RESUMO
This article comprehensively reviews how cerebral hypoxia impacts the physiological state of neurons and dendritic spines through a series of molecular changes, and explores the causal relationship between these changes and neuronal functional impairment. As a severe pathological condition, cerebral hypoxia can significantly alter the morphology and function of neurons and dendritic spines. Specifically, dendritic spines, being the critical structures for neurons to receive information, undergo changes such as a reduction in number and morphological abnormalities under hypoxic conditions. These alterations further affect synaptic function, leading to neurotransmission disorders. This article delves into the roles of molecular pathways like MAPK, AMPA receptors, NMDA receptors, and BDNF in the hypoxia-induced changes in neurons and dendritic spines, and outlines current treatment strategies. Neurons are particularly sensitive to cerebral hypoxia, with their apical dendrites being vulnerable to damage, thereby affecting cognitive function. Additionally, astrocytes and microglia play an indispensable role in protecting neuronal and synaptic structures, regulating their normal functions, and contributing to the repair process following injury. These studies not only contribute to understanding the pathogenesis of related neurological diseases but also provide important insights for developing novel therapeutic strategies. Future research should further focus on the dynamic changes in neurons and dendritic spines under hypoxic conditions and their intrinsic connections with cognitive function.
Assuntos
Espinhas Dendríticas , Neurônios , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/patologia , Animais , Humanos , Neurônios/metabolismo , Neurônios/patologia , Hipóxia Encefálica/patologia , Hipóxia Encefálica/metabolismo , Hipóxia Encefálica/fisiopatologiaRESUMO
Preterm infants can face lasting neurodevelopmental challenges due to hypoxia-induced injury of the cerebral white matter. In this issue of Neuron, Ren et al.1 identify microvascular pericytes as unexpected targets for growth hormone signaling, which enhances angiogenesis and remyelination after hypoxic injury in the developing mouse brain.
Assuntos
Hipóxia Encefálica , Bainha de Mielina , Pericitos , Pericitos/metabolismo , Bainha de Mielina/metabolismo , Animais , Hipóxia Encefálica/metabolismo , Camundongos , Humanos , Animais Recém-Nascidos , Encéfalo/metabolismoRESUMO
Hypoxia stabilizes hypoxia-inducible factors (HIFs), facilitating adaptation to hypoxic conditions. Appropriate hypoxia is pivotal for neurovascular regeneration and immune cell mobilization. However, in central nervous system (CNS) injury, prolonged and severe hypoxia harms the brain by triggering neurovascular inflammation, oxidative stress, glial activation, vascular damage, mitochondrial dysfunction, and cell death. Diminished hypoxia in the brain improves cognitive function in individuals with CNS injuries. This review discusses the current evidence regarding the contribution of severe hypoxia to CNS injuries, with an emphasis on HIF-1α-mediated pathways. During severe hypoxia in the CNS, HIF-1α facilitates inflammasome formation, mitochondrial dysfunction, and cell death. This review presents the molecular mechanisms by which HIF-1α is involved in the pathogenesis of CNS injuries, such as stroke, traumatic brain injury, and Alzheimer's disease. Deciphering the molecular mechanisms of HIF-1α will contribute to the development of therapeutic strategies for severe hypoxic brain diseases.
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Hipóxia Encefálica , Subunidade alfa do Fator 1 Induzível por Hipóxia , Animais , Humanos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Hipóxia Encefálica/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Mitocôndrias/metabolismo , Estresse OxidativoRESUMO
The progression of human degenerative and hypoxic/ischemic diseases is accompanied by widespread cell death. One death process linking iron-catalyzed reactive species with lipid peroxidation is ferroptosis, which shows hallmarks of both programmed and necrotic death in vitro. While evidence of ferroptosis in neurodegenerative disease is indicated by iron accumulation and involvement of lipids, a stable marker for ferroptosis has not been identified. Its prevalence is thus undetermined in human pathophysiology, impeding recognition of disease areas and clinical investigations with candidate drugs. Here, we identified ferroptosis marker antigens by analyzing surface protein dynamics and discovered a single protein, Fatty Acid-Binding Protein 5 (FABP5), which was stabilized at the cell surface and specifically elevated in ferroptotic cell death. Ectopic expression and lipidomics assays demonstrated that FABP5 drives redistribution of redox-sensitive lipids and ferroptosis sensitivity in a positive-feedback loop, indicating a role as a functional biomarker. Notably, immunodetection of FABP5 in mouse stroke penumbra and in hypoxic postmortem patients was distinctly associated with hypoxically damaged neurons. Retrospective cell death characterized here by the novel ferroptosis biomarker FABP5 thus provides first evidence for a long-hypothesized intrinsic ferroptosis in hypoxia and inaugurates a means for pathological detection of ferroptosis in tissue.
