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1.
Int J Mol Sci ; 24(23)2023 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-38068900

RESUMO

S100B, a homodimeric Ca2+-binding protein, is produced and secreted by astrocytes, and its extracellular levels have been used as a glial marker in brain damage and neurodegenerative and psychiatric diseases; however, its mechanism of secretion is elusive. We used primary astrocyte cultures and calcium measurements from real-time fluorescence microscopy to investigate the role of intracellular calcium in S100B secretion. In addition, the dimethyl sulfoxide (DMSO) effect on S100B was investigated in vitro and in vivo using Wistar rats. We found that DMSO, a widely used vehicle in biological assays, is a powerful S100B secretagogue, which caused a biphasic response of Ca2+ mobilization. Our data show that astroglial S100B secretion is triggered by the increase in intracellular Ca2+ and indicate that this increase is due to Ca2+ mobilization from the endoplasmic reticulum. Also, blocking plasma membrane Ca2+ channels involved in the Ca2+ replenishment of internal stores decreased S100B secretion. The DMSO-induced S100B secretion was confirmed in vivo and in ex vivo hippocampal slices. Our data support a nonclassic vesicular export of S100B modulated by Ca2+, and the results might contribute to understanding the mechanism underlying the astroglial release of S100B.


Assuntos
Astrócitos , Dimetil Sulfóxido , Ratos , Animais , Ratos Wistar , Dimetil Sulfóxido/farmacologia , Dimetil Sulfóxido/metabolismo , Astrócitos/metabolismo , Colforsina/farmacologia , Secretagogos/farmacologia , Cálcio/metabolismo , Fatores de Crescimento Neural/metabolismo , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Retículo Endoplasmático/metabolismo , Células Cultivadas
2.
Brain Res ; 1846: 149268, 2024 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-39374840

RESUMO

Early exposure to stressors affects how the organism reacts to stimuli, its emotional state throughout life, and how it deals with emotional memories. Consequently, it may affect susceptibility to psychopathology later in life. We used an animal model of early stress by maternal separation to study its potential impact on the extinction of aversive memories and anxiety-like behavior in adulthood, as well as its effects on mitochondrial functionality, inflammatory and astrocytic markers in the amygdala. We also assessed whether a diet enriched with linseed oil, known for its high content in omega-3 fats, could be used to attenuate the behavioral and neurochemical effects of early stress. Litters of Wistar rats were divided into controls (intact) or subjected to maternal separation (MS). They were subdivided into two groups receiving isocaloric diets enriched in soy or linseed oils at weaning. In adulthood, the animals were exposed to the open field and the elevated plus maze, to evaluate exploratory activity and anxiety-like behavior. They were also trained in a context of fear conditioning, and afterward subjected to an extinction session, followed by a test session to evaluate the extinction memory. Amygdalae were evaluated for inflammatory cytokines (interleukin (IL)-1beta, IL-6, and tumor-necrose factor (TNF)-alpha), mitochondrial functionality, and astrocyte markers (glial fibrillary acidic protein - GFAP, S100B, and glutamine synthetase activity). MS induced anxiety-like behavior in the elevated plus-maze, which was reversed by a diet enriched in linseed oil offered from weaning. When testing the memory of an extinction session of fear conditioning, MS animals showed more freezing behavior. MS males receiving a linseed oil-enriched diet had lower functional mitochondria in the amygdala. In addition, MS led to increased inflammatory cytokines, particularly IL-1beta, and the diet enriched in linseed oil further increased these levels in MS animals. MS also increased S100B levels. These results point to a higher emotionality presented by MS animals, with higher levels of inflammatory cytokines and S100B. While a diet enriched in linseed oil attenuated anxiety-like behavior, it further altered amygdala IL-1beta and reduced mitochondria functionality, particularly in males. MS also increased glutamine synthetase activity in the amygdala, and this effect was higher when the animals received a diet enriched in linseed oil, particularly in females. In conclusion, these results point to MS effects on emotional behavior, and neurochemical alterations in the amygdala, with sex-specific effects. Although a diet enriched in linseed oil appears to be able to reverse some of MS behavioral effects, these results must be considered with caution, since biochemical parameters could be worsened in MS animals receiving a linseed oil-enriched diet. This knowledge is important for the understanding of mechanisms of action of strategies aiming to reverse early stress effects, and future studies are warranted to determine possible interventions to promote resilience.

