Neonatal kaempferol exposure attenuates impact of cerebral palsy model on neuromotor development, cell proliferation, microglia activation, and antioxidant enzyme expression in the hippocampus of rats.

OBJECTIVES: This study aims to assess the effect of neonatal treatment with kaempferol on neuromotor development, proliferation of neural precursor cells, the microglia profile, and antioxidant enzyme gene expression in the hippocampus. METHODS: A rat model of cerebral palsy was established using perinatal anoxia and sensorimotor restriction of hindlimbs during infancy. Kaempferol (1 mg/ kg) was intraperitoneally administered during the neonatal period. RESULTS: Neonatal treatment with kaempferol reduces the impact of the cerebral palsy model on reflex ontogeny and on the maturation of physical features. Impairment of locomotor activity development and motor coordination was found to be attenuated by kaempferol treatment during the neonatal period in rats exposed to cerebral palsy. Neonatal treatment of kaempferol in cerebral palsy rats prevents a substantial reduction in the number of neural precursor cells in the dentate gyrus of the hippocampus, an activated microglia profile, and increased proliferation of microglia in the sub-granular zone and in the granular cell layer. Neonatal treatment with kaempferol increases gene expression of superoxide dismutase and catalase in the hippocampus of rats submitted to the cerebral palsy model. DISCUSSION: Kaempferol attenuates the impact of cerebral palsy on neuromotor behavior development, preventing altered hippocampal microglia activation and mitigating impaired cell proliferation in a neurogenic niche in these rats. Neonatal treatment with kaempferol also increases antioxidant defense gene expression in the hippocampus of rats submitted to the cerebral palsy model.

(R)-ketamine attenuates neurodevelopmental disease-related phenotypes in a mouse model of maternal immune activation.

Infections during pregnancy are associated with an increased risk of neuropsychiatric disorders with developmental etiologies, such as schizophrenia and autism spectrum disorders (ASD). Studies have shown that the animal model of maternal immune activation (MIA) reproduces a wide range of phenotypes relevant to the study of neurodevelopmental disorders. Emerging evidence shows that (R)-ketamine attenuates behavioral, cellular, and molecular changes observed in animal models of neuropsychiatric disorders. Here, we investigate whether (R)-ketamine administration during adolescence attenuates some of the phenotypes related to neurodevelopmental disorders in an animal model of MIA. For MIA, pregnant Swiss mice received intraperitoneally (i.p.) lipopolysaccharide (LPS; 100 µg/kg/day) or saline on gestational days 15 and 16. The two MIA-based groups of male offspring received (R)-ketamine (20 mg/kg/day; i.p.) or saline from postnatal day (PND) 36 to 50. At PND 62, the animals were examined for anxiety-like behavior and locomotor activity in the open-field test (OFT), as well as in the social interaction test (SIT). At PND 63, the prefrontal cortex (PFC) was collected for analysis of oxidative balance and gene expression of the cytokines IL-1ß, IL-6, and TGF-ß1. We show that (R)-ketamine abolishes anxiety-related behavior and social interaction deficits induced by MIA. Additionally, (R)-ketamine attenuated the increase in lipid peroxidation and the cytokines in the PFC of the offspring exposed to MIA. The present work suggests that (R)-ketamine administration may have a long-lasting attenuation in deficits in emotional behavior induced by MIA, and that these effects may be attributed to its antioxidant and anti-inflammatory activity in the PFC.

Environmental Enrichment in Cancer as a Possible Tool to Combat Tumor Development: A Systematic Review.