Assuntos
Biomarcadores , Proteínas de Ligação a Ácido Graxo , Ferroptose , Proteínas de Neoplasias , Proteínas de Ligação a Ácido Graxo/metabolismo , Animais , Humanos , Biomarcadores/metabolismo , Camundongos , Hipóxia Encefálica/metabolismo , Hipóxia Encefálica/patologia , Camundongos Endogâmicos C57BL , Peroxidação de Lipídeos , MasculinoRESUMO
BACKGROUND/AIM: Chronic cerebral hypoxia often leads to brain damage and inflammation. Propofol is suggested to have neuroprotective effects under anaesthesia. MATERIALS AND METHODS: This study used rat models with carotid artery coarctation or closure. Four groups of rats were compared: a control group, a propofol-treated group, a group with bilateral common carotid artery blockage (BCAO), and a BCAO group treated with propofol post-surgery. RESULTS: The Morris water maze test indicated cognitive impairment in BCAO rats, which also showed hippocampal structure changes, oxidative stress markers alteration, and reduced Klotho expression. Propofol treatment post-BCAO surgery improved these outcomes, suggesting its potential in mitigating chronic cerebral hypoxia effects. CONCLUSION: Propofol may increase klotho levels and reduce apoptosis and inflammation linked to oxidative stress in cognitively impaired mice.
Assuntos
Modelos Animais de Doenças , Glucuronidase , Hipocampo , Hipóxia Encefálica , Proteínas Klotho , Estresse Oxidativo , Propofol , Animais , Propofol/farmacologia , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Ratos , Proteínas Klotho/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Hipóxia Encefálica/metabolismo , Hipóxia Encefálica/patologia , Hipóxia Encefálica/etiologia , Glucuronidase/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Doença CrônicaRESUMO
Consciousness is lost within seconds upon cessation of cerebral blood flow. The brain cannot store oxygen, and interruption of oxidative phosphorylation is fatal within minutes. Yet only rudimentary knowledge exists regarding cortical partial oxygen tension (Po2) dynamics under physiological conditions. Here we introduce Green enhanced Nano-lantern (GeNL), a genetically encoded bioluminescent oxygen indicator for Po2 imaging. In awake behaving mice, we uncover the existence of spontaneous, spatially defined "hypoxic pockets" and demonstrate their linkage to the abrogation of local capillary flow. Exercise reduced the burden of hypoxic pockets by 52% compared with rest. The study provides insight into cortical oxygen dynamics in awake behaving animals and concurrently establishes a tool to delineate the importance of oxygen tension in physiological processes and neurological diseases.
Assuntos
Córtex Cerebral , Circulação Cerebrovascular , Hipóxia Encefálica , Medições Luminescentes , Saturação de Oxigênio , Oxigênio , Animais , Camundongos , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Oxigênio/sangue , Oxigênio/metabolismo , Pressão Parcial , Hipóxia Encefálica/sangue , Hipóxia Encefálica/diagnóstico por imagem , Hipóxia Encefálica/metabolismo , Vasodilatação , Medições Luminescentes/métodos , Luciferases/genética , Luciferases/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Hipercapnia/sangue , Hipercapnia/diagnóstico por imagem , Hipercapnia/metabolismoRESUMO
Stroke is the second leading cause of death worldwide, and hypoxia is a major crisis of the brain after stroke. Therefore, providing oxygen to the brain microenvironment can effectively protect neurons from damage caused by cerebral hypoxia. However, there is a lack of timely and effective means of oxygen delivery clinically to the brain for acute cerebral hypoxia. Here, a phase-change based nano oxygen carrier is reported, which can undergo a phase change in response to increasing temperature in the brain, leading to oxygen release. The nano oxygen carrier demonstrate intracerebral oxygen delivery capacity and is able to release oxygen in the hypoxic and inflammatory region of the brain. In the acute ischemic stroke mouse model, the nano oxygen carrier can effectively reduce the area of cerebral infarction and decrease the level of inflammation triggered by cerebral hypoxia. By taking advantage of the increase in temperature during cerebral hypoxia, phase-change oxygen carrier proposes a new intracerebral oxygen delivery strategy for reducing acute cerebral hypoxia.
