reported as a key mechanism involved in the development of diet-induced obesity. Kaempferol (KF), a flavonoid-type polyphenol present in a large number of fruits and vegetables, was shown to regulate both energy metabolism and inflammation. OBJECTIVES: In this work, we studied the effects of both the central and peripheral treatment with KF on hypothalamic inflammation and EB regulation in mice with obesity. METHODS: Obese adult mice were chronically (40 days) treated with KF (0.5 mg/kg/day, intraperitoneally). During the treatment, body weight, food intake (FI), feed efficiency (FE), glucose tolerance, and insulin sensitivity were determined. Analysis of microglia activation in the ARC of the hypothalamus at the end of the treatment was also performed. Body weight, FI, and FE changes were also evaluated in response to 5µg KF, centrally administrated. RESULTS: Chronic administration of KF decreased ∼43% of the density, and ∼30% of the ratio, of activated microglia in the arcuate nucleus. These changes were accompanied by body weight loss, decreased FE, reduced fasting blood glucose, and a tendency to improve insulin sensitivity. Finally, acute central administration of KF reproduced the effects on EB triggered by peripheral administration. CONCLUSION: These findings suggest that KF might fight obesity by regulating central processes related to EB regulation and hypothalamic inflammation.

Effects of the Treatment with Flavonoids on Metabolic Syndrome Components in Humans: A Systematic Review Focusing on Mechanisms of Action.

Diets high in bioactive compounds, such as polyphenols, have been used to mitigate metabolic syndrome (MetS). Polyphenols are a large group of naturally occurring bioactive compounds, classified into two main classes: non-flavonoids and flavonoids. Flavonoids are distributed in foods, such as fruits, vegetables, tea, red wine, and cocoa. Studies have already demonstrated the benefits of flavonoids on the cardiovascular and nervous systems, as well as cancer cells. The present review summarizes the results of clinical studies that evaluated the effects of flavonoids on the components of the MetS and associated complications when offered as supplements over the long term. The results show that flavonoids can significantly modulate several metabolic parameters, such as lipid profile, blood pressure, and blood glucose. Only theaflavin and catechin were unable to affect metabolic parameters. Moreover, only body weight and body mass index were unaltered. Thus, the evidence presented in this systematic review offers bases in support of a flavonoid supplementation, held for at least 3 weeks, as a strategy to improve several metabolic parameters and, consequently, reduce the risk of diseases associated with MetS. This fact becomes stronger due to the rare side effects reported with flavonoids.

Maternal exposure to busulfan reduces the cell number in the somatosensory cortex associated with delayed somatic and reflex maturation in neonatal rats.

Busulfan is a bifunctional alkylating agent used for myeloablative conditioning and in the treatment of chronic myeloid leukemia due to its ability to cause DNA damage. However, in rodent experiments, busulfan presented a potential teratogenic and cytotoxic effect. Studies have evaluated the effects of busulfan on fetuses after administration in pregnancy or directly on pups during the lactation period. There are no studies on the effects of busulfan administration during pregnancy on offspring development after birth. We investigated the effects of busulfan on somatic and reflex development and encephalic morphology in young rats after exposure in pregnancy. The pregnant rats were exposed to busulfan (10 mg/kg, intraperitoneal) during the early developmental stage (days 12-14 of the gestational period). After birth, we evaluated the somatic growth, maturation of physical features and reflex-ontogeny during the lactation period. We also assessed the effects of busulfan on encephalic weight and cortical morphometry at 28 days of postnatal life. As a result, busulfan-induced pathological changes included: microcephaly, evaluated by the reduction of cranial axes, delay in reflex maturation and physical features, as well as a decrease in the morphometric parameters of somatosensory and motor cortex. Thus, these results suggest that the administration of a DNA alkylating agent, such as busulfan, during the gestational period can cause damage to the central nervous system in the pups throughout their postnatal development.

Perinatal serotonergic activity: A decisive factor in the control of food intake / Atividade serotoninérgica perinatal: um fator decisivo para o controle da ingestão alimentar

ABSTRACT The serotoninergic system controls key events related to proper nervous system development. The neurotransmitter serotonin and the serotonin transporter are critical for this control. Availability of these components is minutely regulated during the development period, and the environment may affect their action on the nervous system. Environmental factors such as undernutrition and selective serotonin reuptake inhibitors may increase the availability of serotonin in the synaptic cleft and change its anorectic action. The physiological responses promoted by serotonin on intake control decrease when requested by acute stimuli or stress, demonstrating that animals or individuals develop adaptations in response to the environmental insults they experience during the development period. Diseases, such as anxiety and obesity, appear to be associated with the body's response to stress or stimulus, and require greater serotonergic system action. These findings demonstrate the importance of the level of serotonin in the perinatal period to the development of molecular and morphological aspects of food intake control, and its decisive role in understanding the possible environmental factors that cause diseases in adulthood.