This systematic review aims to evaluate the influence of environmental enrichment (EE) on oncological factors in experimental studies involving various types of cancer models. A comprehensive search was conducted in three databases: PubMed (161 articles), Embase (335 articles), and Scopus (274 articles). Eligibility criteria were applied based on the PICOS strategy to minimize bias. Two independent researchers performed the searches, with a third participant resolving any discrepancies. The selected articles were analyzed, and data regarding sample characteristics and EE protocols were extracted. The outcomes focused solely on cancer and tumor-related parameters, including cancer type, description of the cancer model, angiogenesis, tumor occurrence, volume, weight, mice with tumors, and tumor inhibition rate. A total of 770 articles were identified across the three databases, with 12 studies meeting the inclusion criteria for this systematic review. The findings demonstrated that different EE protocols were effective in significantly reducing various aspects of tumor growth and development, such as angiogenesis, volume, weight, and the number of mice with tumors. Furthermore, EE enhanced the rate of tumor inhibition in mouse cancer models. This systematic review qualitatively demonstrates the impacts of EE protocols on multiple parameters associated with tumor growth and development, including angiogenesis, occurrence, volume, weight, and tumor incidence. Moreover, EE demonstrated the potential to increase the rate of tumor inhibition. These findings underscore the importance of EE as a valuable tool in the management of cancer.

Moderate offspring exercise offsets the harmful effects of maternal protein deprivation on mitochondrial function and oxidative balance by modulating sirtuins.

BACKGROUND AND AIMS: It has been demonstrated that maternal low protein during development induces mitochondrial dysfunction and oxidative stress in the heart. Moderate-intensity exercise in early life, conversely, increases the overall cardiac health. Thus, we hypothesize that moderate-intensity exercise performed during young age could ameliorate the deleterious effect of maternal protein deprivation on cardiac bioenergetics. METHODS AND RESULTS: We used a rat model of maternal protein restriction during gestational and lactation period followed by an offspring treadmill moderate physical training. Pregnant rats were divided into two groups: normal nutrition receiving 17% of casein in the diet and undernutrition receiving a low-protein diet (8% casein). At 30 days of age, the male offspring were further subdivided into sedentary (NS and LS) or exercised (NT and LT) groups. Treadmill exercise was performed as follows: 4 weeks, 5 days/week, 60 min/day at 50% of maximal running capacity. Our results showed that a low-protein diet decreases oxidative metabolism and mitochondrial function associated with higher oxidative stress. In contrast, exercise rescues mitochondrial capacity and promotes a cellular resilience to oxidative stress. Up-regulation of cardiac sirtuin 1 and 3 decreased acetylation levels, redeeming from the deleterious effect of protein restriction. CONCLUSION: Our findings show that moderate daily exercise during a young age acts as a therapeutical intervention opposing the harmful effects of a maternal diet restricted in protein.

Mitochondrial impairment following neonatal overfeeding: A comparison between normal and ischemic-reperfused hearts.

Overweight and obesity are established factors underpin several metabolic impairments, including the cardiovascular. Although the diversity of factors involved in overweight/obesity-induced cardiovascular diseases, mitochondria has been highlighted due to its role in cardiac metabolism. As obesity can be originated in early postnatal life, the current study evaluates the effects of neonatal overfeeding on the cardiac mitochondrial bioenergetics and oxidative balance in rats that underwent an ischemia-reperfusion insult. Seventy-two hours after delivery, Wistar rat litters were randomly assigned into the control (C; nine pups per mother) and the Overfed (OF; three pups per mother) groups throughout the lactation period. At weaning, male offspring were fed with laboratory chow ad libitum until sacrifice at 30 and 60 days of life. Mitochondrial heart bioenergetics and oxidative balance showed to be deeply affected by neonatal overfeeding at both ages. Interestingly, after ischemia-reperfusion insult I/R (Langendorff or mineral oil incubation), most parameters evaluated in OF animals were not influenced by additional ischemic-reperfusion injury. Our findings demonstrated that suckling overfeeding deregulates cardiac mitochondrial alike to ischemia-reperfusion insult by disengaging electrical mitochondrial coupling and potentiate oxidative stress, wherein the neonatal overfeeding shows to be so detrimental as I/R. Our findings support the concept that nutritional insults in the critical development periods increase the risk for cardiovascular disease and mitochondria impairments throughout life while oxidative damage change between molecular targets.