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Oxigênio , Animais , Oxigênio/química , Oxigênio/metabolismo , Camundongos , Hipóxia Encefálica/metabolismo , Masculino , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Transição de FaseRESUMO
Cortical spreading depolarization (SD) imposes a massive increase in energy demand and therefore evolves as a target for treatment following acute brain injuries. Anesthetics are empirically used to reduce energy metabolism in critical brain conditions, yet their effect on metabolism during SD remains largely unknown. We investigated oxidative metabolism during SD in brain slices from Wistar rats. Extracellular potassium ([K+]o), local field potential and partial tissue oxygen pressure (ptiO2) were measured simultaneously. The cerebral metabolic rate of oxygen (CMRO2) was calculated using a reaction-diffusion model. By that, we tested the effect of clinically relevant concentrations of isoflurane on CMRO2 during SD and modeled tissue oxygenation for different capillary pO2 values. During SD, CMRO2 increased 2.7-fold, resulting in transient hypoxia in the slice core. Isoflurane decreased CMRO2, reduced peak [K+]o, and prolonged [K+]o clearance, which indicates reduced synaptic transmission and sodium-potassium ATPase inhibition. Modeling tissue oxygenation during SD illustrates the need for increased capillary pO2 levels to prevent hypoxia. In the absence thereof, isoflurane could improve tissue oxygenation by lowering CMRO2. Therefore, isoflurane is a promising candidate for pre-clinical studies on neuronal survival in conditions involving SD.
Assuntos
Depressão Alastrante da Atividade Elétrica Cortical , Isoflurano , Oxigênio , Ratos Wistar , Animais , Isoflurano/farmacologia , Depressão Alastrante da Atividade Elétrica Cortical/efeitos dos fármacos , Depressão Alastrante da Atividade Elétrica Cortical/fisiologia , Ratos , Oxigênio/metabolismo , Anestésicos Inalatórios/farmacologia , Masculino , Hipóxia/metabolismo , Potássio/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Hipóxia Encefálica/metabolismo , Hipóxia Encefálica/tratamento farmacológicoRESUMO
During hypoxia, increases in cerebral blood flow maintain brain oxygen delivery. Here, we describe a mechanism of brain oxygen sensing that mediates the dilation of intraparenchymal cerebral blood vessels in response to reductions in oxygen supply. In vitro and in vivo experiments conducted in rodent models show that during hypoxia, cortical astrocytes produce the potent vasodilator nitric oxide (NO) via nitrite reduction in mitochondria. Inhibition of mitochondrial respiration mimics, but also occludes, the effect of hypoxia on NO production in astrocytes. Astrocytes display high expression of the molybdenum-cofactor-containing mitochondrial enzyme sulfite oxidase, which can catalyze nitrite reduction in hypoxia. Replacement of molybdenum with tungsten or knockdown of sulfite oxidase expression in astrocytes blocks hypoxia-induced NO production by these glial cells and reduces the cerebrovascular response to hypoxia. These data identify astrocyte mitochondria as brain oxygen sensors that regulate cerebral blood flow during hypoxia via release of nitric oxide.