3.
J Neuroinflammation ; 8: 128, 2011 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-21970823

RESUMO

BACKGROUND: Inflammatory responses in brain are primarily mediated by microglia, but growing evidence suggests a crucial importance of astrocytes. S100B, a calcium-binding protein secreted by astrocytes, has properties of a neurotrophic or an inflammatory cytokine. However, it is not known whether primary signals occurring during induction of an inflammatory response (e.g. lipopolysaccharide, LPS) directly modulate S100B. METHODS: In this work, we evaluated whether S100B levels in cerebrospinal fluid (CSF) and serum of Wistar rats are affected by LPS administered by intraperitoneal (IP) or intracerebroventricular (ICV) injection, as well as whether primary astrocyte cultures respond directly to lipopolysaccharide. RESULTS: Our data suggest that S100B secretion in brain tissue is stimulated rapidly and persistently (for at least 24 h) by ICV LPS administration. This increase in CSF S100B was transient when LPS was IP administered. In contrast to these S100B results, we observed an increase in in TNFα levels in serum, but not in CSF, after IP administration of LPS. In isolated astrocytes and in acute hippocampal slices, we observed a direct stimulation of S100B secretion by LPS at a concentration of 10 µg/mL. An involvement of TLR4 was confirmed by use of specific inhibitors. However, lower levels of LPS in astrocyte cultures were able to induce a decrease in S100B secretion after 24 h, without significant change in intracellular content of S100B. In addition, after 24 h exposure to LPS, we observed a decrease in astrocytic glutathione and an increase in astrocytic glial fibrillary acidic protein. CONCLUSIONS: Together, these data contribute to the understanding of the effects of LPS on astrocytes, particularly on S100B secretion, and help us to interpret cerebrospinal fluid and serum changes for this protein in neuroinflammatory diseases. Moreover, non-brain S100B-expressing tissues may be differentially regulated, since LPS administration did not lead to increased serum levels of S100B.


Assuntos
Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Lipopolissacarídeos/farmacologia , Fatores de Crescimento Neural/líquido cefalorraquidiano , Fatores de Crescimento Neural/metabolismo , Proteínas S100/líquido cefalorraquidiano , Proteínas S100/metabolismo , Animais , Astrócitos/citologia , Células Cultivadas , Córtex Cerebral/citologia , Glutationa/metabolismo , Infusões Intraventriculares , Lipopolissacarídeos/administração & dosagem , Ratos , Ratos Wistar , Subunidade beta da Proteína Ligante de Cálcio S100 , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/líquido cefalorraquidiano
4.
J Alzheimers Dis ; 84(4): 1415-1430, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34719501

RESUMO

One of the changes found in the brain in Alzheimer's disease (AD) is increased calpain, derived from calcium dysregulation, oxidative stress, and/or neuroinflammation, which are all assumed to be basic pillars in neurodegenerative diseases. The role of calpain in synaptic plasticity, neuronal death, and AD has been discussed in some reviews. However, astrocytic calpain changes sometimes appear to be secondary and consequent to neuronal damage in AD. Herein, we explore the possibility of calpain-mediated astroglial reactivity in AD, both preceding and during the amyloid phase. We discuss the types of brain calpains but focus the review on calpains 1 and 2 and some important targets in astrocytes. We address the signaling involved in controlling calpain expression, mainly involving p38/mitogen-activated protein kinase and calcineurin, as well as how calpain regulates the expression of proteins involved in astroglial reactivity through calcineurin and cyclin-dependent kinase 5. Throughout the text, we have tried to provide evidence of the connection between the alterations caused by calpain and the metabolic changes associated with AD. In addition, we discuss the possibility that calpain mediates amyloid-ß clearance in astrocytes, as opposed to amyloid-ß accumulation in neurons.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Astrócitos/metabolismo , Encéfalo/metabolismo , Calpaína/metabolismo , Plasticidade Neuronal , Doença de Alzheimer/patologia , Animais , Astrócitos/patologia , Calcineurina/metabolismo , Quinase 5 Dependente de Ciclina/genética , Quinase 5 Dependente de Ciclina/metabolismo , Modelos Animais de Doenças , Humanos , Doenças Neuroinflamatórias/metabolismo
5.
J Neural Transm (Vienna) ; 117(11): 1295-305, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20953641

RESUMO

The intracerebroventricular infusion of streptozotocin (icv-STZ) has been largely used in research to mimic the main characteristics of Alzheimer's disease (AD), including cognitive decline, impairment of cholinergic transmission, oxidative stress and astrogliosis. Moderate physical exercise has a number of beneficial effects on the central nervous system, as demonstrated both in animals and in human studies. This study aimed to evaluate the effect of 5-week treadmill training, in the icv-SZT model of sporadic AD, on cognitive function, oxidative stress (particularly mediated by NO) and on the astrocyte marker proteins, glial fibrillary acidic protein (GFAP) and S100B. Results confirm the spatial cognitive deficit and oxidative stress in this model, as well as astroglial alterations, particularly a decrease in CSF S100B. Physical exercise prevented these alterations, as well as increasing the hippocampal content of glutathione and GFAP per se in the CA1 region. These findings reinforce the potential neuroprotective role of moderate physical exercise. Astroglial changes observed in this dementia model contribute to understanding AD and other diseases that are accompanied by cognitive deficit.