RESUMO O sistema serotoninérgico apresenta funções no controle de eventos biológicos fundamentais para o desenvolvimento adequado do sistema nervoso. A serotonina e o transportador de serotonina são indispensáveis para esta função de controle. A disponibilidade destes componentes é precisamente regulada durante o período de desenvolvimento, e podem sofrer interferências provindas do ambiente alterando sua ação sobre o sistema nervoso. A desnutrição, a inibição da recaptação da serotonina a partir de fármacos e mudanças na expressão de gênica do transportador de serotonina na gestação e lactação podem induzir o aumento de serotonina alterando sua ação anorexígena. As respostas fisiológicas desempenhadas pela serotonina no controle da ingestão exibem uma resistência quando requisitadas por estímulos ou estresses agudos, demonstrando que os animais ou indivíduos desenvolvem adaptações de acordo com as agressões ambientais sofridas no período de desenvolvimento. Patologias como, ansiedade e obesidade, parecem estar associadas à resposta do organismo a um estresse ou estímulo, necessitando de uma maior ação do sistema serotoninérgico. Estes achados demonstram a importância do conteúdo da serotonina no período perinatal ao desenvolvimento de aspectos moleculares e morfológicos do controle da ingestão alimentar, e sua função determinante para a compreensão das possíveis influências ambientais causadoras de patologias na vida adulta.

Active maternal phenotype is established before breeding and leads offspring to align growth trajectory outcomes and reflex ontogeny.

The main goals of this study were to classify dams according to the level of voluntary physical activity before breeding and during pregnancy/lactation and to evaluate the effects on growth trajectory and reflex ontogenesis of offspring. Voluntary physical activity was ranked by traveled distance, time and daily estimated calorie burned. Thirty-five female Wistar rats were classified as control (C, n=5), inactive (I, n=10), active (A, n=8) and very active (VA, n=12). During 30d before breeding, traveled distance, average speed, time and calorie burned were daily recorded for active and very active groups. Traveled distance was recorded each 2h every day of adaptation. Body weight, food intake and fasting glycemia were measured throughout the experiment. During lactation, litters were evaluated in terms of physical features and reflex ontogeny. VA showed a progressive increase in the traveled distance and time while A dams presented constant values. VA rats showed lower body weight and higher food intake. During pregnancy, both groups performed less than 1km/day. Pups from A and VA dams showed higher lateral-lateral axis of the skull, longitudinal axis, tail length, and anticipation of the pavilion and auditory canal opening, and erupting incisors. I, A and VA groups showed a delay of righting, cliff aversion and vibrissae placing reflexes. In conclusion, active maternal phenotype is established before breeding allowing mothers to fit ecological and influencing growth trajectory outcomes and reflex ontogeny of the offspring based on matrilineal experience.

Desnutrição perinatal e o controle hipotalâmico do comportamento alimentar e do metabolismo do músculo esquelético / Perinatal undernutrition and hypothalamic control of food intake and energy metabolism in the skeletal muscle

A deficiência de nutrientes durante os períodos críticos do desenvolvimento tem sido associada com maior risco para desenvolver obesidade e diabetes Mellitus na vida adulta. Um dos mecanismos propostos refere-se à regulação do comportamento alimentar e às alterações do metabolismo energético do músculo esquelético. Recentemente, tem sido proposta a existência de uma comunicação entre o hipotálamo e o músculo esquelético a partir de sinais autonômicos que podem explicar as repercussões da desnutrição perinatal. Assim, esta revisão tem como objetivo discutir as repercussões da desnutrição perinatal sobre o comportamento alimentar e o metabolismo energético muscular e a comunicação existente entre o hipotálamo e o músculo via sinais adrenérgicos. Foram utilizadas as bases de dados MedLine/PubMed, Lilacs e Bireme, com publicações entre 2000 e 2011. Os termos de indexação utilizados foram: feeding behavior, energy metabolism, protein malnutrition, developmental plasticity, skeletal muscle e autonomic nervous system. Concluiu-se que a desnutrição perinatal pode atuar no controle hipotalâmico do comportamento alimentar e no metabolismo energético muscular, e a comunicação hipotálamo-músculo pode favorecer o desenvolvimento de obesidade e comorbidades durante o desenvolvimento.

