RESUMO
Schizophrenia (SZ) is a multifactorial mental disorder, which has been associated with a number of environmental factors, such as hypoxia. Considering that numerous neural mechanisms depends on energetic supply (ATP synthesis), the maintenance of mitochondrial metabolism is essential to keep cellular balance and survival. Therefore, in the present work, we evaluated functional parameters related to mitochondrial function, namely calcium levels, mitochondrial membrane potential, redox homeostasis, high-energy compounds levels and oxygen consumption, in astrocytes from control (Wistar) and Spontaneously Hypertensive Rats (SHR) animals exposed both to chemical and gaseous hypoxia. We show that astrocytes after hypoxia presented depolarized mitochondria, disturbances in Ca2+ handling, destabilization in redox system and alterations in ATP, ADP, Pyruvate and Lactate levels, in addition to modification in NAD+/NADH ratio, and Nfe2l2 and Nrf1 expression. Interestingly, intrauterine hypoxia also induced augmentation in mitochondrial biogenesis and content. Altogether, our data suggest that hypoxia can induce mitochondrial deregulation and a decrease in energy metabolism in the most prevalent cell type in the brain, astrocytes. Since SHR are also considered an animal model of SZ, our results can likewise be related to their phenotypic alterations and, therefore, our work also allow an increase in the knowledge of this burdensome disorder.
Assuntos
Astrócitos/patologia , Hipóxia Celular , Hipóxia Fetal/complicações , Mitocôndrias/patologia , Esquizofrenia/patologia , Trifosfato de Adenosina/metabolismo , Animais , Animais Recém-Nascidos , Astrócitos/citologia , Encéfalo/citologia , Encéfalo/patologia , Sobrevivência Celular , Células Cultivadas , Modelos Animais de Doenças , Metabolismo Energético , Feminino , Hipóxia Fetal/patologia , Humanos , Masculino , Potencial da Membrana Mitocondrial , Mitocôndrias/metabolismo , Oxirredução , Consumo de Oxigênio , Gravidez , Cultura Primária de Células , Ratos , Ratos Endogâmicos SHR , Esquizofrenia/etiologiaRESUMO
OBJECTIVE: We tested the hypothesis that chronic fetal hypoxia, at a severity present in many types of congenital heart disease, would lead to abnormal neurodevelopment. METHODS: Eight mid-gestation fetal sheep were cannulated onto a pumpless extracorporeal oxygenator via the umbilical vessels and supported in a fluid-filled environment for 22 ± 2 days under normoxic or hypoxic conditions. Total parenteral nutrition was provided. Control fetuses (n = 7) were harvested at gestational age 133 ± 4 days. At necropsy, brains were fixed for histopathology. Neurons were quantified in white matter tracts, and the thickness of the external granular layer of the cerebellum was measured to assess neuronal migration. Capillary density and myelination were quantified in white matter. Data were analyzed with unpaired Student t tests or 1-way analysis of variance, as appropriate. RESULTS: Oxygen delivery was reduced in hypoxic fetuses (15.6 ± 1.8 mL/kg/min vs 24.3 ± 2.3 mL/kg/min, P < .01), but umbilical blood flow and caloric delivery were not different between the 2 groups. Compared with normoxic and control animals, hypoxic fetuses had reduced neuronal density and increased external granular layer thickness. Compared with normoxic and control animals, hypoxic fetuses had increased capillary density in white matter. Cortical myelin integrity score was lower in the hypoxic group compared with normoxic and control animals. There was a significant negative correlation between myelin integrity and capillary density. CONCLUSIONS: Chronic fetal hypoxia leads to white matter hyper-vascularity, decreased neuronal density, and impaired myelination, similar to the neuropathologic findings observed in children with congenital heart disease. These findings support the hypothesis that fetal hypoxia, even in the setting of normal caloric delivery, impairs neurodevelopment.