Assuntos
Hipóxia Encefálica , Nitritos , Humanos , Nitritos/metabolismo , Astrócitos/metabolismo , Óxido Nítrico/metabolismo , Molibdênio/metabolismo , Hipóxia/metabolismo , Oxigênio/metabolismo , Mitocôndrias/metabolismo , Hipóxia Encefálica/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/metabolismo , Circulação CerebrovascularRESUMO
OBJECTIVE: The aim of this study was to investigate the effect of time course on neurological impairment after acute hypobaric hypoxia exposure in mice and clarify the mechanism of acclimatization, so as to provide a suitable mice model and identify potential target against hypobaric hypoxia for further drug research. METHOD: Male C57BL/6J mice were exposed to hypobaric hypoxia at a simulated altitude of 7000 m for 1, 3, and 7 days (1HH, 3HH and 7HH respectively). The behavior of the mice was evaluated by novel object recognition (NOR) and morris water maze test (MWM), then, the pathological changes of mice brain tissues were observed by H&E and Nissl staining. In addition, RNA sequencing (RNA-Seq) was performed to characterize the transcriptome signatures, and enzyme-linked immunosorbent assay (ELISA), Real-time polymerase chain reaction (RT-PCR), and western blot (WB) were used to verify the mechanisms of neurological impairment induced by hypobaric hypoxia. RESULT: The hypobaric hypoxia condition resulted in impaired learning and memory, decreased new object cognitive index, and increased escape latency to the hidden platform in mice, with significant changes seen in the 1HH and 3HH groups. Bioinformatic analysis of RNA-seq results of hippocampal tissue showed that 739 differentially expressed genes (DEGs) appeared in the 1HH group, 452 in the 3HH group, and 183 in the 7HH group compared to the control group. There were 60 key genes overlapping in three groups which represented persistent changes and closely related biological functions and regulatory mechanisms in hypobaric hypoxia-induced brain injuries. DEGs enrichment analysis showed that hypobaric hypoxia-induced brain injuries were associated with oxidative stress, inflammatory responses, and synaptic plasticity. ELISA and WB results confirmed that these responses occurred in all hypobaric hypoxic groups while attenuated in the 7HH group. VEGF-A-Notch signaling pathway was enriched by DEGs in hypobaric hypoxia groups and was validated by RT-PCR and WB. CONCLUSION: The nervous system of mice exposed to hypobaric hypoxia exhibited stress followed by gradual habituation and thus acclimatization over time, which was reflected in the biological mechanism involving inflammation, oxidative stress, and synaptic plasticity, and accompanied by activation of the VEGF-A-Notch pathway.
Assuntos
Lesões Encefálicas , Hipóxia Encefálica , Camundongos , Masculino , Animais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Camundongos Endogâmicos C57BL , Hipóxia/metabolismo , Hipóxia Encefálica/metabolismo , Neurônios/metabolismo , Lesões Encefálicas/metabolismo , Hipocampo/metabolismoRESUMO
BACKGROUND: Obstructive sleep apnea (OSA) is mainly characterized by sleep fragmentation and chronic intermittent hypoxia (CIH), the latter one being associated with multiple organ injury. Recently, OSA-induced cognition dysfunction has received extensive attention from scholars. Astrocytes are essential in neurocognitive deficits via A1/A2 phenotypic changes. Nucleotide oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome is considered the most important factor inducing and maintaining neuroinflammation. However, whether the NLRP3 regulates the A1/A2 transformation of astrocytes in CIH-related brain injury remains unclear. METHODS: We constructed an OSA-related CIH animal model and assessed the rats' learning ability in the Morris water maze; the histopathological assessment was performed by HE and Nissl staining. The expression of GFAP (astrocyte marker), C3d (A1-type astrocyte marker), and S100a10 (A2-type astrocyte marker) were detected by immunohistochemistry and immunofluorescence. Western blotting and RT-qPCR were used to evaluate the changes of A1/A2 astrocyte-related protein and NLRP3/Caspase-1/ASC/IL-1ß. RESULTS: The learning ability of rats decreased under CIH. Further pathological examination revealed that the neurocyte in the hippocampus were damaged. The cell nuclei were fragmented and dissolved, and Nissl bodies were reduced. Immunohistochemistry showed that astrocytes were activated, and morphology and number of astrocytes changed. Immunofluorescence, Western blotting and RT-qPCR showed that the expression of C3d was increased while S100a10 was decreased. Also, the expression of the inflammasome (NLRP3/Caspase-1/ASC/IL-1ß) was increased. After treatment of MCC950 (a small molecule inhibitor of NLRP3), the damage of nerve cells was alleviated, the Nissl bodies increased, the activation of astrocytes was reduced, and the expression of A2-type astrocytes was increased. In contrast, A1-type astrocytes decreased, and the expression of inflammasome NLRP3/Caspase-1/ASC/IL-1ß pathway-related proteins decreased. CONCLUSION: The NLRP3 inflammasome could regulate the A1/A2 transformation of astrocytes in brain injury induced by CIH.