Undernutrition during the critical period of development has been associated with susceptibility to obesity and diabetes Mellitus in adulthood. One of the underlying mechanisms can be related with the relationship between the food intake and the metabolism of skeletal muscle. A communication between the hypothalamus and skeletal muscle has been recently proposed, which can explain the repercussion of perinatal undernutrition. Thus, this review aims mainly to discuss the repercussions of perinatal undernutrition on food intake and skeletal muscle metabolism by adrenergic signals. Articles published from 2000 to 2011 were searched in the Medline/Pubmed, Lilacs and Bireme databases using the following keywords: feeding behavior, energy metabolism, protein malnutrition, developmental plasticity, skeletal muscle and autonomic nervous system. In conclusion, perinatal undernutrition can alter the hypothalamic control of food intake and skeletal muscle metabolism. Additionally, communication between the hypothalamus and skeletal muscle can promote the development of obesity and associated diseases.

Efeitos do treinamento físico durante a gestação sobre a evolução ponderal, glicemia e colesterolemia de ratos adultos submetidos à desnutrição perinatal / Effects of physical training during pregnancy on body weight gain, blood glucose and cholesterol in adult rats submitted to perinatal undernutrition

A incompatibilidade entre a desnutrição perinatal e uma nutrição adequada durante o desenvolvimento aumenta o risco de aparecimento precoce de doenças não transmissíveis na vida adulta. Todavia, acredita-se que a atividade física materna possa atenuar estas consequências. O presente estudo teve como objetivo avaliar os efeitos do treinamento físico durante a gestação na evolução ponderal, circunferência abdominal, glicemia e colesterolemia de filhotes adultos submetidos à desnutrição perinatal. Ratas Wistar (n = 12) foram divididas em quatro grupos: controle (C, n = 3), treinada (T, n = 3), desnutrida (D, n = 3) e treinada desnutrida (T+D, n = 3). Durante a gestação e lactação, os grupos D e T+D receberam dieta baixa em proteína (8% caseína) e os grupos C e T receberam dieta normoproteica (caseína a 17%). O protocolo de treinamento físico moderado foi realizado em esteira ergométrica (cinco dias/semana, 60 min/dia, a 65% do VO2max) e iniciou quatro semanas antes da gestação. Na gestação, a duração e a intensidade do treinamento foram reduzidas (cinco dias/semana, 20 min/dia, a 30% do VO2max) até o 19º dia pré-natal. Após o desmame, os filhotes (C F = 9, T F = 9, D F = 7, T+D F = 9) receberam dieta padrão de biotério e foram avaliados aos 270 dias de idade. A circunferência abdominal (CA) foi avaliada relativa ao peso corporal. Para avaliação da glicemia e colesterolemia foi utilizado o método enzimático colorimétrico da glicose-oxidase/peroxidase e da colesterol-oxidase, respectivamente. Ratos do grupo D F apresentaram um maior ganho de peso corporal ao longo do crescimento, maiores valores de CA, glicemia e colesterolemia quando comparados ao grupo C F. Para o grupo T+D F, o ganho de peso foi atenuado, e a CA, a glicemia e a colesterolemia foram normalizadas (p < 0,05). Esses resultados demonstram que o treinamento físico durante a gestação atenua os efeitos da desnutrição perinatal sobre alguns indicadores murinométricos e bioquímicos nos filhotes adultos.

