RESUMO
Intraneuronal aggregates of neurofibrillary tangles (NFTs), together with beta-amyloid plaques and astrogliosis, are histological markers of Alzheimer's disease (AD). The underlying mechanism of sporadic AD remains poorly understood, but abnormal hyperphosphorylation of tau protein is suggested to have a role in NFTs genesis, which leads to neuronal dysfunction and death. Okadaic acid (OKA), a strong inhibitor of protein phosphatase 2A, has been used to induce dementia similar to AD in rats. We herein investigated the effect of intracerebroventricular (ICV) infusion of OKA (100 and 200ng) on hippocampal tau phosphorylation at Ser396, which is considered an important fibrillogenic tau protein site, and on glucose uptake, which is reduced early in AD. ICV infusion of OKA (at 200ng) induced a spatial cognitive deficit, hippocampal astrogliosis (based on GFAP increment) and increase in tau phosphorylation at site 396 in this model. Moreover, we observed a decreased glucose uptake in the hippocampal slices of OKA-treated rats. In vitro exposure of hippocampal slices to OKA altered tau phosphorylation at site 396, without any associated change in glucose uptake activity. Taken together, these findings further our understanding of OKA neurotoxicity, in vivo and vitro, particularly with regard to the role of tau phosphorylation, and reinforce the importance of the OKA dementia model for studying the neurochemical alterations that may occur in AD, such as NFTs and glucose hypometabolism.
Assuntos
Inibidores Enzimáticos/administração & dosagem , Glucose/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ácido Okadáico/administração & dosagem , Animais , Cognição/efeitos dos fármacos , Relação Dose-Resposta a Droga , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Glutamato-Amônia Ligase/metabolismo , Ácido Glutâmico/metabolismo , Glutationa/metabolismo , Técnicas In Vitro , Injeções Intraventriculares , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidiano , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Proteínas tau/metabolismoRESUMO
Diabetic patients and streptozotocin (STZ)-induced diabetes mellitus (DM) models exhibit signals of brain dysfunction, evidenced by neuronal damage and memory impairment. Astrocytes surrounding capillaries and synapses modulate many brain activities that are connected to neuronal function, such as nutrient flux and glutamatergic neurotransmission. As such, cognitive changes observed in diabetic patients and experimental models could be related to astroglial alterations. Herein, we investigate specific astrocyte changes in the rat hippocampus in a model of DM induced by STZ, particularly looking at glial fibrillary acidic protein (GFAP), S100B protein and glutamate uptake, as well as the content of advanced glycated end products (AGEs) in serum and cerebrospinal fluid (CSF), as a consequence of elevated hyperglycemia and the content of receptor for AGEs in the hippocampus. We found clear peripheral alterations, including hyperglycemia, low levels of proinsulin C-peptide, elevated levels of AGEs in serum and CSF, as well as an increase in RAGE in hippocampal tissue. We found specific astroglial abnormalities in this brain region, such as reduced S100B content, reduced glutamate uptake and increased S100B secretion, which were not accompanied by changes in GFAP. We also observed an increase in the glucose transporter, GLUT-1. All these changes may result from RAGE-induced inflammation; these astroglial alterations together with the reduced content of GluN1, a subunit of the NMDA receptor, in the hippocampus may be associated with the impairment of glutamatergic communication in diabetic rats. These findings contribute to understanding the cognitive deficits in diabetic patients and experimental models.
Assuntos
Astrócitos/metabolismo , Diabetes Mellitus Experimental/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Hipocampo/metabolismo , Animais , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/líquido cefalorraquidiano , Produtos Finais de Glicação Avançada/sangue , Produtos Finais de Glicação Avançada/líquido cefalorraquidiano , Masculino , Técnicas de Cultura de Órgãos , Ratos , Ratos Endogâmicos WKY , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidiano , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , EstreptozocinaRESUMO
Both glial fibrillary acidic protein (GFAP) and S100B have been used as markers of astroglial plasticity, particularly in brain injury; however, they do not necessarily change in the same time frame or direction. Herein, we induced a Parkinson's disease (PD) model via a 6-OHDA intrastriatal injection in rats and investigated the changes in GFAP and S100B using ELISA in the substantia nigra (SN), striatum, and cerebrospinal fluid on the 1st, 7th, and 21st days following the injection. The model was validated using measurements of rotational behaviour induced by methylphenidate and tyrosine hydroxylase in the dopaminergic pathway. To our knowledge, this is the first measurement of cerebrospinal fluid S100B and GFAP in the 6-OHDA model of PD. Gliosis (based on a GFAP increase) was identified in the striatum, but not in the SN. We identified a transitory increment of cerebrospinal fluid S100B and GFAP on the 1st and 7th days, respectively. This initial change in cerebrospinal fluid S100B was apparently related to the mechanical lesion. However, the 6-OHDA-induced S100B secretion was confirmed in astrocyte cultures. Current data reinforce the idea that glial changes precede neuronal damage in PD; however, these findings also indicate that caution is necessary regarding the interpretation of data in this PD model.
