Glioprotective Effects of Sulforaphane in Hypothalamus: Focus on Aging Brain.

Sulforaphane is a natural compound with neuroprotective activity, but its effects on hypothalamus remain unknown. In line with this, astrocytes are critical cells to maintain brain homeostasis, and hypothalamic astrocytes are fundamental for sensing and responding to environmental changes involved in a variety of homeostatic functions. Changes in brain functionality, particularly associated with hypothalamic astrocytes, can contribute to age-related neurochemical alterations and, consequently, neurodegenerative diseases. Thus, here, we investigated the glioprotective effects of sulforaphane on hypothalamic astrocyte cultures and hypothalamic cell suspension obtained from aged Wistar rats (24 months old). Sulforaphane showed anti-inflammatory and antioxidant properties, as well as modulated the mRNA expression of astroglial markers, such as aldehyde dehydrogenase 1 family member L1, aquaporin 4, and vascular endothelial growth factor. In addition, it increased the expression and extracellular levels of trophic factors, such as glia-derived neurotrophic factor and nerve growth factor, as well as the release of brain-derived neurotrophic factor and the mRNA of TrkA, which is a receptor associated with trophic factors. Sulforaphane also modulated the expression of classical pathways associated with glioprotection, including nuclear factor erythroid-derived 2-like 2, heme oxygenase-1, nuclear factor kappa B p65 subunit, and AMP-activated protein kinase. Finally, a cell suspension with neurons and glial cells was used to confirm the predominant effect of sulforaphane in glial cells. In summary, this study indicated the anti-aging and glioprotective activities of sulforaphane in aged astrocytes.

Simvastatin Differentially Modulates Glial Functions in Cultured Cortical and Hypothalamic Astrocytes Derived from Interferon α/ß Receptor Knockout mice.

Astrocytes have key regulatory roles in central nervous system (CNS), integrating metabolic, inflammatory and synaptic responses. In this regard, type I interferon (IFN) receptor signaling in astrocytes can regulate synaptic plasticity. Simvastatin is a cholesterol-lowering drug that has shown anti-inflammatory properties, but its effects on astrocytes, a main source of cholesterol for neurons, remain to be elucidated. Herein, we investigated the effects of simvastatin in inflammatory and functional parameters of primary cortical and hypothalamic astrocyte cultures obtained from IFNα/ß receptor knockout (IFNα/ßR-/-) mice. Overall, simvastatin decreased extracellular levels of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), which were related to a downregulation in gene expression in hypothalamic, but not in cortical astrocytes. Moreover, there was an increase in anti-inflammatory interleukin-10 (IL-10) in both structures. Effects of simvastatin in inflammatory signaling also involved a downregulation of cyclooxygenase 2 (COX-2) gene expression as well as an upregulation of nuclear factor κB subunit p65 (NFκB p65). The expression of cytoprotective genes sirtuin 1 (SIRT1) and nuclear factor erythroid derived 2 like 2 (Nrf2) was also increased by simvastatin. In addition, simvastatin increased glutamine synthetase (GS) activity and glutathione (GSH) levels only in cortical astrocytes. Our findings provide evidence that astrocytes from different regions are important cellular targets of simvastatin in the CNS, even in the absence of IFNα/ßR, which was showed by the modulation of cytokine production and release, as well as the expression of cytoprotective genes and functional parameters.

Changes in Astroglial Water Flow in the Pre-amyloid Phase of the STZ Model of AD Dementia.

Alzheimer's disease (AD) is an age-dependent neurodegenerative disease that is typically sporadic and has a high social and economic cost. We utilized the intracerebroventricular administration of streptozotocin (STZ), an established preclinical model for sporadic AD, to investigate hippocampal astroglial changes during the first 4 weeks post-STZ, a period during which amyloid deposition has yet to occur. Astroglial proteins aquaporin 4 (AQP-4) and connexin-43 (Cx-43) were evaluated, as well as claudins, which are tight junction (TJ) proteins in brain barriers, to try to identify changes in the glymphatic system and brain barrier during the pre-amyloid phase. Glial commitment, glucose hypometabolism and cognitive impairment were characterized during this phase. Astroglial involvement was confirmed by an increase in glial fibrillary acidic protein (GFAP); concurrent proteolysis was also observed, possibly mediated by calpain. Levels of AQP-4 and Cx-43 were elevated in the fourth week post-STZ, possibly accelerating the clearance of extracellular proteins, since these proteins actively participate in the glymphatic system. Moreover, although we did not see a functional disruption of the blood-brain barrier (BBB) at this time, claudin 5 (present in the TJ of the BBB) and claudin 2 (present in the TJ of the blood-cerebrospinal fluid barrier) were reduced. Taken together, data support a role for astrocytes in STZ brain damage, and suggest that astroglial dysfunction accompanies or precedes neuronal damage in AD.