The incompatibility of perinatal undernutrition and adequate nutrition during development increases the risk of early onset of non-communicable diseases in adulthood. However, it has been considered that maternal physical activity may attenuate these effects. This study aimed to evaluate the effects of physical training during pregnancy on body weight gain, waist circumference, glycaemia and cholesterolemia in adult offspring submitted to perinatal undernutrition. Female Wistar rats (n = 12) were divided into four groups: control (C, n = 3), trained (T, n = 3), undernourished (D, n = 3) undernourished and trained (T+D, n = 3). During gestation and lactation, D and T+D groups were fed a low protein diet (8% casein) and C and T groups fed a normal protein diet (17% casein). The protocol of moderate physical training was performed on a treadmill (5 days/week, 60 min/day, at 65% of VO2max) and began 4 weeks before pregnancy. At pregnancy, the duration and intensity of training were reduced (5 days/week, 20 min/day, at 30% VO2max) until the 19th prenatal day. At weaning, male pups (CP = 9, TP = 9, DP = 7, T+DP = 9) received standard diet and evaluations took place at 270 days old. Abdominal circumference (AC) was evaluated in relation to body weight. Enzymatic colorimetric method glucose-oxidase/peroxidase and cholesterol-oxidase was used to evaluate fasting glycaemia and cholesterolemia, respectively. Rats from DP group showed high body weight gain during growth, values of CA, glycaemia and cholesterolemia when compared to CP. Concerning the T+DP group,body weight gain was attenuated, and the CA, glycaemia and cholesterolemia were normalized (p<0.05). These results demonstrate that physical training during pregnancy reduces the effects of perinatal undernutrition on some murinometric and biochemical indicators of adult offspring.

Maternal low-protein diet-induced delayed reflex ontogeny is attenuated by moderate physical training during gestation in rats.

We evaluated the effects of moderate- to low-intensity physical training during gestation on reflex ontogeny in neonate rats whose mothers were undernourished. Virgin female Wistar rats were divided into four groups as follows: untrained (NT, n 7); trained (T, n 7); untrained with a low-protein diet (NT+LP, n 7); trained with a low-protein diet (T+LP, n 4). Trained rats were subjected to a protocol of moderate physical training on a treadmill over a period of 4 weeks (5 d/week and 60 min/d, at 65 % of VO2max). After confirming the pregnancy, the intensity and duration of the exercise were reduced. Low-protein groups were provided with an 8 % casein diet, and controls were provided with a 17 % casein diet. Their respective offspring were evaluated (during the 10th-17th days of postnatal life) in terms of physical feature maturation, somatic growth and reflex ontogeny. Pups born to mothers provided with the low-protein diet during gestation and lactation showed delayed physical feature and reflex maturation and a deficit in somatic growth when compared with controls. However, most of these deficiencies were attenuated in pups of undernourished mothers undergoing training. In conclusion, physical training during gestation attenuates the effects of perinatal undernutrition on some patterns of maturation in the central nervous system during development.

Behavioral satiety sequence: an experimental model for studying feeding behavior: [review] / Sequência comportamental de saciedade: um modelo experimental para o estudo do comportamento alimentar: [revisão]

Feeding behavior is controlled by interactions between psychobiological and physiological systems. In rats, there is a sequence in the feeding behavior that is characterized by similar movements at the beginning and end of a meal, known as the behavioral satiety sequence. In the sequence, eating is followed by grooming and other activities, and ends with resting. The objective of this systematic review is to evaluate the use of the behavioral satiety sequence as an experimental model for the study of feeding behavior. A systematic search of the electronic databases MedLine, Lilacs, SciELO, Cochrane Library and PubMed was done from November 2007 to January 2008, using combinations of the keywords "behavioral," "satiety" and "sequence". Ninety articles were found and, of these, fifteen articles were selected for the review. The studies demonstrated the efficacy of using behavioral satiety sequence to evaluate the effects of some types of manipulations on feeding behavior. With this study method it was also possible to observe different factors that can interfere with feeding behavior, such as sedation, malaise or intake inhibition, by increasing satiety. Behavioral satiety sequence offers solid tools for gaining a better understanding of how treatment can influence feeding behavior.

O comportamento alimentar é controlado por interações entre sistemas psicobiológicos e fisiológicos. Em ratos, existe uma sequência no comportamento alimentar que é caracterizada por movimentos similares no início e no término de uma refeição, conhecida como sequência comportamental de saciedade. Na sequência, o ato de comer é seguido pela limpeza e outra atividades, terminando com o descanso. O objetivo dessa revisão sistemática é avaliar o uso da sequência comportamental de saciedade como um modelo experimental para o estudo do comportamento alimentar. Uma busca sistemática das bases de dados MedLine, Lilacs, SciELO, Biblioteca Cochrane e PubMed foi realizada, no período de novembro de 2007 a janeiro de 2008, usando combinações das palavras chaves "behavioral", "satiety" e "sequence". Noventa artigos foram encontrados e, desses, quinze artigos foram selecionados para a revisão. Os estudos mostraram a eficácia do uso da sequência comportamental de saciedade para a avaliação dos efeitos de alguns tipos de manipulações sobre o comportamento alimentar. Com esse método de estudo, também é possível observar diversos fatores que podem intervir no comportamento alimentar, assim como sedação, mal-estar ou inibição do consumo por aumento da saciedade. A sequência comportamental de saciedade oferece sólidas ferramentas para obter um entendimento melhor de como um tratamento pode influenciar o comportamento alimentar.