Assuntos
Encefalopatias/fisiopatologia , Encéfalo/crescimento & desenvolvimento , Capilares/fisiopatologia , Hipóxia Fetal/fisiopatologia , Neovascularização Fisiológica , Neurogênese , Neurônios , Animais , Apoptose , Encéfalo/metabolismo , Encéfalo/patologia , Encefalopatias/sangue , Encefalopatias/patologia , Capilares/patologia , Doença Crônica , Modelos Animais de Doenças , Feminino , Sangue Fetal/metabolismo , Desenvolvimento Fetal , Hipóxia Fetal/sangue , Hipóxia Fetal/patologia , Idade Gestacional , Bainha de Mielina/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Oxigênio/sangue , Gravidez , Carneiro DomésticoRESUMO
Complications act as stress-inducers during pregnancy so the fetus can develop functional compensatory mechanisms or morphologic changes. The cases analyzed are with congenital malformations or acute stress; chronic included cases with ascending infection (AI) and perinatal hypoxia/anoxia (PHA). The hematoxylin-eosin (H&E) was done to analyze the vacuolization, and the immunohistochemistry to the phagocytosis. The discreet standard of vacuolization was observed in 52.6% of the cases, 22.1% moderate, and 25.3% severe. The number of macrophages was higher in PHA. Changes in these organs are closely related to the cause of death and to the period during which the harmful agent.
Assuntos
Infecções Bacterianas/patologia , Morte Fetal , Doenças Fetais/patologia , Mortalidade Infantil , Complicações Infecciosas na Gravidez/patologia , Estresse Fisiológico , Córtex Suprarrenal/embriologia , Córtex Suprarrenal/metabolismo , Córtex Suprarrenal/patologia , Adulto , Infecções Bacterianas/metabolismo , Infecções Bacterianas/mortalidade , Contagem de Células , Anormalidades Congênitas , Feminino , Doenças Fetais/mortalidade , Hipóxia Fetal/metabolismo , Hipóxia Fetal/mortalidade , Hipóxia Fetal/patologia , Idade Gestacional , Humanos , Recém-Nascido , Infecções , Macrófagos/patologia , Gravidez , Complicações Infecciosas na Gravidez/metabolismo , Complicações Infecciosas na Gravidez/mortalidade , Nascimento Prematuro , Timo/patologia , Vacúolos/patologiaAssuntos
Humanos , Masculino , Feminino , Recém-Nascido , Lactente , Pré-Escolar , Criança , Células Receptoras Sensoriais/imunologia , Convulsões Febris/classificação , Convulsões Febris/diagnóstico , Convulsões Febris/etiologia , Epilepsia/patologia , Hipóxia Fetal/patologia , Infecções do Sistema Nervoso Central/imunologia , PediatriaRESUMO
We previously found that prenatal hypoxia induces a significant increase in the levels of active Caspase 3 at 60 min post-hypoxia (p-h) and in the number of TUNEL-positive pyknotic cells, which peaks at 6h p-h. The aim of this work was to study alterations in MAPKs pathways and the effect of specific inhibitors of the JNK (SP600125) and p38 (SB203580) pathways following acute hypoxia in chick optic lobe at embryonic day (ED) 12. To this end, JNK, p38 and ERK1-2 protein kinase expression levels were determined by Western blot in both their active and inactive forms, evaluated at successive p-h times. At 10 and 30 min p-h the P-JNK/JNK ratio was 1.912+/-0.341 and 1.920+/-0.304, respectively. Concomitantly, at 0 min p-h the P-p38/p38 ratio was 1.657+/-0.203. Lastly, the P-ERK/ERK ratio proving non-significant throughout. When inhibitors for JNK and p38 were used, we observed a decrease in the values of active Caspase 3 at 60 min p-h, which correlated with the control values in the parameters of TUNEL-positive cells at 6h p-h. Analysis for P-ATF-2 demonstrated an increase in hypoxic embryos compared to control ones which was reverted in a dose-dependent manner with the use of both inhibitors. All these results indicate that at ED 12, acute hypoxia might be differentially activating JNK and p38 pathways, without affecting the ERK pathway, which in turn would be activating Caspase 3, thus leading to cell death by apoptosis. Furthermore, JNK and p38 activation precede in time the programmed cell death induced by hypoxia.
Assuntos
Apoptose/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/biossíntese , Hipóxia Fetal/enzimologia , Hipóxia Fetal/patologia , Proteínas Quinases JNK Ativadas por Mitógeno/biossíntese , Proteínas Quinases p38 Ativadas por Mitógeno/biossíntese , Animais , Apoptose/genética , Western Blotting , Caspase 3/biossíntese , Caspase 3/genética , Embrião de Galinha , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/genética , Hipóxia Fetal/genética , Marcação In Situ das Extremidades Cortadas , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/genéticaRESUMO
Se realiza un estudio anatopatológico de las lesiones isquémico-anóxicas en fetos y recién nacidos fallecidos. Se indica que las lesiones encontradas fueron de 2 tipos. Se describen las características estructurales y de localización, su relación con la hemorragia cerebral y la madurez estructural de los fetos y recién nacidos