Calorie restriction protects against acute systemic LPS-induced inflammation.

Caloric restriction (CR) has been proposed as a nutritional strategy to combat chronic diseases, including neurodegenerative diseases, as well as to delay aging. However, despite the benefits of CR, questions remain about its underlying mechanisms and cellular and molecular targets.Objective: As inflammatory processes are the basis or accompany chronic diseases and aging, we investigated the protective role of CR in the event of an acute inflammatory stimulus.Methods: Peripheral inflammatory and metabolic parameters were evaluated in Wistar rats following CR and/or acute lipopolysaccharide (LPS) administration, as well as glial changes (microglia and astrocytes), in two regions of the brain (hippocampus and hypothalamus) involved in the inflammatory response. We used a protocol of 30% CR, for 4 or 8 weeks. Serum and brain parameters were analyzed by biochemical or immunological assays.Results: Benefits of CR were observed during the inflammatory challenge, where the partial reduction of serum interleukin-6, mediated by CR, attenuated the systemic response. In the central nervous system (CNS), specifically in the hippocampus, CR attenuated the response to the LPS, as evaluated by tumor necrosis factor alpha (TNFα) levels. Furthermore, in the hippocampus, CR increased the glutathione (GSH) levels, resulting in a better antioxidant response.Discussion: This study contributes to the understanding of the effects of CR, particularly in the CNS, and expands knowledge about glial cells, emphasizing their importance in neuroprotection strategies.

The role of glial cells in Zika virus-induced neurodegeneration.

Zika virus (ZIKV) is a strongly neurotropic flavivirus whose infection has been associated with microcephaly in neonates. However, clinical and experimental evidence indicate that ZIKV also affects the adult nervous system. In this regard, in vitro and in vivo studies have shown the ability of ZIKV to infect glial cells. In the central nervous system (CNS), glial cells are represented by astrocytes, microglia, and oligodendrocytes. In contrast, the peripheral nervous system (PNS) constitutes a highly heterogeneous group of cells (Schwann cells, satellite glial cells, and enteric glial cells) spread through the body. These cells are critical in both physiological and pathological conditions; as such, ZIKV-induced glial dysfunctions can be associated with the development and progression of neurological complications, including those related to the adult and aging brain. This review will address the effects of ZIKV infection on CNS and PNS glial cells, focusing on cellular and molecular mechanisms, including changes in the inflammatory response, oxidative stress, mitochondrial dysfunction, Ca2+ and glutamate homeostasis, neural metabolism, and neuron-glia communication. Of note, preventive and therapeutic strategies that focus on glial cells may emerge to delay and/or prevent the development of ZIKV-induced neurodegeneration and its consequences.

Serum of COVID-19 patients changes neuroinflammation and mitochondrial homeostasis markers in hippocampus of aged rats.

Patients affected by COVID-19 present mostly with respiratory symptoms but acute neurological symptoms are also commonly observed. Furthermore, a considerable number of individuals develop persistent and often remitting symptoms months after infection, characterizing the condition called long-COVID. Since the pathophysiology of acute and persistent neurological manifestations is not fully established, we evaluated the expression of different genes in hippocampal slices of aged rats exposed to the serum of a post-COVID (sPC) individual and to the serum of patients infected by SARS-CoV-2 [Zeta (sZeta) and Gamma (sGamma) variants]. The expression of proteins related to inflammatory process, redox homeostasis, mitochondrial quality control and glial reactivity was determined. Our data show that the exposure to sPC, sZeta and sGamma differentially altered the mRNA levels of most inflammatory proteins and reduced those of antioxidant response markers in rat hippocampus. Furthermore, a decrease in the expression of mitochondrial biogenesis genes was induced by all serum samples, whereas a reduction in mitochondrial dynamics was only caused by sPC. Regarding the glial reactivity, S100B expression was modified by sPC and sZeta. These findings demonstrate that changes in the inflammatory response and a reduction of mitochondrial biogenesis and dynamics may contribute to the neurological damage observed in COVID-19 patients.