Assuntos
Transtornos Cognitivos/reabilitação , Hipocampo/fisiologia , Atividade Motora/fisiologia , Estresse Oxidativo/fisiologia , Doença de Alzheimer/reabilitação , Animais , Transtornos Cognitivos/induzido quimicamente , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/metabolismo , Glutationa/metabolismo , Hipocampo/efeitos dos fármacos , Imuno-Histoquímica , Injeções Intraventriculares , Masculino , Aprendizagem em Labirinto/fisiologia , Neurotoxinas/administração & dosagem , Neurotoxinas/toxicidade , Ratos , Ratos Wistar , Estreptozocina/administração & dosagem , Estreptozocina/toxicidade
6.
J Neuroimmunol ; 206(1-2): 52-7, 2009 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-19042033

RESUMO

S100B is an astrocyte-derived cytokine implicated in the IL-1beta-triggered cytokine cycle in Alzheimer's disease. However, the secretion of S100B following stimulation by IL-1beta has not been directly demonstrated. We investigated S100B secretion in cortical primary astrocyte cultures, C6 glioma cells and acute hippocampal slices exposed to IL-1beta. S100B secretion was induced by IL-1beta in all preparations, involving MAPK pathway and, apparently, NF-small ka, CyrillicB signaling. Astrocytes and C6 cells exhibited different sensitivities to IL-1beta. These results suggest that IL-1beta-induced S100B secretion is a component of the neuroinflammatory response, which would support the involvement of S100B in the genesis of neurodegenerative diseases.


Assuntos
Hipocampo/efeitos dos fármacos , Interleucina-1beta/farmacologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Fatores de Crescimento Neural/metabolismo , Neuroglia/efeitos dos fármacos , Proteínas S100/metabolismo , Transdução de Sinais/fisiologia , Análise de Variância , Animais , Animais Recém-Nascidos , Células Cultivadas , Córtex Cerebral/citologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Técnicas In Vitro , Indóis , L-Lactato Desidrogenase/metabolismo , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar , Subunidade beta da Proteína Ligante de Cálcio S100 , Transdução de Sinais/efeitos dos fármacos , Frações Subcelulares/efeitos dos fármacos , Fatores de Tempo
7.
J Alzheimers Dis ; 17(1): 193-202, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19494442

RESUMO

Although the exact cause of Alzheimer's disease remains elusive, many possible risk factors and pathological alterations have been used in the elaboration of in vitro and in vivo models of this disease in rodents, including intracerebral infusion of streptozotocin (STZ). Using this model, we evaluated spatial cognitive deficit and neurochemical hippocampal alterations, particularly astroglial protein markers such as glial fibrillary acidic protein (GFAP) and S100B, glutathione content, nitric oxide production, and cerebrospinal fluid (CSF) S100B. In addition, prevention of these alterations by aminoguanidine administration was evaluated. Results confirm a spatial cognitive deficit and nitrative stress in this dementia model as well as specific astroglial alterations, particularly S100B accumulation in the hippocampus and decreased CSF S100B. The hippocampal astroglial activation occurred independently of the significant alteration in GFAP content. Moreover, all these alterations were completely prevented by aminoguanidine administration, confirming the neuroprotective potential of this compound, but suggesting that nitrative stress and/or glycation may be underlying these alterations. These findings contribute to the understanding of diseases accompanied by cognitive deficits and the STZ-model of dementia.


Assuntos
Demência , Inibidores Enzimáticos/uso terapêutico , Guanidinas/uso terapêutico , Hipocampo/patologia , Estreptozocina , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Demência/induzido quimicamente , Demência/patologia , Demência/prevenção & controle , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/metabolismo , Glutationa/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Fatores de Crescimento Neural/líquido cefalorraquidiano , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Subunidade beta da Proteína Ligante de Cálcio S100 , Proteínas S100/líquido cefalorraquidiano
8.
Neurochem Res ; 34(9): 1603-11, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19288274

RESUMO

Hippocampal slices have been widely used to investigate electrophysiological and metabolic neuronal parameters, as well as parameters of astroglial activity including protein phosphorylation and glutamate uptake. S100B is an astroglial-derived protein, which extracellularly plays a neurotrophic activity during development and excitotoxic insult. Herein, we characterized S100B secretion in acute hippocampal slices exposed to different concentrations of K(+) and Ca(2+) in the extracellular medium. Absence of Ca(2+) and/or low K(+) (0.2 mM KCl) caused an increase in S100B secretion, possibly by mobilization of internal stores of Ca(2+). In contrast, high K(+) (30 mM KCl) or calcium channel blockers caused a decrease in S100B secretion. This study suggests that exposure of acute hippocampal slices to low- and high-K(+) could be used as an assay to evaluate astrocyte activity by S100B secretion: positively regulated by low K(+) (possibly involving mobilization of internal stores of Ca(2+)) and negatively regulated by high-K(+) (likely secondary to influx of K(+)).