Assuntos
Corpo Estriado/metabolismo , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Transtornos Parkinsonianos/líquido cefalorraquidiano , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidiano , Substância Negra/metabolismo , Animais , Astrócitos/metabolismo , Células Cultivadas , Corpo Estriado/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/análise , Masculino , Atividade Motora/efeitos dos fármacos , Oxidopamina , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Ratos , Ratos Wistar , Subunidade beta da Proteína Ligante de Cálcio S100/análise , Substância Negra/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Alcohol consumption by women during gestation has become increasingly common. Although it is widely accepted that exposure to high doses of ethanol has long-lasting detrimental effects on brain development, the case for moderate doses is underappreciated, and benchmark studies have demonstrated structural and behavioral defects associated with moderate prenatal alcohol exposure in humans and animal models. This study aimed to investigate the influence of in utero exposure to moderate levels of ethanol throughout pregnancy on learning/memory, anxiety parameters and neuroglial parameters in adolescent offspring. Female rats were exposed to an experimental protocol throughout gestation up to weaning. After mating, the dams were divided into three groups and treated with only water (control), non-alcoholic beer (vehicle) or 10% (vv) beer solution (moderate prenatal alcohol exposure - MPAE). Adolescent male offspring were subjected to the plus-maze discriminative avoidance task to evaluate learning/memory and anxiety-like behavior. Hippocampi were dissected and slices were obtained for immunoquantification of GFAP, NeuN, S100B and the NMDA receptor. The MPAE group clearly presented anxiolytic-like behavior, even though they had learned how to avoid the aversive arm. S100B protein was increased in the cerebrospinal fluid (CSF) in the group treated with alcohol, and alterations in GFAP expression were also shown. This study indicates that moderate ethanol doses administered during pregnancy could induce anxiolytic-like effects, suggesting an increase in risk-taking behavior in adolescent male offspring. Furthermore, the data show the possibility that glial cells are involved in the altered behavior present after prenatal ethanol treatment.
Assuntos
Ansiedade/fisiopatologia , Aprendizagem da Esquiva , Transtornos do Espectro Alcoólico Fetal/fisiopatologia , Hipocampo/fisiopatologia , Memória/fisiologia , Neuroglia/fisiologia , Efeitos Tardios da Exposição Pré-Natal , Animais , Cerveja , Depressores do Sistema Nervoso Central/toxicidade , Etanol/toxicidade , Feminino , Transtornos do Espectro Alcoólico Fetal/patologia , Hipocampo/crescimento & desenvolvimento , Hipocampo/patologia , Masculino , Atividade Motora , Neuroglia/patologia , Neurônios/patologia , Neurônios/fisiologia , Gravidez , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Assunção de Riscos , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidianoRESUMO
OBJECTIVE: The present study is to describe the clinical impact of S100 and S100ß for the evaluation of cerebral damage in cardiac surgery with or without the use of cardiopulmonary bypass (CPB). METHODS: Quantitative results of S100 and S100ß reported in the literature of the year range 1990-2014 were collected, screened and analyzed. RESULTS: Cerebrospinal fluid and serum S100 levels showed a same trend reaching a peak at the end of CPB. The cerebrospinal fluid/serum S100 ratio decreased during CPB, reached a nadir at 6 h after CPB and then increased and kept high untill 24 h after CPB. Serum S100 at the end of CPB was much higher in infant than in adults, and in on-pump than in off-pump coronary artery bypass patients. ∆S100 increased with age and CPB time but lack of statistical significances. Patients receiving an aorta replacement had a much higher ∆S100 than those receiving a congenital heart defect repair. Serum S100ß reached a peak at the end of CPB, whereas cerebrospinal fluid S100 continued to increase and reached a peak at 6 h after CPB. The cerebrospinal fluid/serum S100ß ratio decreased during CPB, increased at the end of CPB, peaked 1 h after CPB, and then decreased abruptly. The increase of serum S100ß at the end of CPB was associated with type of operation, younger age, lower core temperature and cerebral damages. ∆S100ß displayed a decreasing trend with age, type of operation, shortening of CPB duration, increasing core temperature, lessening severity of cerebral damage and the application of intervenes. Linear correlation analysis revealed that serum S100ß concentration at the end of CPB correlated closely with CPB duration. CONCLUSION: S100 and S100ß in cerebrospinal fluid can be more accurate than in the serum for the evaluations of cerebral damage in cardiac surgery. However, cerebrospinal fluid biopsies are limited. But serum S100ß and ∆S100ß seem to be more sensitive than serum S100 and ∆S100. The cerebral damage in cardiac surgery might be associated with younger age, lower core temperature and longer CPB duration during the operation. Effective intervenes with modified CPB circuit filters or oxygenators and supplemented anesthetic agents or priming components may alleviate the cerebral damage.