Sulfite Impairs Bioenergetics and Redox Status in Neonatal Rat Brain: Insights into the Early Neuropathophysiology of Isolated Sulfite Oxidase and Molybdenum Cofactor Deficiencies.

Isolated sulfite oxidase (ISOD) and molybdenum cofactor (MoCD) deficiencies are genetic diseases biochemically characterized by the toxic accumulation of sulfite in the tissues of patients, including the brain. Neurological dysfunction and brain abnormalities are commonly observed soon after birth, and some patients also have neuropathological alterations in the prenatal period (in utero). Thus, we investigated the effects of sulfite on redox and mitochondrial homeostasis, as well as signaling proteins in the cerebral cortex of rat pups. One-day-old Wistar rats received an intracerebroventricular administration of sulfite (0.5 µmol/g) or vehicle and were euthanized 30 min after injection. Sulfite administration decreased glutathione levels and glutathione S-transferase activity, and increased heme oxygenase-1 content in vivo in the cerebral cortex. Sulfite also reduced the activities of succinate dehydrogenase, creatine kinase, and respiratory chain complexes II and II-III. Furthermore, sulfite increased the cortical content of ERK1/2 and p38. These findings suggest that redox imbalance and bioenergetic impairment induced by sulfite in the brain are pathomechanisms that may contribute to the neuropathology of newborns with ISOD and MoCD. Sulfite disturbs antioxidant defenses, bioenergetics, and signaling pathways in the cerebral cortex of neonatal rats. CII: complex II; CII-III: complex II-III; CK: creatine kinase; GST: glutathione S-transferase; HO-1: heme oxygenase-1; SDH: succinate dehydrogenase; SO32-: sulfite.

Effects of long-term resveratrol treatment in hypothalamic astrocyte cultures from aged rats.

Aging is intrinsically related to metabolic changes and characterized by the accumulation of oxidative and inflammatory damage, as well as alterations in gene expression and activity of several signaling pathways, which in turn impact on homeostatic responses of the body. Hypothalamus is a brain region most related to these responses, and increasing evidence has highlighted a critical role of astrocytes in hypothalamic homeostatic functions, particularly during aging process. The purpose of this study was to investigate the in vitro effects of a chronic treatment with resveratrol (1 µM during 15 days, which was replaced once every 3 days), a recognized anti-inflammatory and antioxidant molecule, in primary hypothalamic astrocyte cultures obtained from aged rats (24 months old). We observed that aging process changes metabolic, oxidative, inflammatory, and senescence parameters, as well as glial markers, while long-term resveratrol treatment prevented these effects. In addition, resveratrol upregulated key signaling pathways associated with cellular homeostasis, including adenosine receptors, nuclear factor erythroid-derived 2-like 2 (Nrf2), heme oxygenase 1 (HO-1), sirtuin 1 (SIRT1), proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and phosphoinositide 3-kinase (PI3K). Our data corroborate the glioprotective effect of resveratrol in aged hypothalamic astrocytes, reinforcing the beneficial role of resveratrol in the aging process.

Early effects of LPS-induced neuroinflammation on the rat hippocampal glycolytic pathway.