Assuntos
Cálcio/metabolismo , Hipocampo/metabolismo , Fatores de Crescimento Neural/metabolismo , Potássio/metabolismo , Proteínas S100/metabolismo , Animais , Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Espaço Extracelular/metabolismo , Ácido Glutâmico/metabolismo , Glutationa/metabolismo , Hipocampo/efeitos dos fármacos , Masculino , Fosfopiruvato Hidratase/metabolismo , Potássio/farmacologia , Ratos , Ratos Wistar , Subunidade beta da Proteína Ligante de Cálcio S100 , Verapamil/farmacologia
9.
Behav Brain Res ; 190(2): 206-11, 2008 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-18395808

RESUMO

Lesion of the nucleus basalis magnocellularis (nbm) is a suitable approach to study cognitive deficit and behavior alterations involving cholinergic dysfunction, which is associated with the major types of dementia. Cortical astrogliosis also has been described in this model, but it is not clear whether hippocampal astrocytes are activated. In this study, we investigated possible specific astrocyte alterations in the hippocampi of Wistar rats submitted to nbm damage with ibotenic acid, investigating the content and immunohistochemistry of glial fibrillary acidic protein (GFAP), as well as S100B protein content, glutamate uptake and glutamine synthetase activity on the 7th and 28th post-lesion days. Cognitive deficit was confirmed by the step-down inhibitory avoidance task. Interestingly, we found a decrease in GFAP content, S100B content and glutamate uptake activity in the hippocampus on the 28th day after nbm lesion. No alterations were observed in glutamine synthetase activity or in the cerebrospinal fluid S100B content. Although our data suggest caution in the use of nbm lesion with ibotenic acid as a dementia model, it is possible that these alterations could contribute to the cognitive deficit observed in these rats.


Assuntos
Astrócitos/citologia , Aprendizagem da Esquiva/fisiologia , Núcleo Basal de Meynert/fisiologia , Fibras Colinérgicas/metabolismo , Demência/fisiopatologia , Hipocampo/citologia , Animais , Astrócitos/metabolismo , Núcleo Basal de Meynert/citologia , Núcleo Basal de Meynert/efeitos dos fármacos , Dano Encefálico Crônico/induzido quimicamente , Contagem de Células , Demência/metabolismo , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Seguimentos , Proteína Glial Fibrilar Ácida/metabolismo , Glutamato-Amônia Ligase/metabolismo , Ácido Glutâmico/metabolismo , Habituação Psicofisiológica/fisiologia , Hipocampo/metabolismo , Ácido Ibotênico , Imuno-Histoquímica , Masculino , Fatores de Crescimento Neural/metabolismo , Ratos , Ratos Wistar , Subunidade beta da Proteína Ligante de Cálcio S100 , Proteínas S100/metabolismo , Estatísticas não Paramétricas , Fatores de Tempo
10.
Brain Res ; 1187: 33-41, 2008 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-18021757

RESUMO

Pre- and postnatal protein malnutrition (PMN) adversely affects the developing brain in numerous ways, but only a few studies have investigated specific glial parameters. This study aimed to evaluate specific glial changes of rats exposed to pre and postnatal PMN, based on glial fibrillary acidic protein (GFAP) and S100B immunocontents as well as glutamine synthetase (GS), in cerebral cortex, hippocampus, cerebellum and cerebrospinal fluid, on the 2nd, 15th and 60th postnatal days. We found increases in GFAP, S100B and GS in the cerebral cortex at birth, suggesting an astrogliosis. Hippocampus and cerebellum also exhibited this profile at birth. However, a significant interaction between age and diet in postnatal life was observed only in the S100B of the cerebral cortex. No changes in the content of GFAP and S100B and GS activity were found on the 60th postnatal day in malnourished rats. In contrast, following an increase in the levels of S100B in the cerebrospinal fluid, during the early developmental stages, levels remained elevated on the 60th postnatal day. Our data support the concept of astrogliosis at birth, induced by PMN, and involve extracellular-regulated kinase activation. Specific alterations in cerebral cortex emphasize the regional vulnerability of the brain to malnutrition; some alterations were observed only at birth (e.g. GFAP); others were observed on the 2nd and 15th post-natal days (e.g. ERK phosphorylation). Taken together, transient and persistent alterations (e.g. elevated extracellular levels of S100B) suggest some brain damage or a risk of brain diseases in rats exposed to PMN.