Neonatal treatment with fluoxetine improves mitochondrial respiration and reduces oxidative stress in liver of adult rats.

Recent studies have shown that exposure to fluoxetine treatment induces excessive production of ROS, and alters the antioxidant defense system in various tissues and cell types, mainly the liver. When fluoxetine is administered intraperitoneally, the drug rapidly reaches high concentrations in the liver, has potentially multiple toxic effects on energy metabolism in rat liver mitochondria. The aim of this study was to evaluate the effect of pharmacological treatment with fluoxetine during critical period for development on the mitochondrial bioenergetics and oxidative stress in liver of rat adult. To perform this study, the rat pups received Fx, or vehicle (Ct) from postnatal day 1 to postnatal day 21 (ie, during lactation period). We evaluated mitochondrial oxygen consumption, respiratory control ratio, ROS production, mitochondrial swelling by pore opening, oxidative stress biomarkers, and antioxidant defense in liver of rats at 60 days of age. Our studies have shown, that treatment with Fx during the lactation period resulted in reduced body mass gain, improvement of the mitochondrial respiratory capacity, induced higher mitochondrial resistance to calcium ion preventing the mitochondrial permeability transition pore opening, as well as decreased oxidative stress biomarkers, and increased the SH levels and enzymes antioxidant activities (SOD, CAT, GST) in liver of treated rats at 60 days of age. These findings suggest that pharmacological treatment with fluoxetine during critical period of development result in positive changes in liver of rats, as improvement of the mitochondrial bioenergetics and hepatic oxidative metabolism that persist in adulthood.

Serotonin transporter inhibition during neonatal period induces sex-dependent effects on mitochondrial bioenergetics in the rat brainstem.

The serotonin reuptake is mainly regulated by the serotonin transporters (SERTs), which are abundantly found in the raphe nuclei, located in the brainstem. Previous studies have shown that dysfunction in the SERT has been associated with several disorders, including depression and cardiovascular diseases. In this manuscript, we aimed to investigate how gender and the treatment with a serotonin selective reuptake inhibitor (SSRI) could affect mitochondrial bioenergetics and oxidative stress in the brainstem of male and female rats. Fluoxetine, our chosen SSRI, was used during the neonatal period (i.e., from postnatal Day 1 to postnatal Day 21-PND1 to PND21) in both male and female animals. Thereafter, experiments were conducted in adult rats (60 days old). Our results demonstrate that, during lactation, fluoxetine treatment modulates the mitochondrial bioenergetics in a sex-dependent manner, such as improving male mitochondrial function and female antioxidant capacity.

Oxidative injuries induced by maternal low-protein diet in female brainstem.

Many studies have shown that a maternal low-protein diet increases the susceptibility of offspring to cardiovascular disease in later-life. Moreover, a lower incidence of cardiovascular disease in females than in males is understood to be largely due to the protective effect of high levels of estrogens throughout a woman's reproductive life. However, to our knowledge, the role of estradiol in moderating the later-life susceptibility of offspring of nutrient-deprived mothers to cardiovascular disease is not fully understood. The present study is aimed at investigating whether oxidative stress in the brainstem caused by a maternal low-protein diet administered during a critical period of fetal/neonatal brain development (i.e during gestation and lactation) is affected by estradiol levels. Female Wistar rat offspring were divided into four groups according to their mothers' diets and to the serum estradiol levels of the offspring at the time of testing: (1) 22 days of age/control diet: (2) 22 days of age/low-protein diet; (3) 122 days of age/control diet: (4) 122 days of age/low-protein diet. Undernutrition in the context of low serum estradiol compared to undernutrition in a higher estradiol context resulted in increased levels of oxidative stress biomarkers and a reduction in enzymatic and non-enzymatic antioxidant defenses. Total global oxy-score showed oxidative damage in 22-day-old rats whose mothers had received a low-protein diet. In the 122-day-old group, we observed a decrease in oxidative stress biomarkers, increased enzymatic antioxidant activity, and a positive oxy-score when compared to control. We conclude from these results that following a protein deficiency in the maternal diet during early development of the offspring, estrogens present at high levels at reproductive age may confer resistance to the oxidative damage in the brainstem that is very apparent in pre-pubertal rats.