Neuroinflammation is a common feature during the development of neurological disorders and neurodegenerative diseases, where glial cells, such as microglia and astrocytes, play key roles in the activation and maintenance of inflammatory responses in the central nervous system. Neuroinflammation is now known to involve a neurometabolic shift, in addition to an increase in energy consumption. We used two approaches (in vivo and ex vivo) to evaluate the effects of lipopolysaccharide (LPS)-induced neuroinflammation on neurometabolic reprogramming, and on the modulation of the glycolytic pathway during the neuroinflammatory response. For this, we investigated inflammatory cytokines and receptors in the rat hippocampus, as well as markers of glial reactivity. Mitochondrial respirometry and the glycolytic pathway were evaluated by multiple parameters, including enzymatic activity, gene expression and regulation by protein kinases. Metabolic (e.g., metformin, 3PO, oxamic acid, fluorocitrate) and inflammatory (e.g., minocycline, MCC950, arundic acid) inhibitors were used in ex vivo hippocampal slices. The induction of early inflammatory changes by LPS (both in vivo and ex vivo) enhanced glycolytic parameters, such as glucose uptake, PFK1 activity and lactate release. This increased glucose consumption was independent of the energy expenditure for glutamate uptake, which was in fact diverted for the maintenance of the immune response. Accordingly, inhibitors of the glycolytic pathway and Krebs cycle reverted neuroinflammation (reducing IL-1ß and S100B) and the changes in glycolytic parameters induced by LPS in acute hippocampal slices. Moreover, the inhibition of S100B, a protein predominantly synthesized and secreted by astrocytes, inhibition of microglia activation and abrogation of NLRP3 inflammasome assembly confirmed the role of neuroinflammation in the upregulation of glycolysis in the hippocampus. Our data indicate a neurometabolic glycolytic shift, induced by inflammatory activation, as well as a central and integrative role of astrocytes, and suggest that interference in the control of neurometabolism may be a promising strategy for downregulating neuroinflammation and consequently for diminishing negative neurological outcomes.

Mild Hyperhomocysteinemia Causes Anxiety-like Behavior and Brain Hyperactivity in Rodents: Are ATPase and Excitotoxicity by NMDA Receptor Overstimulation Involved in this Effect?

Mild hyperhomocysteinemia is a risk factor for psychiatric and neurodegenerative diseases, whose mechanisms between them are not well-known. In the present study, we evaluated the emotional behavior and neurochemical pathways (ATPases, glutamate homeostasis, and cell viability) in amygdala and prefrontal cortex rats subjected to mild hyperhomocysteinemia (in vivo studies). The ex vivo effect of homocysteine on ATPases and redox status, as well as on NMDAR antagonism by MK-801 in same structures slices were also performed. Wistar male rats received a subcutaneous injection of 0.03 µmol Homocysteine/g of body weight or saline, twice a day from 30 to 60th-67th days of life. Hyperhomocysteinemia increased anxiety-like behavior and tended to alter locomotion/exploration of rats, whereas sucrose preference and forced swimming tests were not altered. Glutamate uptake was not changed, but the activities of glutamine synthetase and ATPases were increased. Cell viability was not altered. Ex vivo studies (slices) showed that homocysteine altered ATPases and redox status and that MK801, an NMDAR antagonist, protected amygdala (partially) and prefrontal cortex (totally) effects. Taken together, data showed that mild hyperhomocysteinemia impairs the emotional behavior, which may be associated with changes in ATPase and glutamate homeostasis, including glutamine synthetase and NMDAR overstimulation that could lead to excitotoxicity. These findings may be associated with the homocysteine risk factor on psychiatric disorders development and neurodegeneration.

Sulforaphane Induces Glioprotection After LPS Challenge.

Sulforaphane is a natural compound that presents anti-inflammatory and antioxidant properties, including in the central nervous system (CNS). Astroglial cells are involved in several functions to maintain brain homeostasis, actively participating in the inflammatory response and antioxidant defense systems. We, herein, investigated the potential mechanisms involved in the glioprotective effects of sulforaphane in the C6 astrocyte cell line, when challenged with the inflammogen, lipopolysaccharide (LPS). Sulforaphane prevented the LPS-induced increase in the expression and/or release of pro-inflammatory mediators, possibly due to nuclear factor κB and hypoxia-inducible factor-1α activation. Sulforaphane also modulated the expressions of the Toll-like and adenosine receptors, which often mediate inflammatory processes induced by LPS. Additionally, sulforaphane increased the mRNA levels of nuclear factor erythroid-derived 2-like 2 (Nrf2) and heme oxygenase-1 (HO1), both of which mediate several cytoprotective responses. Sulforaphane also prevented the increase in NADPH oxidase activity and the elevations of superoxide and 3-nitrotyrosine that were stimulated by LPS. In addition, sulforaphane and LPS modulated superoxide dismutase activity and glutathione metabolism. Interestingly, the anti-inflammatory and antioxidant effects of sulforaphane were blocked by HO1 pharmacological inhibition, suggesting its dependence on HO1 activity. Finally, in support of a glioprotective role, sulforaphane prevented the LPS-induced decrease in glutamate uptake, glutamine synthetase activity, and glial-derived neurotrophic factor (GDNF) levels, as well as the augmentations in S100B release and Na+, K+ ATPase activity. To our knowledge, this is the first study that has comprehensively explored the glioprotective effects of sulforaphane on astroglial cells, reinforcing the beneficial effects of sulforaphane on astroglial functionality.