Assuntos
Dano Encefálico Crônico/etiologia , Dano Encefálico Crônico/fisiopatologia , Transtornos da Nutrição Fetal/fisiopatologia , Gliose/etiologia , Gliose/fisiopatologia , Deficiência de Proteína/fisiopatologia , Envelhecimento/metabolismo , Animais , Animais Recém-Nascidos , Biomarcadores/análise , Biomarcadores/líquido cefalorraquidiano , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiopatologia , Dano Encefálico Crônico/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Gliose/metabolismo , Glutamato-Amônia Ligase/líquido cefalorraquidiano , Masculino , Fatores de Crescimento Neural/líquido cefalorraquidiano , Neuroglia/metabolismo , Gravidez , Ratos , Ratos Wistar , Subunidade beta da Proteína Ligante de Cálcio S100 , Proteínas S100/líquido cefalorraquidiano
11.
Prog Neuropsychopharmacol Biol Psychiatry ; 32(6): 1580-3, 2008 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-18582527

RESUMO

S100B is a calcium-binding protein, produced and secreted by astrocytes, which has a putative paracrine neurotrophic activity. Clinical studies have suggested that peripheral elevation of this protein is positively correlated with a therapeutic antidepressant response, particularly to selective serotonin reuptake inhibitors (SSRIs); however, the mechanism underlying this response remains unclear. Here, we measured S100B secretion directly in hippocampal astrocyte cultures and hippocampal slices exposed to fluoxetine and observed a significant increment of S100B release in the presence of this SSRI, apparently dependent on protein kinase A (PKA). Moreover, we found that serotonin (possibly via the 5HT1A receptor) reduces S100B secretion and antagonizes the effect of fluoxetine on S100B secretion. These data reinforce the effect of fluoxetine, independently of serotonin and serotonin receptors, suggesting a putative role for S100B in depressive disorders and suggesting that other molecular targets may be relevant for antidepressant activity.


Assuntos
Astrócitos/metabolismo , Fluoxetina/farmacologia , Fatores de Crescimento Neural/metabolismo , Proteínas S100/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Serotonina/fisiologia , Animais , Astrócitos/efeitos dos fármacos , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ratos , Ratos Wistar , Receptores de Serotonina/efeitos dos fármacos , Subunidade beta da Proteína Ligante de Cálcio S100 , Serotonina/farmacologia
12.
Front Neurosci ; 12: 1035, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30728759

RESUMO

Based on the concept of the tripartite synapse, we have reviewed the role of glucose-derived compounds in glycolytic pathways in astroglial cells. Glucose provides energy and substrate replenishment for brain activity, such as glutamate and lipid synthesis. In addition, glucose metabolism in the astroglial cytoplasm results in products such as lactate, methylglyoxal, and glutathione, which modulate receptors and channels in neurons. Glucose has four potential destinations in neural cells, and it is possible to propose a crossroads in "X" that can be used to describe these four destinations. Glucose-6P can be used either for glycogen synthesis or the pentose phosphate pathway on the left and right arms of the X, respectively. Fructose-6P continues through the glycolysis pathway until pyruvate is formed but can also act as the initial compound in the hexosamine pathway, representing the left and right legs of the X, respectively. We describe each glucose destination and its regulation, indicating the products of these pathways and how they can affect synaptic communication. Extracellular L-lactate, either generated from glucose or from glycogen, binds to HCAR1, a specific receptor that is abundantly localized in perivascular and post-synaptic membranes and regulates synaptic plasticity. Methylglyoxal, a product of a deviation of glycolysis, and its derivative D-lactate are also released by astrocytes and bind to GABAA receptors and HCAR1, respectively. Glutathione, in addition to its antioxidant role, also binds to ionotropic glutamate receptors in the synaptic cleft. Finally, we examined the hexosamine pathway and evaluated the effect of GlcNAc-modification on key proteins that regulate the other glucose destinations.

13.
Brain Res ; 1698: 54-61, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29932894

RESUMO

Sepsis is one of the main causes of hospitalization and mortality in Intensive Care Units. One of the first manifestations of sepsis is encephalopathy, reported in up to 70% of patients, being associated with higher mortality and morbidity. The factors that cause sepsis-associated encephalopathy (SAE) are still not well known, and may be multifactorial, as perfusion changes, neuroinflammation, oxidative stress and glycolytic metabolism alterations. Fructose-1,6-bisphosphate (FBP), a metabolite of the glycolytic route, has been reported as neuroprotective agent. The present study used an experimental sepsis model in C57BL/6 mice. We used in vivo brain imaging to evaluate glycolytic metabolism through microPET scans and the radiopharmaceutical 18F-fluoro-2-deoxy-D-glucose (18F-FDG). Brain images were obtained before and 12 h after the induction of sepsis in animals with and without FBP treatment. We also evaluated the treatment effects in the brain oxidative stress by measuring the production of reactive oxygen species (ROS), the activity of catalase (CAT) and glutathione peroxidase (GPx), and the levels of fluorescent marker 2'7'-dichlorofluorescein diacetate (DCF). There was a significant decrease in brain glucose metabolism due to experimental sepsis. A significant protective effect of FBP treatment was observed in the cerebral metabolic outcomes. FBP also modulated the production of ROS, evidenced by reduced CAT activity and lower levels of DCF. Our results suggest that FBP may be a possible candidate in the treatment of SAE.