Assuntos
Astrócitos , Hipóxia Encefálica , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Apneia Obstrutiva do Sono , Animais , Ratos , Astrócitos/metabolismo , Lesões Encefálicas/genética , Lesões Encefálicas/metabolismo , Caspases , Hipóxia/etiologia , Hipóxia/genética , Hipóxia/metabolismo , Inflamassomos/genética , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/genética , Apneia Obstrutiva do Sono/metabolismo , Hipóxia Encefálica/etiologia , Hipóxia Encefálica/genética , Hipóxia Encefálica/metabolismoRESUMO
Previous reports have indicated that natural muscone has neuroprotective effects against cerebral hypoxia injury; however, little is known in regards to its pharmacological mechanism. In this study, we tried to evaluate the neuroprotective effects and mechanisms of muscone against cerebral hypoxia injury using an in vitro model. The cerebral hypoxia injury cell model was produced by hypoxia/reoxygenation (H/R). The cell viability and apoptosis were measured using the cell counting Kit-8 and the Annexin V-FITC/PI Apoptosis Detection kit, respectively. To screen microRNAs regulated by muscone, we analyzed the gene expression datasets of GSE84216 retrieved from gene expression omnibus (GEO). Here, it was demonstrated that muscone treatment significantly alleviated the cell apoptosis, oxidative stress and inflammation in H/R-exposed neurons. Subsequently, through analyzing GSE84216 from the GEO database, miR-142-5p was markedly upregulated by treatment of muscone in this cell model of cerebral hypoxia injury. Further experiments revealed that downregulation of miR-142-5p eliminated the neuroprotective effects of muscone against H/R induced neuronal injury. Additionally, high mobility group box 1 (HMGB1), an important inflammatory factor, was identified as a direct target of miR-142-5p in neurons. Meanwhile, we further demonstrated that muscone could reduce the expression of HMGB1 by upregulating miR-142-5p expression, which subsequently resulted in the inactivation of TLR4/NF-κB pathway, finally leading to the improvement of cell injury in H/R-exposed neurons. Overall, we demonstrate for the first time that muscone treatment alleviates cerebral hypoxia injury in in vitro experiments through blocking activation of the TLR4/NF-κB signaling pathway by targeting HMGB1, suggesting that muscone may serve as a potential therapeutic drug for treating cerebral hypoxia injury.
Assuntos
Proteína HMGB1 , Hipóxia Encefálica , MicroRNAs , Fármacos Neuroprotetores , Proteína HMGB1/genética , Hipóxia/tratamento farmacológico , Hipóxia Encefálica/metabolismo , MicroRNAs/genética , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , NF-kappa B/genética , Receptor 4 Toll-Like/genéticaRESUMO
Hypoxia-induced neuroinflammation in stroke, neonatal hypoxic encephalopathy, and other diseases subsequently contributes to neurological damage and neuronal diseases. Microglia are the primary neuroimmune cells that play a crucial role in cerebral inflammation. Epigallocatechin gallate (EGCG) has a protective antioxidant and anti-inflammatory effects against neuroinflammation. However, the effects of EGCG on hypoxia-induced inflammation in microglia and the underlying mechanism remain unclear. In this study, we investigated whether EGCG might have a protective effect against hypoxia injury in microglia by treatment with CoCl2 to establish a hypoxic model of BV2 microglia cells following EGCG pre-treatment. An exposure of cells to CoCl2 caused an increase in inflammatory mediator interleukin (IL)-6, inducible nitric oxide synthase (iNOS), and cyclooxygenase (COX)-2 expression, which were significantly ameliorated by EGCG via inhibition of NF-κB pathway. In addition, EGCG attenuated the expression of hypoxia-inducible factor (HIF)-1α and the generation of ROS in hypoxic BV2 cells. Furthermore, the suppression of hypoxia-induced IL-6 production by EGCG was mediated via the inhibition of HIF-1α expression and the suppression of ROS generation in BV2 cells. Notably, EGCG increased the Nrf-2 levels and HO-1 levels in the presence of CoCl2. Additionally, EGCG suppressed hypoxia-induced apoptosis of BV2 microglia with cleavage of poly (ADP-ribose) polymerase (PARP) and caspase-3. In summary, EGCG protects microglia from hypoxia-induced inflammation and oxidative stress via abrogating the NF-κB pathway as well as activating the Nrf-2/HO-1 pathway.