Methylmalonic acid induces inflammatory response and redox homeostasis disruption in C6 astroglial cells: potential glioprotective roles of melatonin and resveratrol.

Methylmalonic acidemia is a neurometabolic disorder biochemically characterized by the accumulation of methylmalonic acid (MMA) in different tissues, including the central nervous system (CNS). In this sense, it has been shown that high levels of this organic acid have a key role in the progressive neurological deterioration in patients. Astroglial cells actively participate in a wide range of CNS functions, such as antioxidant defenses and inflammatory response. Considering the role of these cells to maintain brain homeostasis, in the present study, we investigated the effects of MMA on glial parameters, focusing on redox homeostasis and inflammatory process, as well as putative mediators of these events in C6 astroglial cells. MMA decreased cell viability, glutathione levels, and antioxidant enzyme activities, increased inflammatory response, and changed the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear factor kappa B (NFκB), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), and adenosine receptors, suggesting that these transcriptional factors and proteins may underlie the glial responses induced by MMA. Moreover, we also demonstrated the protective roles of melatonin and resveratrol against MMA-induced inflammation and decrease in glutathione levels. In summary, our findings support the hypothesis that astroglial changes are associated with pathogenesis of methylmalonic acidemia. In addition, we showed that these cells might be potential targets for preventive/therapeutic strategies by using molecules, such as melatonin and resveratrol, which mediated glioprotection in this inborn error of metabolism.

Short-Term Alterations in Behavior and Astroglial Function After Intracerebroventricular Infusion of Methylglyoxal in Rats.

Methylglyoxal (MG) is a by-product of glycolysis. In pathological conditions, particularly diabetes mellitus, this molecule is unbalanced, causing widespread protein glycation. In addition to protein glycation, other effects resulting from high levels of MG in the central nervous system may involve the direct modulation of GABAergic and glutamatergic neurotransmission, with evidence suggesting that the effects of MG may be related to behavioral changes and glial dysfunction. In order to evaluate the direct influence of MG on behavioral and biochemical parameters, we used a high intracerebroventricular final concentration (3 µM/µL) to assess acute effects on memory and locomotor behavior in rats, as well as the underlying alterations in glutamatergic and astroglial parameters. MG induced, 12 h after injection, a decrease in locomotor activity in the Open field and anxiolytic effects in rats submitted to elevated plus-maze. Subsequently, 36 h after surgery, MG injection also induced cognitive impairment in both short and long-term memory, as evaluated by novel object recognition task, and in short-term spatial memory, as evaluated by the Y-maze test. In addition, hippocampal glutamate uptake decreased and glutamine synthetase activity and glutathione levels diminished during seventy-two hours after infusion of MG. Interestingly, the astrocytic protein, S100B, was increased in the cerebrospinal fluid, accompanied by decreased hippocampal S100B mRNA expression, without any change in protein content. Taken together, these results may improve our understanding of how this product of glucose metabolism can induce the brain dysfunction observed in diabetic patients, as well as in other neurodegenerative conditions, and further defines the role of astrocytes in disease and therapeutics.

Zika Virus Infection Associated with Autism Spectrum Disorder: A Case Report.

INTRODUCTION: The aim of this case was to investigate the association of the Zika virus infection in utero with the autism spectrum disorder (ASD) as clinical outcome that presented no congenital anomalies. METHODS: ASD was diagnosed in the second year of life by different child neurologists and confirmed by DSM-5 and ASQ. After that, an extensive clinical, epidemiological, and genetic evaluations were performed, with main known ASD causes ruled out. RESULTS: An extensive laboratorial search was done, with normal findings. SNP array identified no pathogenic variants. Normal neuroimaging and EEG findings were also obtained. ZIKV (Zika virus) IgG was positive, while IgM was negative. Other congenital infections were negative. The exome sequencing did not reveal any pathogenic variant in genes related to ASD. CONCLUSION: Accordingly, this report firstly associates ZIKV exposure to ASD.

ZIKAVID-Zika virus infection database: a new platform to analyze the molecular impact of Zika virus infection.

