Fernanda Urruth Fontella
Universidade Federal do Rio Grande do Sul, Farmacologia, Graduate Student
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BackgroundSevere systemic inflammation can spread to the central nervous system, promoting neuronal dysfunction. Individuals who survive to a severe inflammatory episode, have greater chances to develop cognitive impairment. In this... more
BackgroundSevere systemic inflammation can spread to the central nervous system, promoting neuronal dysfunction. Individuals who survive to a severe inflammatory episode, have greater chances to develop cognitive impairment. In this context, brain inflammatory changes have been considered a risk factor for Alzheimer’s disease (AD). We previously demonstrated, a significant [18F]FDG hypometabolism 24 h after the induction of severe systemic inflammation by cecal ligation and perforation (CLP), a sepsis model. However, whether severe systemic inflammation causes long‐term effects on brain energy metabolism remains unclear. Here, we aim at Investigating persistent consequences of a severe systemic inflammatory episode on brain energy metabolism. We hypothesized that brain energetic metabolism does not completely recover from a systemic inflammatory episode, which could be a trigger for neurodegeneration.MethodWistar rats (90 days old) were submitted to CLP and, examined in vivo via Mic...
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Acute liver failure (ALF) is a life-threatening medical condition that often leads to hepatic encephalopathy (HE). Animals and humans with HE have shown elevated cerebrospinal fluid (CSF) levels of glutamine and glutamate, which may be... more
Acute liver failure (ALF) is a life-threatening medical condition that often leads to hepatic encephalopathy (HE). Animals and humans with HE have shown elevated cerebrospinal fluid (CSF) levels of glutamine and glutamate, which may be associated with brain impairment. In this study, we aim to evaluate the relationship between blood-brain barrier (BBB) integrity and CSF amino acid levels with the neurological status of rats after subtotal hepatectomy. Adult male Wistar rats underwent a subtotal hepatectomy (removing 92% of hepatic mass or SHAM group) and were divided into 4 (four) cohorts. Animals with ALF presented severe neurological impairment and high mortality rates when compared to the SHAM group (Cohort 1). We performed a hepatic function test 24 hours after subtotal hepatectomy, which demonstrated a significant increase of Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Total Bilirubin, Direct Bilirubin, Prothrombin time and Ammonia levels in blood (Cohort ...
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BackgroundGlyphosate‐based herbicides (GBH) are the most widely used pesticides, mainly due to their use in genetically modified crops. Lately, GBH induced‐neurotoxic effects are gaining attention since they are potential risk factors for... more
BackgroundGlyphosate‐based herbicides (GBH) are the most widely used pesticides, mainly due to their use in genetically modified crops. Lately, GBH induced‐neurotoxic effects are gaining attention since they are potential risk factors for developing neurodegenerative diseases, including Alzheimer’s disease (AD). It has been shown that GBH exposure is associated to brain glutamatergic excitotoxicity ‐ a key pathological feature in AD, which may cause blood‐brain barrier (BBB) breakdown. In addition, the activity of some urea cycle enzymes and arginine downstream metabolites seem to be altered in AD patient brains. Based on that, we aimed at evaluating central and peripheral effects of GBH acute exposure.MethodGBH was administered into adult male Wistar rats (90 day‐old, n = 14) in a single oral dose (400 mg/kg). The AA and albumin levels in CSF were assessed by High‐Performance Liquid Chromatography in control conditions and 3, 24 and 48 h after administration. Serum urea content was...
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Research Interests: Food Science and Medicina
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Research Interests: Free Radicals, Neurochemistry, Oxidative Stress, Medicine, Free Radical, and 15 moreBiological Sciences, Antioxidants, Reactive Oxygen Species, Female, Animals, Spinal Cord, Male, Gender Difference, Rats, Sex Factors, Chronic Stress, Physical Restraint, Neurochemical, Medical and Health Sciences, and Restraint stress
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Research Interests: Neuroscience, Cognitive Science, Medicine, Chronic Disease, Animals, and 15 moreAnesthesia, Morphine, Rats, Saline, Nociception, Chronic Stress, Opioid, Physiological Stress Markers, Physical Restraint, Neurosciences, Hyperalgesia, Acute stress, Tail flick, Stress Physiological, and Restraint stress
Early life events lead to behavioral and neurochemical changes in adulthood. The aim of this study is to verify the effects of neonatal handling on spatial memory, nitric oxide (NO) production, antioxidant enzymatic activities and DNA... more
Early life events lead to behavioral and neurochemical changes in adulthood. The aim of this study is to verify the effects of neonatal handling on spatial memory, nitric oxide (NO) production, antioxidant enzymatic activities and DNA breaks in the hippocampus of male and female adult rats. Litters of rats were non-handled or handled (10 min/day, days 1-10 after birth). In adulthood they were subjected to a Morris water maze or used for biochemical evaluations. Female handled rats showed impairment in spatial learning. They also showed decreased NO production, while no effects were observed in these parameters in male rats. No effects were observed on the number of hippocampal NADPH diaphorase positive cells. In the Comet Assay, male handled rats showed increased DNA breaks index when compared to non-handled ones. We conclude that neonatal handling impairs learning performance in a sex-specific manner, what may be related to NO decreased levels.