Efeito do treinamento físico e da desnutrição durante a gestação sobre os eixos cranianos de ratos neonatos / Effects of physical training and malnutrition during pregnancy on the skull axis of newborn rats

Nos períodos críticos de desenvolvimento do organismo, estímulos ambientais como o exercício físico e a dieta podem influenciar o fluxo placentário e o crescimento somático fetal. O objetivo do presente estudo foi avaliar as repercussões do treinamento físico e da desnutrição durante a gestação sobre os eixos cranianos de ratos neonatos. Ratos machos Wistar foram divididos de acordo com a manipulação de suas mães: não treinados controle (Cf, n = 25), treinados (Tf, n = 25), não treinados e desnutridos (Df, n = 25), treinados e desnutridos (TDf, n = 25). Mães treinadas (T e TD) foram submetidas a oito semanas de treinamento físico moderado antes e durante a gestação (60min/dia, cinco dias/sem a 65 por cento do VO2max). Mães desnutridas (D e TD) receberam dieta hipoproteica durante a gestação (8 por cento caseína) enquanto as nutridas (C e T) receberam dieta normoproteica (17 por cento caseína). No primeiro dia pós-natal foi verificado número de filhotes nascidos por ninhada, peso da ninhada e peso ao nascer, eixo látero-lateral do crânio (ELLC) e anteroposterior do crânio (EAPC), eixo longitudinal do corpo (EL) e comprimento da cauda (CC) de cada neonato. No terceito dia pós-parto, os encéfalos foram extraídos e pesados. Durante a gestação, as fêmeas dos grupos T e D apresentaram menor ganho de peso em comparação ao grupo C na terceira semana (C = 34,4 ± 1,3; T = 30,7 ± 0,60; D = 25,8 ± 0,78; TD = 29,9 ± 0,83). Os grupos desnutridos apresentaram menor peso ao nascer em relação aos seus respectivos controles (Cf = 6,3 ± 0,1; Tf = 6,3 ± 0,1; Df = 4,7 ± 0,07; TDf = 5,0 ± 0,06). O grupo Df apresentou as medidas do ELLC (Cf = 9,8 ± 0,06; Tf = 9,8 ± 0,05; Df = 9,2 ± 0,04; TDf = 9,6 ± 0,13) e EAPC (Cf = 18,1 ± 0,1; Tf = 18,2 ± 0,1; Df = 17,5 ± 0,1; TDf = 18,0 ± 0,2) menores comparadas aos filhotes controles. Com base nos resultados, pode-se concluir que a desnutrição no período fetal alterou o desenvolvimento somático enquanto o treinamento físico influenciou positiv...

In critical periods of body development, environmental stimuli such as physical exercise and diet may influence on placental flow and fetal somatic growth. The aim of this study was to evaluate the effects of physical training and malnutrition during pregnancy on the skull axis of newborn rats. Male Wistar rats were divided according to manipulation of their mothers: untrained control (Cf, n = 25), trained (Tf, n = 25), untrained and malnourished (Mf, n = 25), trained and malnourished (TMf, n = 25). Trained mothers (T and TM) were submitted to 8 weeks of moderate physical training before and during pregnancy (60min/day, 5 days/wk to 65 percent of VO2max). Malnourished mothers (M and TM) received a low protein diet during pregnancy (8 percent casein) while the nourished (C and T) were fed with normal diet (17 percent casein). On the 1st postnatal day, the number of pups born per litter, litter weight and birth weight, latero-lateral axis of skull (LLAS) and antero-posterior axis of skull (APAS), longitudinal axis of the body (LA) and length of tail (LT) of each neonate were verified. On the 3rd day after delivery, the brains were extracted and weighed. During pregnancy, the females of the T and M groups showed lower weight gain compared with group C at 3rd week (C = 34.4 ± 1.3, T = 30.7 ± 0.60, M = 25.8 ± 0.78, TM = 29.9 ± 0.83). The malnourished group had lower birth weight in relation to their respective controls (Cf = 6.3 ± 0.1, Tf = 6.3 ± 0.1, Mf = 4.7 ± 0.07; TMf = 5.0 ± 0.06). Group Mf presented measures of LLAS (Cf = 9.8 ± 0.06, Tf = 9.8 ± 0.05, Mf = 9.2 ± 0.04; TMf = 9.6 ± 0.13) and EAPC (Cf = 18.1 ± 0.1, Tf = 18.2 ± 0.1, Mf = 17.5 ± 0.1, TMf = 18.0 ± 0.2) lower compared to controls. Based on the results, it can be concluded that malnutrition during fetal period changed somatic development, while physical training positively influenced on the skull axis of the concepts.