Assuntos
Catequina , Hipóxia Encefálica , Microglia , Humanos , Catequina/análogos & derivados , Catequina/farmacologia , Ciclo-Oxigenase 2/metabolismo , Hipóxia Encefálica/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos , Microglia/metabolismo , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
This study is to investigate the underlying mechanisms of mitochondrial quality control (MQC) regulated by HtrA2/Omi during ischemia/reperfusion (I/R). We utilized the mnd2 mouse model, which has a missense mutation in HtrA2/Omi, to investigate the HtrA2/Omi regulation in mitochondria after I/R injury in the cerebral cortex. Compared to homozygous (HtrA2mnd2) mice, heterozygous (HtrA2Hetero) mice showed aging signs at a later age, increased HtrA2/Omi expression in the brain cortex, and lesser neurodegenerative signs. The brain cortex of HtrA2Hetero mice had increased superoxide dismutase (SOD) activity; lower levels of malondialdehyde (MDA); higher expressions of mitochondrial unfolded protein response (mtUPR)-related proteins, NADH dehydrogenase [ubiquinone] iron-sulfur protein 7 (Ndufs7), and uncoupling protein 2 (UCP2) proteins; more mitochondrial fission; higher levels of ATP and mtDNA copies; elevated sirtuin 3 (SIRT3) activity; and increased NAD+/NADH ratio. After 1.5 h of I/R, the brain cortex of HtrA2Hetero mice had a larger infarction size, reduced HtrA2/Omi expression, decreased S-X-linked inhibitor of apoptosis protein (XIAP), and increased C-Caspase3 than that of wild-type animals (WT). Mitochondria from the HtrA2Hetero brain cortex showed decreased ATP production and MQC deficiency after 1.5 h I/R. Genipin pre-treatment reduced the aforementioned I/R injury in the HtrA2Hetero brain cortex. In conclusion, mitochondrial function is compensated in the HtrA2Hetero brain cortex via the upregulation of the UCP2-SIRT3-PGC1 axis. Decreased HtrA2/Omi function damages mitochondrial quality in the HtrA2Hetero mouse brain cortex, leading to more brain I/R injury. Genipin pre-treatment ameliorates brain damages via the mitochondrial UCP2-SIRT3-PGC1 axis.
Assuntos
Reprogramação Celular/genética , Córtex Cerebral/metabolismo , Serina Peptidase 2 de Requerimento de Alta Temperatura A/fisiologia , Hipóxia Encefálica/genética , Hipóxia Encefálica/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , Sirtuína 3/metabolismo , Proteína Desacopladora 2/metabolismo , Animais , Modelos Animais de Doenças , Camundongos TransgênicosRESUMO
Perinatal hypoxia is a major cause of infant brain damage, lifelong neurological disability, and infant mortality. N-Acetyl-Cysteine (NAC) is a powerful antioxidant that acts directly as a scavenger of free radicals. We hypothesized that maternal-antenatal and offspring-postnatal NAC can protect offspring brains from hypoxic brain damage.Sixty six newborn rats were randomized into four study groups. Group 1: Control (CON) received no hypoxic intervention. Group 2: Hypoxia (HYP)-received hypoxia protocol. Group 3: Hypoxia-NAC (HYP-NAC). received hypoxia protocol and treated with NAC following each hypoxia episode. Group 4: NAC Hypoxia (NAC-HYP) treated with NAC during pregnancy, pups subject to hypoxia protocol. Each group was evaluated for: neurological function (Righting reflex), serum proinflammatory IL-6 protein levels (ELISA), brain protein levels: NF-κB p65, neuronal nitric oxide synthase (nNOS), TNF-α, and IL-6 (Western blot) and neuronal apoptosis (histology evaluation with TUNEL stain). Hypoxia significantly increased pups brain protein levels compared to controls. NAC administration to dams or offspring demonstrated lower brain NF-κB p65, nNOS, TNF-α and IL-6 protein levels compared to hypoxia alone. Hypoxia significantly increased brain apoptosis as evidenced by higher grade of brain TUNEL reaction. NAC administration to dams or offspring significantly reduce this effect. Hypoxia induced acute sensorimotor dysfunction. NAC treatment to dams significantly attenuated hypoxia-induced acute sensorimotor dysfunction. Prophylactic NAC treatment of dams during pregnancy confers long-term protection to offspring with hypoxia associated brain injury, measured by several pathways of injury and correlated markers with pathology and behavior. This implies we may consider prophylactic NAC treatment for patients at risk for hypoxia during labor.