Safflower (Carthamus tinctorius L.) oil during pregnancy and lactation influences brain excitability and cortex oxidative status in the rat offspring.

OBJECTIVES: To evaluate how safflower oil (SFO) influences brain electrophysiology and cortical oxidative status in the offspring, mothers received a diet with SFO during brain development period. METHODS: Beginning on the 14th day of gestation and throughout lactation, rats received safflower (safflower group - SG) or soybean oil (control group - CG) in their diet. At 65 days old, cortical spreading depression (CSD) and cortex oxidative status were analyzed in the offspring. RESULTS: SG presented reduction of the CSD velocity as compared to the CG (SG: 3.24 ± 0.09; CG: 3.37 ± 0.07 mm/min). SFO reduced levels of lipid peroxidation by 39.4%. SG showed the following increases: glutathione-S-transferase, 40.8% and reduced glutathione, 34.3%. However, SFO decreased superoxide dismutase by 40.4% and catalase by 64.1%. To control for interhemispheric effects, since CSD was recorded only in the right cortex, we evaluated the oxidative status in both sides of the cortex; no differences were observed. DISCUSSION: Data show that when SFO is consumed by the female rats during pregnancy and lactation, the offspring present long-term effects on brain electrophysiology and cortical oxidative state. The present study highlights the relevance of understanding the SFO intake of pregnant and lactating mammals.

Targeted disruption of PDE3B, but not PDE3A, protects murine heart from ischemia/reperfusion injury.

Although inhibition of cyclic nucleotide phosphodiesterase type 3 (PDE3) has been reported to protect rodent heart against ischemia/reperfusion (I/R) injury, neither the specific PDE3 isoform involved nor the underlying mechanisms have been identified. Targeted disruption of PDE3 subfamily B (PDE3B), but not of PDE3 subfamily A (PDE3A), protected mouse heart from I/R injury in vivo and in vitro, with reduced infarct size and improved cardiac function. The cardioprotective effect in PDE3B(-/-) heart was reversed by blocking cAMP-dependent PKA and by paxilline, an inhibitor of mitochondrial calcium-activated K channels, the opening of which is potentiated by cAMP/PKA signaling. Compared with WT mitochondria, PDE3B(-/-) mitochondria were enriched in antiapoptotic Bcl-2, produced less reactive oxygen species, and more frequently contacted transverse tubules where PDE3B was localized with caveolin-3. Moreover, a PDE3B(-/-) mitochondrial fraction containing connexin-43 and caveolin-3 was more resistant to Ca(2+)-induced opening of the mitochondrial permeability transition pore. Proteomics analyses indicated that PDE3B(-/-) heart mitochondria fractions were enriched in buoyant ischemia-induced caveolin-3-enriched fractions (ICEFs) containing cardioprotective proteins. Accumulation of proteins into ICEFs was PKA dependent and was achieved by ischemic preconditioning or treatment of WT heart with the PDE3 inhibitor cilostamide. Taken together, these findings indicate that PDE3B deletion confers cardioprotective effects because of cAMP/PKA-induced preconditioning, which is associated with the accumulation of proteins with cardioprotective function in ICEFs. To our knowledge, our study is the first to define a role for PDE3B in cardioprotection against I/R injury and suggests PDE3B as a target for cardiovascular therapies.

Fighting Oxidative Stress: Increased Resistance of Male Rat Cerebellum at Weaning Induced by Low Omega 6/Omega 3 Ratio in a Protein-Deficient Diet.