Efeito do tratamento com triptofano sobre parâmetros do comportamento alimentar em ratos adultos submetidos à desnutrição neonatal / Effects of tryptophan on the eating behavior of adult rats with neonatal malnutrition

OBJETIVO: Investigou-se os efeitos do tratamento com triptofano sobre o consumo alimentar em ratos adultos, submetidos ou não a desnutrição precoce. MÉTODOS: Sessenta e quatro ratos Wistar machos foram divididos em nutridos (n=32, caseína=17 por cento) e desnutridos (n=32, caseína=8 por cento), de acordo com a dieta materna empregada no período de lactação. Após o desmame, todos os ratos receberam dieta com 23 por cento de proteína. Pesos corporais foram avaliados no sétimo, vigésimo primeiro e septuagésimo dias de vida. Aos setenta dias de idade, cada grupo nutricional foi dividido em subgrupos: Nutrido-Salina (n=16) e Nutrido-Triptofano (n=16), Desnutrido-Salina (n=16) e Desnutrido-Triptofano (n=16). Os grupos receberam diariamente 1,0mL/100g de triptofano, na dose de 50mg/kgP ou salina (0,9 por centoNaCl), durante 14 dias. Neste período foram realizados os estudos dos parâmetros do comportamento alimentar. Posteriormente obteve-se a média do consumo alimentar relativo e a média do ganho de peso relativo. As análises estatísticas foram feitas utilizando os testes t Student e ANOVA seguido de Tukey, com p<0,05. RESULTADOS: As ninhadas de mães alimentadas com dieta hipoproteica mantiveram pesos inferiores comparados com as ninhadas nutridas (p<0,01) até os setenta dias de vida. Os ratos nutridos tratados com triptofano (M=6,88, DP=0,05) reduziram a ingestão alimentar comparados aos nutridos salina (M=7,27, DP=0,08) (p<0,01). Contudo, não houve efeito sobre o ganho de peso. Entre os desnutridos nenhuma diferença foi encontrada. CONCLUSÃO: Nesse estudo, a restrição proteica neonatal alterou a evolução ponderal em ratos. Além disso, a desnutrição precoce tornou os ratos adultos resistentes aos efeitos inibitórios do triptofano sobre a ingestão alimentar.

OBJECTIVE: This study investigated the effects of tryptophan on the eating behavior of adult rats submitted or not to early malnutrition. METHODS: Sixty-four male Wistar rats were divided into nourished (n=32, casein=17 percent) and malnourished (n=32, casein=8 percent) according to the diet given to the dam during lactation. After weaning, all rats were fed a diet with a protein content of 23 percent. The rats were weighed on day 7, day 21 and day 70 after birth. On day 70 after birth, each nutritional group was divided into 4 subgroups: nourished-saline (n=16), nourished-tryptophan (n=16), malnourished-saline (n=16) and malnourished-tryptophan (n=16). The tryptophan groups were given 1.0mL/100g of tryptophan for 14 days, at a dosage of 50mg/kgw of body weight and the saline groups were given 1.0mL/100g of 0.9 percent NaCl, also for 14 days. The eating behavior parameters were assessed during this period. The mean relative food intake and mean relative weight gain were then determined. The statistical analyses were done by the Student's t-test and ANOVA, followed by the Tukey test, with p<0.05. RESULTS: During the first 70 days of life, pups from protein-malnourished damns remained lighter than pups from well-nourished damns (p<0.01). Well-nourished rats treated with tryptophan (M=6.88, SD=0.05) ate less than those given saline (M=7.27, SD=0.08) (p<0.01) but weight was unaffected. No difference was found for the malnourished rats. CONCLUSION: In this study, neonatal protein restriction affected weight gain in rats. Furthermore, early malnutrition made adult rats resistant to the inhibitory effects of tryptophan on food intake.

Perinatal malnutrition programs sustained alterations in nitric oxide released by activated macrophages in response to fluoxetine in adult rats.