Assuntos
Acetilcisteína/metabolismo , Asfixia Neonatal/complicações , Encéfalo/metabolismo , Hipóxia Encefálica/prevenção & controle , Inflamação , Estresse Oxidativo , Animais , Animais Recém-Nascidos , Antioxidantes/metabolismo , Regulação da Expressão Gênica , Hipóxia Encefálica/etiologia , Hipóxia Encefálica/metabolismo , Marcação In Situ das Extremidades Cortadas , Interleucina-6/genética , Óxido Nítrico Sintase Tipo I/genética , Ratos , Ratos Sprague-Dawley , Fator de Transcrição RelA/genética , Fator de Necrose Tumoral alfa/genéticaRESUMO
In adult cornu ammonis hippocampi, erythropoietin (EPO) expression drives the differentiation of new neurons, independent of DNA synthesis, and increases dendritic spine density. This substantial brain hardware upgrade is part of a regulatory circle: during motor-cognitive challenge, neurons experience "functional" hypoxia, triggering neuronal EPO production, which in turn promotes improved performance. Here, we show an unexpected involvement of resident microglia. During EPO upregulation and stimulated neurodifferentiation, either by functional or inspiratory hypoxia, microglia numbers decrease. Treating mice with recombinant human (rh)EPO or exposure to hypoxia recapitulates these changes and reveals the involvement of neuronally expressed IL-34 and microglial CSF1R. Surprisingly, EPO affects microglia in phases, initially by inducing apoptosis, later by reducing proliferation, and overall dampens microglia activity and metabolism, as verified by selective genetic targeting of either the microglial or pyramidal neuronal EPO receptor. We suggest that during accelerating neuronal differentiation, EPO acts as regulator of the CSF1R-dependent microglia.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Eritropoetina/farmacologia , Hipocampo/metabolismo , Hipóxia Encefálica/metabolismo , Microglia/metabolismo , Neurogênese/efeitos dos fármacos , Células Piramidais/metabolismo , Animais , Diferenciação Celular/genética , Hipóxia Encefálica/tratamento farmacológico , Camundongos , Camundongos TransgênicosRESUMO
Adaptation of organisms to stressors is coordinated by the hypothalamic-pituitary-adrenal axis (HPA), which involves glucocorticoids (GCs) and glucocorticoid receptors (GRs). Although the effects of GCs are well characterized, their impact on brain adaptation to hypoxia/ischemia is still understudied. The brain is not only the most susceptible to hypoxic injury, but also vulnerable to GC-induced damage, which makes studying the mechanisms of brain hypoxic tolerance and resistance to stress-related elevation of GCs of great importance. Cross-talk between the molecular mechanisms activated in neuronal cells by hypoxia and GCs provides a platform for developing the most effective and safe means for prevention and treatment of hypoxia-induced brain damage, including hypoxic pre- and post-conditioning. Taking into account that hypoxia- and GC-induced reprogramming significantly affects the development of organisms during embryogenesis, studies of the effects of prenatal and neonatal hypoxia on health in later life are of particular interest. This mini review discusses the accumulated data on the dynamics of the HPA activation in injurious and non-injurious hypoxia, the role of the brain GRs in these processes, interaction of GCs and hypoxia-inducible factor HIF-1, as well as cross-talk between GC and hypoxic signaling. It also identifies underdeveloped areas and suggests directions for further prospective studies.
Assuntos
Resistência à Doença , Glucocorticoides/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Hipóxia Encefálica/metabolismo , Precondicionamento Isquêmico , Sistema Hipófise-Suprarrenal/metabolismo , Transdução de Sinais , Animais , Humanos , Sistema Hipotálamo-Hipofisário/patologia , Hipóxia Encefálica/prevenção & controle , Sistema Hipófise-Suprarrenal/patologiaRESUMO
Changed NMDA receptor (NMDAr) physiology is implicated with cognitive deficit resulting from conditions ranging from normal aging to neurological disease. Using intermittent hypoxia (IH) to experimentally model untreated sleep apnea, a clinical condition whose comorbidities include neurocognitive impairment, we recently demonstrated that IH causes a pro-oxidant condition that contributes to deficits in spatial memory and in NMDAr-dependent long-term potentiation (LTP). However, the impact of IH on additional forms of synaptic plasticity remains ill-defined. Here we show that IH prevents the induction of NMDAr-dependent LTP and long-term depression (LTD) in hippocampal brain slices from mice exposed to ten days of IH (IH10) yet spares NMDAr-independent forms of synaptic plasticity. Deficits in synaptic plasticity were accompanied by a reduction in hippocampal GluN1 expression. Acute manipulation of redox state using the reducing agent, Dithiothreitol (DTT) stimulated the NMDAr-dependent fEPSP following IH10. However, acute use of either DTT or MnTMPyP did not restore NMDAr-dependent synaptic plasticity after IH10 or prevent the IH-dependent reduction in GluN1, the obligatory subunit of the NMDAr. In contrast, MnTMPyP during IH10 (10-MnTMPyP), prevented the suppressive effects of IH on both NMDAr-dependent synaptic plasticity and GluN1 expression. These findings indicate that while the IH-dependent pro-oxidant state causes reversible oxidative neuromodulation of NMDAr activity, acute manipulation of redox state is ineffective in rescuing two key effects of IH related to the NMDAr within the hippocampus. These IH-dependent changes associated with the NMDAr may be a primary avenue by which IH enhances the vulnerability to impaired learning and memory when sleep apnea is left untreated in normal aging and in disease.