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Rede nacional de pesquisa clínica : implantando boas práticas clínicas como garantia de adequação dos projetos de pesquisa. ...
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We report a chemically-induced model of maple syrup urine disease (MSUD) in 10- and 30-day-old rats produced by subcutaneous administration of a branched-chain amino acids (BCAA) pool along with the analyses of plasma and brain amino acid... more
We report a chemically-induced model of maple syrup urine disease (MSUD) in 10- and 30-day-old rats produced by subcutaneous administration of a branched-chain amino acids (BCAA) pool along with the analyses of plasma and brain amino acid levels by HPLC at 0-120 min after administration. We observed an increase of plasma leucine (Leu), isoleucine (Ile) and valine (Val) concentrations in both 10- and 30-day-old rats. These increases were accompanied by a concomitant reduction of plasma concentrations of methionine (Met), phenylalanine (Phe), tyrosine (Tyr), histidine (His), alanine (Ala), lysine (Lys), and ornithine (Orn) in 10-day-old rats and of Met, Phe, Tyr, tryptophan (Trp), and Orn in 30-day-old rats. These results are similar to those observed in MSUD patients during crises, when plasma levels of large neutral amino acids (LNAA) are also reduced when BCAA concentrations are increased. In the brain, increased concentrations of Leu, Ile and Val were achieved in 10-day-old rats at all times after injection. In contrast, no differences in cerebral concentrations of BCAA were observed in 30-day-old rats. In conclusion, the present MSUD model, using 10- rather than 30-day-old rats, has a similar amino acid profile to that of MSUD untreated patients and is suitable to investigate the mechanisms of brain damage characteristic of this disorder.
Research Interests: Neuroscience, Cognitive Science, Electrochemistry, Animals, Male, and 14 moreAnimal Model, High Pressure Liquid Chromatography, Amino Acids, Rats, Time Factors, Wistar Rats, Amino Acid Profile, Amino Acid Sequence, Brain Chemistry, Statistical Methods for Neuroscience, Neurosciences, MAPLE SYRUP URINE DISEASE, Brain Damage, and Neuroscience Methods
Propionic acidemia is an inherited neurometabolic disorder characterized by progressive neurological deterioration with psychomotor delay/mental retardation, convulsions and coma, and whose pathophysiology is poorly unknown. In the... more
Propionic acidemia is an inherited neurometabolic disorder characterized by progressive neurological deterioration with psychomotor delay/mental retardation, convulsions and coma, and whose pathophysiology is poorly unknown. In the present study, we investigated the effect of chronic administration (from the 5th to the 28th days of life) of propionic acid (PA), the major metabolite accumulating in tissues of patients affected by propionic acidemia, on the cognitive performance of adult rats in the Morris water maze task. PA doses ranged from 1.44 to 1.92 micromol/g body weight as a function of animal age. Control rats were treated with saline in the same volumes. Chronic postnatal days (5-28) PA treatment had no effect on body weight. However, it impaired spatial performance in the water maze. We also determined the effect of ascorbic acid (AA) administered, alone or combined with PA, on the same behavioral parameters in order to test whether free radicals could be responsible for t...
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In this study we investigated the in vitro effects of the metabolites accumulating in maple syrup urine disease on lipid peroxidation in brain of young rats. Chemiluminescence and thiobarbituric acid-reactive substances were measured in... more
In this study we investigated the in vitro effects of the metabolites accumulating in maple syrup urine disease on lipid peroxidation in brain of young rats. Chemiluminescence and thiobarbituric acid-reactive substances were measured in brain homogenates from 7- and 30-day-old rats in the presence of 10 mM of the branched-chain amino acids L-leucine, L-isoleucine, or L-valine; their keto acids L-2-ketoisocaproic acid, L-2-keto-3-methylvaleric acid, or L-2-ketoisovaleric acid; or the hydroxy derivatives L-2-hydroxyisocaproic acid, L-2-hydroxy-3-methylvaleric acid, or L-2-hydroxyisovaleric acid separately added to the incubation medium. We observed that all amino acids, keto acids, and hydroxy acids accumulating in this disease stimulate to a variable degree the in vitro parameters of lipid peroxidation tested in homogenates of rat brain. The results indicate a possible participation of oxidative stress in the neuropathology of maple syrup urine disease patients, especially during a c...