The cerebellum is vulnerable to malnutrition effects. Notwithstanding, it is able to incorporate higher amount of docosahexaenoic acid (DHA) than the cerebral cortex (Cx) when low n-6/n-3 fatty acid ratio is present in a multideficient diet. Considering importance of DHA for brain redox balance, we hypothesize that this cerebellum feature improves its antioxidant status compared to the Cx. A chronic malnutrition status was induced on dams before mating and kept until weaning or adulthood (offspring). A group nutritionally rehabilitated from weaning was also analyzed. Morphometric parameters, total-superoxide dismutase (t-SOD) and catalase activities, lipoperoxidation (LP), nitric oxide (NO), reduced (GSH) and oxidized (GSSG) glutathione, reactive oxygen species (ROS), and reduced nicotinamide adenine dinucleotide/phosphate levels were assessed. Both ROS and LP levels were increased (∼53 %) in the Cx of malnourished young animals while the opposite was seen in the cerebellum (72 and 20 % of the control, respectively). Consistently, lower (∼35 %) and higher t-SOD (∼153 %) and catalase (CAT) (∼38 %) activities were respectively detected in the Cx and cerebellum compared to the control. In malnourished adult animals, redox balance was maintained in the cerebellum and recovered in the Cx (lower ROS and LP levels and higher GSH/GSSG ratio). NO production was impaired by malnutrition at either age, mainly in the cerebellum. The findings suggest that despite a multinutrient deficiency and a modified structural development, a low dietary n-6/n-3 ratio favors early antioxidant resources in the male cerebellum and indicates an important role of astrocytes in the redox balance recovery of Cx in adulthood.

Perinatal low-protein diet alters brainstem antioxidant metabolism in adult offspring.

BACKGROUND AND OBJECTIVES: Studies in humans and animal models have established a close relationship between early environment insult and subsequent risk of development of non-communicable diseases, including the cardiovascular. Whereas experimental evidences highlight the early undernutrition and the late cardiovascular disease relation, the central mechanisms linking the two remain unknown. Owing to the oxidative balance influence in several pathologies, the aim of the present study was to evaluate the effects of maternal undernutrition (i.e. a low-protein (LP) diet) on oxidative balance in the brainstem. METHODS AND RESULTS: Male rats from mothers fed with an LP diet (8% casein) throughout the perinatal period (i.e. gestation and lactation) showed 10× higher lipid peroxidation levels than animals treated with normoprotein (17% casein) at 100 days of age. In addition, we observed the following reductions in enzymatic activities: superoxide dismutase, 16%; catalase, 30%; glutathione peroxidase, 34%; glutathione-S-transferase, 51%; glutathione reductase, 23%; glucose-6-phosphate dehydrogenase, 31%; and in non-enzymatic glutathione system, 46%. DISCUSSION: This study is the first to focus on the role of maternal LP nutrition in oxidative balance in a central nervous system structure responsible for cardiovascular control in adult rats. Our data observed changes in oxidative balance in the offspring, therefore, bring a new concept related to early undernutrition and can help in the development of a new clinical strategy to combat the effects of nutritional insult. Wherein the central oxidative imbalance is a feasible mechanism underlying the hypertension risk in adulthood triggered by maternal LP diet.

Maternal protein restriction induced-hypertension is associated to oxidative disruption at transcriptional and functional levels in the medulla oblongata.

Maternal protein restriction during pregnancy and lactation predisposes the adult offspring to sympathetic overactivity and arterial hypertension. Although the underlying mechanisms are poorly understood, dysregulation of the oxidative balance has been proposed as a putative trigger of neural-induced hypertension. The aim of the study was to evaluate the association between the oxidative status at transcriptional and functional levels in the medulla oblongata and maternal protein restriction induced-hypertension. Wistar rat dams were fed a control (normal protein; 17% protein) or a low protein ((Lp); 8% protein) diet during pregnancy and lactation, and male offspring was studied at 90 days of age. Direct measurements of baseline arterial blood pressure (ABP) and heart rate (HR) were recorded in awakened offspring. In addition, quantitative RT-PCR was used to assess the mRNA expression of superoxide dismutase 1 (SOD1) and 2 (SOD2), catalase (CAT), glutathione peroxidase (GPx), Glutamatergic receptors (Grin1, Gria1 and Grm1) and GABA(A)-receptor-associated protein like 1 (Gabarapl1). Malondialdehyde (MDA) levels, CAT and SOD activities were examined in ventral and dorsal medulla. Lp rats exhibited higher ABP. The mRNA expression levels of SOD2, GPx and Gabarapl1 were down regulated in medullary tissue of Lp rats (P<.05, t test). In addition, we observed that higher MDA levels were associated to decreased SOD (approximately 45%) and CAT (approximately 50%) activities in ventral medulla. Taken together, our data suggest that maternal protein restriction induced-hypertension is associated with medullary oxidative dysfunction at transcriptional level and with impaired antioxidant capacity in the ventral medulla.