Assuntos
Frutosedifosfatos/farmacologia , Glucose/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sepse/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encefalopatias/tratamento farmacológico , Modelos Animais de Doenças , Fluordesoxiglucose F18 , Frutose/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Sepse/tratamento farmacológico
14.
Neurochem Int ; 50(5): 774-82, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17350141

RESUMO

S100B is an astrocyte calcium-binding protein that plays a regulatory role in the cytoskeleton and cell cycle. Moreover, extracellular S100B, a marker of glial activation in several conditions of brain injury, has a trophic or apoptotic effect on neurons, depending on its concentration. Hyperglycemic rats show changes in glial parameters, including S100B expression. Here, we investigated cell density, morphological and biochemical alterations in primary cortical astrocytes from rats and C6 glioma cells cultured in high-glucose medium. Astrocytes and C6 glioma cells have a reduced content of S100B and glial fibrillary acidic protein when cultured in a high-glucose environment, as well as a reduced content of glutathione and cell proliferation rate. Although these cells have been used indistinctly to study S100B secretion, we observed a contrasting profile of S100B secretion in a high-glucose medium: a decrease in primary astrocytes and an increase in C6 glioma cells. Based on the in vitro neurotrophic effects of the S100B protein, our data suggest that chronic elevated glucose levels affect astrocyte activity, reducing extracellular secretion of S100B and that this, in turn, could affect neuronal activity and survival. Such astrocyte alterations could contribute to cognitive deficit and other impairments observed in diabetic patients.


Assuntos
Astrócitos/metabolismo , Fatores de Crescimento Neural/metabolismo , Proteínas S100/metabolismo , Animais , Astrócitos/citologia , Linhagem Celular Tumoral , Proliferação de Células , Células Cultivadas , Meios de Cultura/química , Glucose/metabolismo , Ácido Glutâmico/metabolismo , Glutationa/metabolismo , Neuroglia/citologia , Ratos , Ratos Wistar , Subunidade beta da Proteína Ligante de Cálcio S100
15.
J Neurosci Methods ; 162(1-2): 282-6, 2007 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-17303248

RESUMO

Glial fibrillary acid protein (GFAP) is used commonly as a marker of astrogliosis and astrocyte activation in several situations involving brain injury. Its content may be measured by immunocytochemistry, immunoblotting or enzyme-linked immunosorbent assay (ELISA), usually employing commercial antibodies. Two major post-translational modifications in GFAP (phosphorylation and proteolysis) may alter the interpretation of results or for immunoassay standardization. This study using a non-sandwich ELISA aimed to investigate the putative changes in the immunorecognition due to the phosphorylated state of the antigen by a routinely used polyclonal anti-GFAP antibody from DAKO. Results involving in vitro phosphorylation of purified GFAP or biological samples (brain tissue, cell culture and cerebrospinal fluid) mediated by protein kinase dependent on cAMP indicate that GFAP phosphorylation improves the recognition by the used antibody. These results provide support to the understanding of fast changes in the GFAP-immunoreactivity and suggest that caution is necessary in the interpretation of results using this antibody, as well as indicate that the effect of post-translational modifications must be considered during the standardization of immunoassays with other antibodies.


Assuntos
Astrócitos/fisiologia , Encéfalo/fisiologia , Proteína Glial Fibrilar Ácida/análise , Neuroglia/citologia , Animais , Anticorpos , Astrócitos/citologia , Encéfalo/citologia , Química Encefálica , Córtex Cerebral/citologia , Córtex Cerebral/fisiologia , Ensaio de Imunoadsorção Enzimática , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Proteína Glial Fibrilar Ácida/metabolismo , Cinética , Neuroglia/fisiologia , Fosforilação , Ratos , Ratos Wistar
16.
Brain Res ; 1144: 107-16, 2007 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-17335785

