Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Hypoxic-Ischemic Encephalopathy (HIE) is a severe illness of the unborn, respectively of the newborn. About 90 percent of the causes occur in utero, about 10 percent after birth. The risk for HIE arises from anatomical and pathophysiological particularities: little overlapping between the great cerebral arteries, poor periventricular vascularisation, and a loss of the autoregulation of cerebral blood flow during asphyxia. Most important is the early detection of intrauterine asphyxia. After birth the general measures include: thermoneutral temperature, oxygenation, normal pCO2, regular blood pressure monitoring, glucose infusion, therapy of convulsions and of an inherent brain edema. After birth the five most common clinical settings in which HIE occurs, are: postpartum asphyxia, PFC, septic shock, pneumothorax and apneas. Therapeutic measures (e.g. volume therapy) have to be prompt but subtle, to prevent ischemia, avoiding overtherapy with its risk of intracranial hemorrhage.
 ...
PMID:[Hypoxic-ischemic encephalopathy. Clinical considerations]. 643 98

Hypoxic-ischemic brain injury in survivors of perinatal asphyxia is a frequently encountered clinical problem for which there is currently no effective therapy. Neurotrophins, such as brain-derived neurotrophic factor (BDNF), can protect responsive neurons against cell death in some injury paradigms. While the role of BDNF in hypoxic-ischemic brain injury is not clear, evidence suggests that BDNF may have different effects in the developing, as opposed to the adult, brain. We found that a single intracerebroventricular (ICV) injection of BDNF resulted in rapid and robust phosphorylation of trk receptors in multiple brain regions in the postnatal day (PD) 7 rat brain. BDNF also markedly protected against hypoxic-ischemic brain injury at PD7. It protected against 90% of tissue loss due to hypoxic-ischemia when given just prior to the insult and against 50% of tissue loss when give after the insult. In contrast, ICV injection of BDNF in PD21 and adult rats resulted in little trk phosphorylation and less dramatic protection against unilateral hypoxic-ischemic injury at PD21. Because of its potent neuroprotective actions in the developing brain, BDNF may be a potential treatment for asphyxia and other forms of acute injury in the perinatal period.
 ...
PMID:Marked age-dependent neuroprotection by brain-derived neurotrophic factor against neonatal hypoxic-ischemic brain injury. 912 10

Hypoxic-ischemic brain injury involves an increased formation of reactive oxygen species. Key factors in the cellular protection against such agents are the GSH-associated reactions. In the present study we examined alterations in total glutathione and GSSG concentrations in mitochondria-enriched fractions and tissue homogenates from the cerebral cortex of 7-day-old rats at 0, 1, 3, 8, 14, 24 and 72 h after hypoxia-ischemia. The concentration of total glutathione was transiently decreased immediately after hypoxia-ischemia in the mitochondrial fraction, but not in the tissue, recovered, and then decreased both in mitochondrial fraction and homogenate after 14 h, reaching a minimum at 24 h after hypoxia-ischemia. The level of GSSG was approximately 4% of total glutathione and increased selectively in the mitochondrial fraction immediately after hypoxia-ischemia. The decrease in glutathione may be important in the development of cell death via impaired free radical inactivation and/or redox related changes. The effects of hypoxia-ischemia on the concentrations of selected amino acids varied. The levels of phosphoethanolamine, an amine previously reported to be released in ischemia, mirrored the changes in glutathione. GABA concentrations initially increased (0-3 h) followed by a decrease at 72 h. Glutamine levels increased, whereas glutamate and aspartate were unchanged up to 24 h after the insult. The results on total glutathione and GSSG are discussed in relation to changes in mitochondrial respiration and microtubule associated protein-2 (MAP2) which are reported on in accompanying paper [64].
 ...
PMID:Alterations in glutathione and amino acid concentrations after hypoxia-ischemia in the immature rat brain. 1115 60