Glutamine-Loaded Liposomes: Preliminary Investigation, Characterization, and Evaluation of Neutrophil Viability.

Glutamine has received attention due to its ability to ameliorate the immune system response. Once conventional liposomes are readily recognized and captured by immune system cells, the encapsulation of glutamine into those nanosystems could be an alternative to reduce glutamine dosage and target then to neutrophils. Our goals were to nanoencapsulate glutamine into conventional liposomes (Gln-L), develop an analytical high-performance liquid chromatography (HPLC) method for its quantification, and evaluate the viability of neutrophils treated with Gln-L. Liposomes were prepared using the thin-film hydration technique followed by sonication and characterized according to pH, mean size, zeta potential, and drug encapsulation efficiency (EE%). We also aimed to study the effect of liposomal constituent concentrations on liposomal characteristics. The viability of neutrophils was assessed using flow cytometry after intraperitoneal administration of free glutamine (Gln), Gln-L, unloaded-liposome (UL), and saline solution as control (C) in healthy Wistar rats. The selected liposomal formulation had a mean vesicle size of 114.65 ± 1.82 nm with a polydispersity index of 0.30 ± 0.00, a positive surface charge of 36.30 ± 1.38 mV, and an EE% of 39.49 ± 0.74%. The developed chromatographic method was efficient for the quantification of encapsulated glutamine, with a retention time at 3.8 min. A greater viability was observed in the group treated with glutamine encapsulated compared to the control group (17%), although neutrophils remain viable in all groups. Thus, glutamine encapsulated into liposomes was able to increase the number of viable neutrophils at low doses, thereby representing a promising strategy for the treatment of immunodeficiency conditions.

Omega-3 deficiency and neurodegeneration in the substantia nigra: involvement of increased nitric oxide production and reduced BDNF expression.

BACKGROUND: Our previous study demonstrated that essential fatty acid (EFA) dietary restriction over two generations induced midbrain dopaminergic cell loss and oxidative stress in the substantia nigra (SN) but not in the striatum of young rats. In the present study we hypothesized that omega-3 deficiency until adulthood would reduce striatum's resilience, increase nitric oxide (NO) levels and the number of BDNF-expressing neurons, both potential mechanisms involved in SN neurodegeneration. METHODS: Second generation rats were raised from gestation on control or EFA-restricted diets until young or adulthood. Lipoperoxidation, NO content, total superoxide dismutase (t-SOD) and catalase enzymatic activities were assessed in the SN and striatum. The number of tyrosine hydroxylase (TH)- and BDNF-expressing neurons was analyzed in the SN. RESULTS: Increased NO levels were observed in the striatum of both young and adult EFA-deficient animals but not in the SN, despite a similar omega-3 depletion (~65%) in these regions. Increased lipoperoxidation and decreased catalase activity were found in both regions, while lower tSOD activity was observed only in the striatum. Fewer TH- (~40%) and BDNF-positive cells (~20%) were detected at the SN compared to the control. CONCLUSION: The present findings demonstrate a differential effect of omega-3 deficiency on NO production in the rat's nigrostriatal system. Prolonging omega-3 depletion until adulthood impaired striatum's anti-oxidant resources and BDNF distribution in the SN, worsening dopaminergic cell degeneration. GENERAL SIGNIFICANCE: Omega-3 deficiency can reduce the nigrostriatal system's ability to maintain homeostasis under oxidative conditions, which may enhance the risk of Parkinson's disease.