RESUMO

This study was undertaken to verify if repeated long-term separation from dams would affect the development of parameters related to post-traumatic stress disorder (PTSD) after animals are subjected to inescapable shock when adults. Wistar rats were subjected to repeated maternal separation during post-natal days 1-10. When adults, rats from both sexes were submitted to a PTSD model consisting of exposure to inescapable footshock, followed by situational reminders. We observed long-lasting effects of both interventions. Exposure to shock increased fear conditioning. Anxiety-like behavior was increased and exploratory activity decreased by both treatments, and these effects were more robust in males. Additionally, basal corticosterone in plasma was decreased, paralleling effects observed in PTSD patients. Levels of S100B protein in serum and cerebrospinal fluid (CSF) were measured. Levels in serum correlated with the effects observed in anxiety-like behavior, increasing in males exposed to shock, and presenting no effect in females. S100B in CSF was increased in females submitted to maternal separation during the neonatal period. These results suggest that, in rats, an early stress experience such as maternal separation may aggravate some effects of exposure to a stressor during adult age, and that this effect is sex-specific. Additionally, data suggest that the increased S100B levels, observed in serum, have an extracerebral origin, possibly mediated by an increase in the noradrenergic tonus. Increased S100B in brain could be related to its neurotrophic actions.


Assuntos
Comportamento Animal/fisiologia , Privação Materna , Fatores de Crescimento Neural/metabolismo , Proteínas S100/metabolismo , Caracteres Sexuais , Transtornos de Estresse Pós-Traumáticos/metabolismo , Análise de Variância , Animais , Animais Recém-Nascidos , Condicionamento Psicológico/fisiologia , Corticosterona/sangue , Modelos Animais de Doenças , Eletrochoque/efeitos adversos , Comportamento Exploratório/fisiologia , Medo/fisiologia , Feminino , Masculino , Gravidez , Ratos , Ratos Wistar , Subunidade beta da Proteína Ligante de Cálcio S100
17.
Mol Neurobiol ; 54(8): 6356-6377, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27722926

RESUMO

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces motor and nonmotor dysfunctions resembling Parkinson's disease (PD); however, studies investigating the effects of 1-methyl-4-phenylpyridinium (MPP+), an active oxidative product of MPTP, are scarce. This study investigated the behavioral and striatal neurochemical changes (related to oxidative damage, glial markers, and neurotrophic factors) 24 h after intracerebroventricular administration of MPP+ (1.8-18 µg/mouse) in C57BL6 mice. MPP+ administration at high dose (18 µg/mouse) altered motor parameters, since it increased the latency to leave the first quadrant and reduced crossing, rearing, and grooming responses in the open-field test and decreased rotarod latency time. MPP+ administration at low dose (1.8 µg/mouse) caused specific nonmotor dysfunctions as it produced a depressive-like effect in the forced swim test and tail suspension test, loss of motivational and self-care behavior in the splash test, anxiety-like effect in the elevated plus maze test, and short-term memory deficit in the step-down inhibitory avoidance task, without altering ambulation. MPP+ at doses of 1.8-18 µg/mouse increased tyrosine hydroxylase (TH) immunocontent and at 18 µg/mouse increased α-synuclein and decreased parkin immunocontent. The astrocytic calcium-binding protein S100B and glial fibrillary acidic protein (GFAP)/S100B ratio was decreased following MPP+ administration (18 µg/mouse). At this highest dose, MPP+ increased the ionized calcium-binding adapter molecule 1 (Iba-1) immunocontent, suggesting microglial activation. Also, MPP+ at a dose of 18 µg/mouse increased thiobarbituric acid reactive substances (TBARS) and glutathione (GSH) levels and increased glutathione peroxidase (GPx) and hemeoxygenase-1 (HO-1) immunocontent, suggesting a significant role for oxidative stress in the MPP+-induced striatal damage. MPP+ (18 µg/mouse) also increased striatal fibroblast growth factor 2 (FGF-2) and brain-derived neurotrophic factor (BDNF) levels. Moreover, MPP+ decreased tropomyosin receptor kinase B (TrkB) immunocontent. Finally, MPP+ (1.8-18 µg/mouse) increased serum corticosterone levels and did not alter acetylcholinesterase (AChE) activity in the striatum but increased it in cerebral cortex and hippocampus. Collectively, these results indicate that MPP+ administration at low doses may be used as a model of emotional and memory/learning behavioral deficit related to PD and that MPP+ administration at high dose could be useful for analysis of striatal dysfunctions associated with motor deficits in PD.