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Several studies have shown that high corticosteroid hormone levels increase neuronal vulnerability. Here we evaluate the consequences of in vivo acute or repeated restraint stress on cellular viability in rat hippocampal slices suffering... more
Several studies have shown that high corticosteroid hormone levels increase neuronal vulnerability. Here we evaluate the consequences of in vivo acute or repeated restraint stress on cellular viability in rat hippocampal slices suffering an in vitro model of ischemia. Cellular injury was quantified by measuring lactate dehydrogenase (LDH) and neuron-specific enolase released into the medium. Acute stress did not affect cellular death when oxygen and glucose deprivation (OGD) was applied both immediately or 24h after restraint. The exposure to OGD, followed by reoxygenation, resulted in increased LDH in the medium. Repeated stress potentiated the effect of OGD both, on LDH and neuron-specific enolase released to the medium. There was no effect of repeated stress on the release of S100B, an astrocytic protein. Additionally, no effect of repeated stress was observed on glutamate uptake by the tissue. These results suggest that repeated stress increases the vulnerability of hippocampal ...
Research Interests: Cognitive Science, Hippocampus, Glutamate, Brain, Anoxia, and 17 moreGlucose, Animals, Male, Astrocyte, Rats, Sodium, Analysis of Variance, Time Factors, Wistar Rats, Physiological Stress Markers, Lactate dehydrogenase, Physical Restraint, Neurosciences, Enzyme Linked Immunosorbent Assay, Glutamic Acid, Glucocorticoids, and Acute stress
Stress responses cover a wide range of physiological changes, including alterations in the perception of and response to pain. Animals submitted to repeated stress present altered nociception and this effect is part of this process of... more
Stress responses cover a wide range of physiological changes, including alterations in the perception of and response to pain. Animals submitted to repeated stress present altered nociception and this effect is part of this process of adaptation; in addition pleasant and unpleasant experiences with tastes and odors have been shown to affect distinct behavioral aspects, such as pain perception. The aim of the present study is to verify the responses of repeatedly stressed rats (1 h of daily immobilization during 40 days) to pleasant and unpleasant tastes on nociception, when compared to control animals. An increase in the tail-flick latency (TFL) was observed 5 min after exposure to a sweet taste in the control group, whereas no effect was observed in chronically stressed animals. When submitted to an unpleasant taste (5% acetic acid), the chronically stressed group presented an increase in TFL, whereas no effect was observed in the control group. In conclusion, chronically stressed animals present different nociceptive responses to sweet and acid tastes; although control animals suitably respond to a sweet stimulus, stressed animals seem to be more apt to react to the unpleasant stimulus.
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Hyperactivity of the stress response has long been recognized as maladaptive. The hippocampus, a brain structure important in mediating this response, is known to be affected by chronic stress, a situation reported to induce changes in... more
Hyperactivity of the stress response has long been recognized as maladaptive. The hippocampus, a brain structure important in mediating this response, is known to be affected by chronic stress, a situation reported to induce changes in adenine nucleotide hydrolysis in the rat. The enzymes catalyzing the hydrolysis of ATP to adenosine in the synaptic cleft are thought to have a role in modulating and controlling synaptic transmission. This study aimed to investigate the effect of acute and repeated restraint stress on the ATP, ADP and AMP hydrolyses in rat hippocampal synaptosomes. Adult male Wistar rats were submitted to acute or repeated (15 and 40 days) stress, and ATPase-ADPase, and 5'nucleotidase activities were assayed in the hippocampal synaptosomal fraction. Acute stress induced increased hydrolyses of ATP (21%), ADP (21%) and AMP (40%). In contrast, ATP hydrolysis was increased by 20% in repeatedly stressed rats, without changes in the ADP or AMP hydrolysis. The same results were observed after 15 or 40 days of stress. Therefore, acute stress increases ATP diphosphohydrolase activity which, in association with 5'-nucleotidase, contributes to the elimination of ATP and provides extracellular adenosine. Interestingly, increased ecto-ATPase activity in response to chronic stress reveals an adaptation to this treatment.