OBJECTIVE: Nutritional restriction during lactation has long-term consequences on the functioning of neuroimmune systems. Receptors and transporter serotonin (5-HT) are present in macrophages and may influence their role. This study evaluated nitric oxide release by alveolar macrophages (AMs) in adult control rats and rats malnourished during lactation in response to different fluoxetine (FLX) concentrations and 5-HT(1A) and 5-HT(1B) agonists at different times. METHODS: Male Wistar rats were distributed into two groups according to maternal diet during lactation: a control group of 12 rats whose dams had received a 23% protein diet and a malnourished group of 12 rats whose dams had received an 8% protein diet. After weaning, all rats received a 23% protein diet. On the 90th day after birth, nitric oxide (NO) release kinetics was measured in supernatants of AMs cultured with FLX. The NO release following the adjunction of serotoninergic agonists was also quantified. RESULTS: The malnourished rats weighed less at weaning (control rats = 15.3 +/- 0.4 g, malnourished rats = 11.8 +/- 0.4 g); this difference persisted until 90 days of life (control rats = 355.4 +/- 8.6 g; malnourished rats = 267.8 +/- 7.9 g). In the presence of 10(-6)M FLX, NO release by AMs in control rats was lower. The addition of agonists did not interfere with NO release by AMs in control rats. NO release by AMs from malnourished rats was modified neither by FLX nor by agonists. As a consequence of malnutrition, there were lower numbers of cells and AMs in the bronchoalveolar lavage fluid, and cell viability and NO release by AMs were impaired. CONCLUSIONS: Nutritional manipulation in the perinatal period seems to interfere with the functional programming of macrophages; it also seems to affect their serotoninergic regulation through adulthood.

Perinatal undernutrition-induced obesity is independent of the developmental programming of feeding.

Protein or calorie restriction during gestation and/or suckling induces hyperphagia and increases the susceptibility to develop obesity, glucose intolerance and hypertension in adulthood. The mechanisms by which early nutrient restriction affects the normal physiological regulation of feeding as well as to what extent the metabolic programming of hyperphagia contributes to the long-term risk of obesity and insulin resistance remain, however, to be determined. Here the temporal pattern of food intake and the behavioural satiety sequence were investigated in the offspring of Sprague-Dawley rats fed a control (C) or a low-protein (LP) diet throughout pregnancy and lactation. During the first two months of their post-natal life, protein-restricted animals exhibited hyperphagia characterized by a delayed appearance of satiety, an increase in meal size and reduced latency to eat. Protein-restricted pups also exhibited an enhanced expression of the orexigenic peptides Agouti-related protein and neuropeptide Y and decreased hypothalamic levels of the anorexigenic peptide pro-opiomelanocortin. At 8 months, LP rats still consumed larger meals than their control counterparts but they ingested daily the same amount of food as control offspring and exhibited enhanced abdominal fat and increased levels of triglycerides and fatty acids in serum. These observations indicate that the hyperphagia observed in young LP rats results from a decreased action of negative feedback signals critical to meal termination and an enhanced function of the positive signals that initiate and maintain eating. These results also suggest that perinatal malnutrition programmes obesity through a mechanism independent of its effects on feeding behaviour.

Neonatal administration of fluoxetine did not alter the anxiety indicators, but decreased the locomotor activity in adult rats in the elevated plus-maze / Administração neonatal de fluoxetina não alterou os indicadores de ansiedade, mas diminuiu a atividade locomotora em ratos adultos no labirinto elevado em cruz

The objective of this study was evaluate the anxiety and locomotor activity (LA) in 52 Wistar adult male rats, being 26 treated with fluoxetine (10 mg/Kg - sc) in the neonatal period. These same rats received foot shock (FS) (1.6-mA - 2-s) in the 90th day. The anxiety and LA were appraised by plus-maze. The time spent in the open arms was used as anxiety index and the LA was measured by number of entries in closed arms (NECA) and the total of entries (TE). T-test was used with p<0.05 and expresses data in mean±SEM. There were reductions with the fluoxetine group in the NECA (2.35±0.33) and in the TE (3.96±0.61) compared to the controls (4.65±0.52) and (6.96±0.94). The neonatal administration of fluoxetine did not alter the anxiety, but reduced the LA in the animals that received FS.