Assuntos
1-Metil-4-fenilpiridínio/toxicidade , Corpo Estriado/efeitos dos fármacos , Emoções/efeitos dos fármacos , Aprendizagem/efeitos dos fármacos , Memória/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Animais , Corpo Estriado/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Glutationa/metabolismo , Camundongos , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
18.
Arch Med Res ; 37(5): 683-6, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16740441

RESUMO

BACKGROUND: S100B is a calcium-binding protein expressed and secreted by astrocytes; serum and cerebrospinal fluid (CSF) S100B elevation has been proposed as an index of brain damage. However, other tissues are shown to produce this protein and the clinical significance of serum S100B elevation has been discussed. METHODS: We investigated the levels of serum and CSF S100B in fasting Wistar rats. Animals were divided into two groups, control and fasting for 48 h, and S100B levels in serum and CSF were determined by ELISA. S100B secretion in dissociated epididymal fat cells was investigated in the presence of epinephrine. RESULTS: We observed a significant >2-fold increase of S100B levels in serum of fasting rats, without changes in its CSF content. Moreover, we demonstrated in vitro epinephrine stimulated S100B release from fat cells. CONCLUSIONS: Present results reinforce that extracerebral sources of S100B, particularly adipocytes, contribute to its serum levels and support the idea that caution is needed when interpreting serum S100B increase as a clinical marker of brain damage.


Assuntos
Proteínas Secretadas pelo Epidídimo/análise , Jejum/sangue , Jejum/líquido cefalorraquidiano , Fatores de Crescimento Neural/sangue , Fatores de Crescimento Neural/líquido cefalorraquidiano , Proteínas S100/sangue , Proteínas S100/líquido cefalorraquidiano , Animais , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Lesões Encefálicas/sangue , Células Cultivadas , Epididimo/citologia , Epididimo/metabolismo , Epinefrina/farmacologia , Masculino , Ratos , Ratos Wistar , Subunidade beta da Proteína Ligante de Cálcio S100 , Fatores de Tempo , Vasoconstritores/farmacologia
19.
PLoS One ; 10(5): e0127845, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25978644

RESUMO

The developing brain is vulnerable to the effects of ethanol. Glutamate is the main mediator of excitatory signals in the brain and is probably involved in most aspects of normal brain function during development. The aim of this study was to investigate vulnerability to and the impact of ethanol toxicity on glutamate uptake signaling in adolescent rats after moderate pre and postnatal ethanol exposure. Pregnant female rats were divided into three groups and treated only with water (control), non-alcoholic beer (vehicle) or 10% (v/v) beer solution (moderate prenatal alcohol exposure-MPAE). Thirty days after birth, adolescent male offspring were submitted to hippocampal acute slice procedure. We assayed glutamate uptake and measured glutathione content and also quantified glial glutamate transporters (EAAT 1 and EAAT 2). The glutamate system vulnerability was tested with different acute ethanol doses in naïve rats and compared with the MPAE group. We also performed a (lipopolysaccharide-challenge (LPS-challenge) with all groups to test the glutamate uptake response after an insult. The MPAE group presented a decrease in glutamate uptake corroborating a decrease in glutathione (GSH) content. The reduction in GSH content suggests oxidative damage after acute ethanol exposure. The glial glutamate transporters were also altered after prenatal ethanol treatment, suggesting a disturbance in glutamate signaling. This study indicates that impairment of glutamate uptake can be dose-dependent and the glutamate system has a higher vulnerability to ethanol toxicity after moderate ethanol exposure In utero. The effects of pre- and postnatal ethanol exposure can have long-lasting impacts on the glutamate system in adolescence and potentially into adulthood.


Assuntos
Etanol/efeitos adversos , Ácido Glutâmico/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Feminino , Glutationa/metabolismo , Masculino , Gravidez , Ratos
20.
Psychiatry Res ; 220(3): 745-51, 2014 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-25457283

RESUMO

The role of cholesterol in psychiatric diseases has aroused the interest of the medical community, particularly in association with violent and suicidal behavior. Herein, we discuss some aspects of brain cholesterol metabolism, exploring possible mechanisms underlying the findings and reviewing the available literature on the possible neurochemical link between suicide and low or reduced levels of serum cholesterol. Most of the current hypotheses suggest a decreased serotonergic activity due to a decrease in cholesterol in the lipid rafts of synaptic membranes. Some aspects and limitations of this assumption are emphasized. In addition to serotonin hypofunction, other mechanisms have been proposed to explain increased impulsivity in suicidal individuals, including steroid modulation and brain-derived neurotrophic factor decrease, which could also be related to changes in lipid rafts. Other putative markers of suicidal behavior (e.g. protein S100B) are discussed in connection with cholesterol metabolism in the brain tissue.


Assuntos
Encéfalo/metabolismo , Colesterol/metabolismo , Transtornos Mentais/metabolismo , Ideação Suicida , Suicídio , Biomarcadores/metabolismo , Fator Neurotrófico Derivado do Encéfalo/sangue , Colesterol/sangue , Humanos , Transtornos Mentais/diagnóstico , Transtornos Mentais/psicologia , Serotonina/sangue , Serotonina/metabolismo , Suicídio/psicologia
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