Fluoxetine treatment of rat neonates significantly reduces oxidative stress in the hippocampus and in behavioral indicators of anxiety later in postnatal life.

The brain, more than any other organ in the body, is vulnerable to oxidative stress damage, owing to its requirement for high levels of oxygenation. This is needed to fulfill its metabolic needs in the face of relatively low levels of protective antioxidants. Recent studies have suggested that oxidative stress is directly involved in the etiology of both eating and anxiety behavior. The aim of this study was to evaluate the effect of fluoxetine-inhibited serotonin reuptake in nursing rat neonates on behavior and on oxidative stress in the hypothalamus and the hippocampus; brain areas responsible for behavior related to food and anxiety, respectively. The results show that increased serotonin levels during a critical period of development do not induce significant differences in food-related behavior (intake and satiety), but do result in a in a significant decrease in anxiety. Measurements of oxidative stress showed a significant reduction of lipid peroxidation in the hippocampus (57%). In the hypothalamus, antioxidant enzymes were unchanged, but in the hippocampus, the activity of catalase and glutathione-S-transferase was increased (80% and 85% respectively). This suggests that protecting neural cells from oxidative stress during brain development contributes to the anxiolytic effects of serotonin.

The deleterious effects of maternal protein deprivation on the brainstem are minimized with moderate physical activity by offspring during early life.

Maternal protein malnutrition during developmental periods might impair the redox state and the brain's excitatory/inhibitory neural network, increasing central sympathetic tone. Conversely, moderate physical exercise at an early age reduces the risk of chronic diseases. Thus, we hypothesized that a moderate training protocol could reduce the harmful effects of a low-protein maternal diet on the brainstem of young male offspring. We used a rat model of maternal protein restriction during the gestational and lactation period followed by an offspring's continuous treadmill exercise. Pregnant rats were divided into two groups according to the protein content in the diet: normoprotein (NP), receiving 17% of casein, and low protein (LP), receiving 8% of casein until the end of lactation. At 30 days of age, the male offspring were further subdivided into sedentary (NP-Sed and LP-Sed) or exercised (NP-Ex and LP-Ex) groups. Treadmill exercise was performed as follows: 4 weeks, 5 days/week, 60 min/day at 50% of maximal running capacity. The trained animals performed a treadmill exercise at 50% of the maximal running capacity, 60 min/day, 5 days/week, for 4 weeks. Our results indicate that a low-protein diet promotes deficits in the antioxidant system and a likely mitochondrial uncoupling. On the other hand, physical exercise restores the redox balance, which leads to decreased oxidative stress caused by the diet. In addition, it also promotes benefits to GABAergic inhibitory signaling. We conclude that regular moderate physical exercise performed in youthhood protects the brainstem against changes induced by maternal protein restriction.

Overweight during development dysregulates cellular metabolism and critical genes that control food intake in the prefrontal cortex.

BACKGROUNDS AND AIMS: Childhood obesity is increasing substantially across the world. The World Obesity Federation (WOF) and World Health Organization (WHO) predicted that in 2030 > 1 billion people will be obese, and by 2035 over 4 billion will reach obesity worldwide. According to WHO, the world soon cannot afford the economic cost of obesity, and we need to act to stop obesity acceleration now. Data in the literature supports that the first 1000 days of life are essential in preventing obesity and related adversities. Therefore, using basic research, the present a study that focuses on the immediate effect of overnutrition and serotonin modulation during the lactation period. METHODS: Using a neonatal overfeeding model, male Wistar rats were divided into four groups based on nutrition or serotonin modulation by pharmacological treatment up to 22 days of life. Cellular and mitochondrial function markers, oxidative stress biomarkers and mRNA levels of hedonic and homeostatic genes were evaluated. RESULTS: Our data showed that overfeeding during lactation decrease NAD/NADH ratio, citrate synthase activity, and increase ROS production. Lipid and protein oxidation were increased in overfed animals, with a decrease in antioxidant defenses, we also observe a differential expression of mRNA levels of homeostatic and hedonic genes. On the contrary, serotonin modulation with selective serotonin reuptake inhibitors treatment reduces harmful effects caused by overnutrition. CONCLUSION: Early effects of overnutrition significantly affect the prefrontal cortex at molecular and cellular level, which could mediate obesity-related neurodegenerative dysfunction.