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Propionic acidemia is an inherited neurometabolic disorder characterized by progressive neurological deterioration with psychomotor delay/mental retardation, convulsions and coma, and whose pathophysiology is poorly unknown. In the... more
Propionic acidemia is an inherited neurometabolic disorder characterized by progressive neurological deterioration with psychomotor delay/mental retardation, convulsions and coma, and whose pathophysiology is poorly unknown. In the present study, we investigated the effect of chronic administration (from the 5th to the 28th days of life) of propionic acid (PA), the major metabolite accumulating in tissues of patients affected by propionic acidemia, on the cognitive performance of adult rats in the Morris water maze task. PA doses ranged from 1.44 to 1.92 micromol/g body weight as a function of animal age. Control rats were treated with saline in the same volumes. Chronic postnatal days (5-28) PA treatment had no effect on body weight. However, it impaired spatial performance in the water maze. We also determined the effect of ascorbic acid (AA) administered, alone or combined with PA, on the same behavioral parameters in order to test whether free radicals could be responsible for the behavioral alterations observed in PA-treated animals. AA was able to prevent the behavioral alterations provoked by PA, implying that oxidative stress may be involved in these effects. Furthermore, we also investigated the total radical-trapping antioxidant potential (TRAP) in the hippocampus of the animals. We observed that TRAP was significantly reduced in the brain of propionic acidemic rats and that co-administration of AA prevented this effect. The results provide evidence that early PA treatment induces long-lasting behavioral deficits, which are possibly caused by oxygen reactive species generation, and suggest that oxidative stress may be involved in the neuropathology of propionic acidemia.
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Research Interests: Psychology, Cognitive Science, Aging, Animals, Spinal Cord, and 8 moreMale, Neurons, Morphine, Rats, SYNAPTOSOMES, Wistar Rats, Neurosciences, and Glutamic Acid
The in vitro effects of propionic and L-methylmalonic acids on some parameters of oxidative stress were investigated in the cerebral cortex of 21-day-old rats. Chemiluminescence, thiobarbituric acid-reactive substances (TBA-RS) and total... more
The in vitro effects of propionic and L-methylmalonic acids on some parameters of oxidative stress were investigated in the cerebral cortex of 21-day-old rats. Chemiluminescence, thiobarbituric acid-reactive substances (TBA-RS) and total radical-trapping antioxidant capacity (TRAP) were measured in brain tissue homogenates in the presence of propionic or L-methylmalonic acids at concentrations ranging from 1 to 10mM. Both acids significantly increased chemiluminescence and TBA-RS and decreased TRAP, indicating a simulation of lipid peroxidation and a reduction of tissue antioxidant potential. Other organic acids tested which accumulate in some organic acidemias (suberic, sebacic, adipic, 3-methylglutaric and 4-hydroxybutyric acids) did not affect these parameters. This study provides evidence that free radical generation may participate in the neurological dysfunction of propionic and methylmalonic acidemias.
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Research Interests: Spatial Memory, Space perception, Memory, Biological Sciences, Hippocampus, and 18 moreNitric oxide, Female, Animals, Male, Catalase, Glutathione Peroxidase, Spatial Learning, Superoxide Dismutase, Comet Assay, Rats, Sex Factors, Wistar Rats, Indexation, Enzymatic Activity, Maze Learning, LIFE EVENT, Morris water maze, and Neurochemical
Previous studies have shown sex-specific oxidative changes in spinal cord of rats submitted to chronic stress, which may be due to gonadal hormones. Here, we assessed total radical-trapping potential (TRAP), superoxide dismutase (SOD) and... more
Previous studies have shown sex-specific oxidative changes in spinal cord of rats submitted to chronic stress, which may be due to gonadal hormones. Here, we assessed total radical-trapping potential (TRAP), superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities and lipid peroxidation (evaluated by the TBARS test) in the spinal cord of ovariectomized (OVX) female rats. Female rats were subjected to OVX, and half of the animals received estradiol replacement. Animals were subdivided into controls and chronically stressed (for 40 days). Our findings demonstrate that chronic stress decreased TRAP, and increased SOD activity in spinal cord homogenates from ovariectomized female rats and had no effect on GPx activity. On the other hand, groups receiving 17β-estradiol replacement presented a decreased GPx activity, but no alteration in TRAP and in SOD activity. No differences in the TBARS test were found in any of the groups analyzed. In conclusion, our results support the idea that chronic stress induces an imbalance between SOD and GPx activities, additionally decreasing TRAP. Estradiol replacement did not reverse the effects of chronic stress, but induced a decrease in GPx activity. Therefore, estradiol replacement in ovariectomized chronically stressed rats could make the spinal cord more susceptible to oxidative injury.