The recent outbreak of Zika virus (ZIKV) in Brazil and other countries globally demonstrated the relevance of ZIKV studies. During and after this outbreak, there was an intense increase in scientific production on ZIKV infections, especially toward alterations promoted by the infection and related to clinical outcomes. Considering this massive amount of new data, mainly thousands of genes and proteins whose expression is impacted by ZIKV infection, the ZIKA Virus Infection Database (ZIKAVID) was created. ZIKAVID is an online database that comprises all genes or proteins, and associated information, for which expression was experimentally measured and found to be altered after ZIKV infection. The database, available at https://zikavid.org, contains 16,984 entries of gene expression measurements from a total of 7348 genes. It allows users to easily perform searches for different experimental hosts (cell lines, tissues, and animal models), ZIKV strains (African, Asian, and Brazilian), and target molecules (messenger RNA [mRNA] and protein), among others, used in differential expression studies regarding ZIKV infection. In this way, the ZIKAVID will serve as an additional and important resource to improve the characterization of the molecular impact and pathogenesis associated with ZIKV infection.

High-glucose medium induces cellular differentiation and changes in metabolic functionality of oligodendroglia.

Oligodendrocyte precursor cells (OPC) are a uniformly distributed population of glial cells that are well known for proliferating and differentiating into mature oligodendrocytes to form the myelin sheet in the central nervous system (CNS). Since monocarboxylate transporter 1 (MCT1) has shown to be expressed by oligodendroglia, the involvement of these cells with the metabolic support to axons has emerged as an important role in the maintenance of neuronal functionality. Hyperglycemia is a metabolic dysfunction highly associated with oxidative stress, a classical feature linked to many disorders such as diabetes mellitus. Despite of being widely investigated in several different cell cultures, including astrocytes and neurons, such condition has been poorly investigated in OPC culture. Thus, the aim of this study was to explore the possible effects of high-glucose exposure in acute and chronic conditions on oligodendroglial development and functionality in vitro. In this sense, we have demonstrated that under high-glucose exposure OPC improved its differentiation rate without affecting its membrane integrity and its morphology. Besides, chronic high-glucose condition also increased glucose uptake and lactate release. On the other hand, our findings also showed that, unlike what happens in other glial cells and neurons, high-glucose exposure did not seem to induce oxidative stress in OPC culture. Therefore, as far as we have investigated in this present study, we suggest that OPC may be able to support neurons and other glial cells during hyperglycemia events.

Effect of a trans fatty acid-enriched diet on mitochondrial, inflammatory, and oxidative stress parameters in the cortex and hippocampus of Wistar rats.

PURPOSE: Previously showed that dietary trans fatty acids (TFAs) may cause systemic inflammation and affect the central nervous system (CNS) in Wistar rats by increased levels of cytokines in the cerebrospinal fluid (CSF) and serum (Longhi et al. Eur J Nutr 56(3):1003-1016, 1). Here, we aimed to clarifying the impact of diets with different TFA concentrations on cerebral tissue, focusing on hippocampus and cortex and behavioral performance. METHODS: Wistar rats were fed either a normolipidic or a hyperlipidic diet for 90 days; diets had the same ingredients except for fat compositions, concentrations, and calories. We used lard in the cis fatty acid (CFA) group and PHSO in the TFA group. The intervention groups were as follows: (1) low lard (LL), (2) high lard (HL), (3) low partially hydrogenated soybean oil (LPHSO), and (4) high partially hydrogenated soybean oil (HPHSO). Mitochondrial parameters, tumor necrosis factor alpha (TNF-α), 2'7'-dichlorofluorescein (DCFH) levels in brain tissue, and open field task were analyzed. RESULTS: A worse brain tissue response was associated with oxidative stress in cortex and hippocampus as well as impaired inflammatory and mitochondrial parameters at both PHSO concentrations and there were alterations in the behavioral performance. In many analyses, there were no significant differences between the LPHSO and HPHSO diets. CONCLUSIONS: Partially hydrogenated soybean oil impaired cortical mitochondrial parameters and altered inflammatory and oxidative stress responses, and the hyperlipidic treatment caused locomotor and exploratory effects, but no differences on weight gain in all treatments. These findings suggest that quality is more important than the quantity of fat consumed in terms of CFA and TFA diets.

Resveratrol prevents ammonia-induced mitochondrial dysfunction and cellular redox imbalance in C6 astroglial cells.