Assuntos
Região CA1 Hipocampal/metabolismo , Hipóxia Encefálica/metabolismo , Plasticidade Neuronal/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Síndromes da Apneia do Sono/metabolismo , Animais , Células Cultivadas , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/fisiologiaRESUMO
Repetitive hypoxia (RH) exposure affects the initiation and progression of cognitive dysfunction, but little is known about the mechanisms of hypoxic brain damage. In this study, we show that sublethal RH increased anxiety, impaired learning and memory (L/M), and triggered downregulation of brain levels of glucose and several glucose metabolites in zebrafish, and that supplementation of glucose or glucosamine (GlcN) restored RH-induced L/M impairment. Fear conditioning (FC)-induced brain activation of and PKA/CREB signaling was abrogated by RH, and this effect was reversed by GlcN supplementation. RH was associated with decreased brain O-GlcNAcylation and an increased O-GlcNAcase (OGA) level. RH increased brain inflammation and p-Tau and amyloid ß accumulation, and these effects were suppressed by GlcN. Our observations collectively suggest that changes in O-GlcNAc flux during hypoxic exposure could be an important causal factor for neurodegeneration, and that supplementation of the HBP/O-GlcNAc flux may be a potential novel therapeutic or preventive target for addressing hypoxic brain damage.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/metabolismo , Glucosamina/farmacologia , Hipóxia/metabolismo , Peixe-Zebra/metabolismo , Proteínas tau/metabolismo , Animais , Ansiedade/metabolismo , Encéfalo/metabolismo , Estudos de Casos e Controles , Disfunção Cognitiva/etiologia , Encefalite/metabolismo , Feminino , Cromatografia Gasosa-Espectrometria de Massas/métodos , Glucosamina/metabolismo , Glucosamina/uso terapêutico , Glucose/metabolismo , Hipóxia/complicações , Hipóxia Encefálica/metabolismo , Hipóxia Encefálica/prevenção & controle , Deficiências da Aprendizagem/metabolismo , Masculino , Transtornos da Memória/metabolismo , N-Acetilglucosaminiltransferases/metabolismo , Proteínas de Peixe-Zebra/metabolismo , beta-N-Acetil-Hexosaminidases/metabolismoRESUMO
Thrombolytic stroke therapy with tissue plasminogen activator (tPA) is limited by risks of hemorrhagic transformation (HT). We have reported that a new 12/15-lipoxygenase (12/15-LOX) inhibitor ML351 reduced tPA related HT in mice subjected to experimental stroke under anticoagulation. In this study, we asked whether ML351 can ameliorate tPA induced HT in an embolic stroke model. Rats were subjected to embolic middle cerebral artery occlusion with 2 or 3 hr ischemia and tPA infusion, with or without ML351. Regional cerebral blood flow was monitored 2 hr after ischemia and continuously monitored for 1 hr after treatment for determining reperfusion. Hemoglobin was determined in brain homogenates and infarct volume was quantified at 24 hr after stroke.12/15-LOX, cluster of differentiation 68(CD68), immunoglobulin G (IgG), and tight junction proteins expression was detected by immunohistochemistry. ML351 significantly reduced tPA related hemorrhage after stroke without affecting its thrombolytic efficacy. ML351 also reduced blood-brain barrier disruption and improved preservation of junction proteins. ML351 and tPA combination improved neurological deficit of rats even though ML351 did not further reduce the infarct volume compared to tPA alone treated animals. Pro-inflammatory cytokines were suppressed by ML351 both in vivo and in vitro experiments. We further showed that ML351 suppressed the expression of c-Jun-N-terminal kinase (JNK) in brains and microglia cultures, whereas exogenous 12-HETE attenuated this effect in vitro. In conclusion, ML351 and tPA combination therapy is beneficial in ameliorating HT after ischemic stroke. This protective effect is probably because of 12/15-LOX inhibition and suppression of JNK-mediated microglia/macrophage activation.