O objetivo deste estudo foi avaliar a ansiedade e a atividade locomotora (AL) em 52 ratos Wistar adultos machos, sendo 26 tratados no período neonatal com fluoxetina (10 mg/Kg - sc) e no 90º dia, receberam estímulos elétricos nas patas (1,6-mA-2-s). A ansiedade e a AL foram avaliadas por meio do labirinto elevado em cruz. O tempo de permanência dos animais nos braços abertos (BA) foi utilizado como índice de ansiedade e a AL medida pelo número de entradas nos braços fechados (NEBF) e pelo total de entradas (TE) nos BA e BF. O teste t foi utilizado, com (p<0,05) e os dados apresentados em média±erro padrão. Os animais tratados reduziram o NEBF (2,35±0,33) e o TE (3,96±0,61) comparados a seus controles (4,65±0,52) e (6,96±0,94). A administração neonatal de fluoxetina não alterou a ansiedade, mas diminuiu a AL dos animais que receberam EE.

Neonatal exposure to citalopram, a serotonin selective reuptake inhibitor, programs a delay in the reflex ontogeny in rats / Exposição neonatal ao citalopram, um inibidor seletivo da recaptação de serotonina, programa retardo na ontogênese reflexa em ratos

Serotonin influences the growth and development of the nervous system, as well as its behavioral manifestations. The possibility exists that increased brain serotonin availability in young animals modulates their neuro-behavioral responses. This study investigated the body weight gain and reflex ontogeny of neonatal rats treated during the suckling period with two doses of citalopram (5 mg, or 10 mg/kg, sc, daily). The time of the appearance of reflexes (palm grasp righting, free-fall righting, vibrissa placing, auditory startle response, negative geotaxis and cliff avoidance) as well as the body weight evolution were recorded. In general, a delay in the time of reflex development and a reduced weight gain were observed in drug-treated animals. These findings suggest that serotoninergic mechanisms play a role in modulating body weight gain and the maturation of most reflex responses during the perinatal period in rats.

A serotonina influencia o crescimento e o desenvolvimento do sistema nervoso e sua expressão comportamental. O aumento da disponibilidade de serotonina no cérebro de ratos jovens parece modular as respostas neurocomportamentais. Neste estudo, foram investigados o ganho de peso corporal e a ontogênese dos reflexos em ratos neonatos, tratados diariamente, durante o período de aleitamento, com duas doses de citalopram (5 ou 10 mg/Kg de peso corporal, via subcutânea). Foram avaliados, o tempo de aparecimento dos reflexos (preensão palmar, endireitamento, colocação pelas vibrissas, resposta ao susto, geotáxico negativo e aversão ao precipício), e a evolução do peso corporal. Foi observado atraso no tempo de desenvolvimento de alguns reflexos e redução no ganho de peso corporal. Os achados em ratos sugerem que as alterações no ganho de peso corporal e na maturação dos reflexos são programadas, durante o período perinatal, com participação de mecanismos serotoninérgicos de modulação.

Perinatal protein restriction reduces the inhibitory action of serotonin on food intake.

Early malnutrition has been associated with a high risk of developing obesity, diabetes and cardiovascular diseases in adulthood. In animals, poor perinatal nutrition produces hyperphagia and persistent increased levels of serotonin (5-HT) in the brain. Inasmuch as 5-HT is directly related to the negative regulation of food intake, here we have investigated whether the anorexic effects of 5-HT are altered by protein malnutrition. Pregnant Sprague-Dawley rats were fed ad libitum either a control (20% protein) or a low-protein (8% protein) diet throughout pregnancy and lactation. At weaning, pups received a standard diet and at 35 days their feeding behaviour was evaluated after the administration of DL-fenfluramine (DL-FEN), an anorexic compound that blocks the reuptake of 5-HT and stimulates its release. Male offspring born to protein-restricted dams exhibited significantly decreased body weight and hyperphagia compared with controls. DL-FEN dose-dependently reduced the 1 h chow intake at the onset of the dark cycle in both control and undernourished rats. However, the hypophagic effects of DL-FEN were significantly attenuated in animals submitted perinatally to protein restriction. The stimulatory action of DL-FEN on c-fos immunoreactivity within the paraventricular nucleus of the hypothalamus was also decreased in low-protein-fed rats. Further pharmacological analysis with selective 5-HT(1B) and 5-HT(2C) receptor agonist showed that the reduced anorexic effects of 5-HT in malnourished animals were coupled to a desensitization of 5-HT(1B) receptors. These observations indicate that the hyperphagia associated with metabolic programming is at least partially related to a reduced regulatory function of 5-HT on food intake.