BACKGROUND: Resveratrol is a polyphenolic compound that presents several protective effects in the central nervous system, including gliotoxicity associated to hyperammonemia, a key element for the development of hepatic encephalopathy. In this condition, mitochondrial dysfunction leads to a reactive oxygen species (ROS) overproduction, which, in turn, exacerbates mitochondrial failure and causes cellular damage. OBJECTIVE: This study sought to determine whether prevention of mitochondrial dysfunction and the maintenance of cellular redox status by resveratrol contribute to its protective action toward ammonia toxicity. METHODS: C6 astrocyte cell line was pre-incubated in the presence or absence of resveratrol (100 µM) for 1 hour. After pre-incubation, resveratrol was maintained and 5 mM ammonia was added for 24 hours, followed by the evaluation of ROS production, mitochondrial functionality, antioxidant enzymatic and non-enzymatic defenses, energy metabolic parameters, and genotoxicity. RESULTS: We showed that resveratrol prevented the increase in ROS production, the decrease of mitochondrial membrane potential (ΔΨm), and bioenergetics deficit caused by ammonia in C6 astroglial cells. In addition, resveratrol avoided the ammonia-induced upregulation of NOX activity and impairment in enzymatic and non-enzymatic antioxidant defenses. Ammonia also induced DNA damage that was prevented by resveratrol, indicating its genoprotective effect. CONCLUSIONS: In summary, our study demonstrates that resveratrol prevents ammonia-induced cytotoxicity, as well as supports the role of resveratrol on mitochondrial/cellular redox functionality.

Leptin stimulates the release of pro-inflammatory cytokines in hypothalamic astrocyte cultures from adult and aged rats.

Leptin is an adipose tissue-derived hormone that acts on the hypothalamus in order to maintain energy homeostasis. However, leptin can also induce an inflammatory response. Increasing evidence has highlighted a critical role of astrocytes in the effects of leptin on the hypothalamus. In addition, astrocytes participate in neuroinflammation by producing and releasing a wide range of inflammatory mediators. In this study, we aimed to investigate the age-dependent effect of leptin on pro- and anti-inflammatory cytokines released by the hypothalamic astrocyte cultures obtained from newborn, adult, and aged Wistar rats. In hypothalamic astrocytes from newborn rats, leptin did not change the release of pro-inflammatory cytokines, tumor necrosis factor α (TNF-α) and interleukin 1ß (IL-1ß). On the other contrary, leptin increased the release of both TNF-α and IL-1ß in astrocyte cultures from adult and aged animals. Regarding the anti-inflammatory cytokine interleukin 10 (IL-10), we did not observe any change in response to leptin. In conclusion, our data suggests a pro-inflammatory action of leptin on the hypothalamus during aging. This in turn may be related to the triggering of metabolic disorders, as both of these conditions are associated with neuroinflammation.

Signaling mechanisms underlying the glioprotective effects of resveratrol against mitochondrial dysfunction.

Resveratrol, a polyphenol found in grapes and red wine, exhibits antioxidant, anti-inflammatory, anti-aging and, neuroprotective effects. Resveratrol also plays a significant role modulating glial functionality, protecting the health of neuroglial cells against several neuropsychiatric in vivo and in vitro experimental models. Mitochondrial impairment strongly affected astrocyte functions and consequently brain homeostasis. Molecules that promote astrocyte mitochondrial protection are fundamental to maintain brain energy balance and cellular redox state, contributing to brain healthy. Thus, the present study was designed to evaluate some glioprotective mechanisms of resveratrol against mitochondrial damage promoted by azide exposure in hippocampal primary astrocyte cultures. Azide treatment provoked deleterious effects, including the dysfunction of mitochondria, the deterioration of redox homeostasis, the augmentation of pro-inflammatory cytokines and impairment of glutamate uptake activity. However, resveratrol prevented these effects, protecting hippocampal astrocytes against azide-induced cytotoxicity through the heme-oxygenase-1 (HO-1) pathway and inhibiting p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor kappa B (NFκB) activation. Resveratrol also protected astrocytes via phosphatidylinositide 3-kinase (PI3K)/Akt. These results contribute to the comprehension of the mechanisms by which resveratrol mediates hippocampal astrocyte protection against mitochondrial failure and implicate resveratrol as an important glioprotective molecule.