The impact of enriched environments on cerebral oxidative balance in rodents: a systematic review of environmental variability effects.

Introduction: The present review aimed to systematically summarize the impacts of environmental enrichment (EE) on cerebral oxidative balance in rodents exposed to normal and unfavorable environmental conditions. Methods: In this systematic review, four databases were used: PubMed (830 articles), Scopus (126 articles), Embase (127 articles), and Science Direct (794 articles). Eligibility criteria were applied based on the Population, Intervention, Comparison, Outcomes, and Study (PICOS) strategy to reduce the risk of bias. The searches were carried out by two independent researchers; in case of disagreement, a third participant was requested. After the selection and inclusion of articles, data related to sample characteristics and the EE protocol (time of exposure to EE, number of animals, and size of the environment) were extracted, as well as data related to brain tissues and biomarkers of oxidative balance, including carbonyls, malondialdehyde, nitrotyrosine, oxygen-reactive species, and glutathione (reduced/oxidized). Results: A total of 1,877 articles were found in the four databases, of which 16 studies were included in this systematic review. The results showed that different EE protocols were able to produce a global increase in antioxidant capacity, both enzymatic and non-enzymatic, which are the main factors for the neuroprotective effects in the central nervous system (CNS) subjected to unfavorable conditions. Furthermore, it was possible to notice a slowdown in neural dysfunction associated with oxidative damage, especially in the prefrontal structure in mice. Discussion: In conclusion, EE protocols were determined to be valid tools for improving oxidative balance in the CNS. The global decrease in oxidative stress biomarkers indicates refinement in reactive oxygen species detoxification, triggering an improvement in the antioxidant network.

Metformin preconditioning protects against myocardial stunning and preserves protein translation in a mouse model of cardiac arrest.

Cardiac arrest (CA) causes high mortality due to multi-system organ damage attributable to ischemia-reperfusion injury. Recent work in our group found that among diabetic patients who experienced cardiac arrest, those taking metformin had less evidence of cardiac and renal damage after cardiac arrest when compared to those not taking metformin. Based on these observations, we hypothesized that metformin's protective effects in the heart were mediated by AMPK signaling, and that AMPK signaling could be targeted as a therapeutic strategy following resuscitation from CA. The current study investigates metformin interventions on cardiac and renal outcomes in a non-diabetic CA mouse model. We found that two weeks of metformin pretreatment protects against reduced ejection fraction and reduces kidney ischemia-reperfusion injury at 24 h post-arrest. This cardiac and renal protection depends on AMPK signaling, as demonstrated by outcomes in mice pretreated with the AMPK activator AICAR or metformin plus the AMPK inhibitor compound C. At this 24-h time point, heart gene expression analysis showed that metformin pretreatment caused changes supporting autophagy, antioxidant response, and protein translation. Further investigation found associated improvements in mitochondrial structure and markers of autophagy. Notably, Western analysis indicated that protein synthesis was preserved in arrest hearts of animals pretreated with metformin. The AMPK activation-mediated preservation of protein synthesis was also observed in a hypoxia/reoxygenation cell culture model. Despite the positive impacts of pretreatment in vivo and in vitro, metformin did not preserve ejection fraction when deployed at resuscitation. Taken together, we propose that metformin's in vivo cardiac preservation occurs through AMPK activation, requires adaptation before arrest, and is associated with preserved protein translation.