Hypoxic-ischemic brain injury in premature infants results in cerebral white matter lesions with prominent oligodendroglial injury and loss, a disorder termed periventricular leukomalacia (PVL). We have previously shown that glutamate receptors mediate hypoxic-ischemic injury to oligodendroglial precursor cells (OPCs) in a model of PVL in the developing rodent brain. We used primary OPC cultures to examine the mechanism of cellular toxicity induced by oxygen-glucose deprivation (OGD) to simulate brain ischemia. OPCs were more sensitive to OGD-induced toxicity than mature oligodendrocytes, and OPC toxicity was attenuated by nonselective [2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline (NBQX), 6-cyano-7-nitroquinoxaline-2,3-dione], alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-preferring (GYKI 52466), kainate-preferring (gamma-d-glutamylaminomethanesulfonic acid), or Ca2+-permeable AMPA/kainate receptor antagonists (joro spider toxin, JSTx) administered either during or after OGD. Furthermore, NBQX or JSTx blocked OGD-induced Ca2+ influx. Relevant to recurrent hypoxic-ischemic insults in developing white matter, we examined the effects of sublethal OGD preconditioning. A prior exposure of OPCs to sublethal OGD resulted in enhanced vulnerability to subsequent excitotoxic or OGD-induced injury associated with an increased Ca2+ influx. AMPA/kainate receptor blockade with NBQX or JSTx either during or after sublethal OGD prevented its priming effect. Furthermore, OGD preconditioning resulted in a down-regulation of the AMPA receptor subunit GluR2 on cell surface that increased Ca2+ permeability of the receptors. Overall, these data suggest that aberrantly enhanced activation of Ca2+-permeable AMPA/kainate receptors may be a major mechanism in acute and repeated hypoxic-ischemic injury to OPCs in disorders of developing cerebral white matter, such as PVL.
 ...
PMID:Calcium-permeable AMPA/kainate receptors mediate toxicity and preconditioning by oxygen-glucose deprivation in oligodendrocyte precursors. 1274 62

Perinatal hypoxic-ischemic brain damage is a major cause of neuronal and behavior deficits, in which the onset of injury can be before, at or after birth, and the effects may be delayed. Pontosubicular neuron necrosis (PSN) is one of perinatal hypoxic-ischemic brain injury and its pathological peculiarity is neuronal apoptosis. In this study, we investigated whether apoptotic cascade of PSN used a caspase-pathway or not, and whether hypoglycemia activated apoptosis or not. Sections of the pons of PSN with and without hypoglycemia were stained using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) and immunohistochemistry for glial fibrillary acidic protein (GFAP), Bcl-2, Bcl-x and activated caspase 3. Additionally, we performed immunoblot analysis of Bcl-2, Bcl-x and activated caspase 3. TUNEL-positive cell was closely associated with the presence of karyorrhexis. Under combination of karyorrhectic and TUNEL-positive cells, number of apoptotic cells in premature brains was significantly more than in mature brains. Hypoxic-ischemic brain injury was considered to easily lead to apoptosis in premature infants. Moreover, as this pathophysiology, caspase-pathway activation contributed to neuronal death from caspase-immunoexpression analyses. PSN with hypoglycemia showed large number of apoptotic cells and higher expression of activated caspase 3. The result may be more severe with the background of hypoglycemia and prematurity complicated by hypoxia and/or ischemia.
 ...
PMID:A histopathological study of premature and mature infants with pontosubicular neuron necrosis: neuronal cell death in perinatal brain damage. 1671 12

Hypoxic-ischemic brain injury is regulated in part by neurotransmitter and chemokine signaling via G-protein-coupled receptors (GPCRs). GPCR-kinase 2 (GRK2) protects these receptors against overstimulation by inducing desensitization. Neonatal hypoxic-ischemic brain damage is preceded by a reduction in cerebral GRK2 expression. We determined the functional importance of GRK2 in hypoxic-ischemic brain damage. Nine-day-old wild-type and GRK2(+/-) mice with a approximately 50% reduction in GRK2 protein were exposed to unilateral carotid artery occlusion and hypoxia. In GRK2(+/-) animals, gray and white matter damage was aggravated at 3 weeks after hypoxia-ischemia. In addition, cerebral neutrophil infiltration was increased in GRK2(+/-) animals. Neutrophil depletion reduced brain damage, but neuronal loss was still more pronounced in GRK2(+/-) animals. Onset of neuronal loss was advanced in GRK2(+/-) animals regardless of neutrophil depletion. White matter injury was advanced in GRK2(+/-) animals and was not affected by neutrophil depletion. Activation/infiltration of microglia/macrophages was stronger in GRK2(+/-) brains but only occurred 24 h after hypoxia-ischemia and is therefore not the primary cause of increased damage. During hypoxia, cerebral blood flow was reduced to the same extent in both genotypes. In vitro, GRK2(+/-) hippocampal slices and cerebellar granular neurons were more sensitive to glutamate-induced death. We propose the novel concept that the kinase GRK2 regulates onset and magnitude of hypoxic-ischemic brain damage. Increased gray and white matter damage in GRK2(+/-) animals was not dependent on infiltrating neutrophils and occurred before microglia/macrophage activation was detected. Collectively, our data suggest that cerebral GRK2 has an important endogenous neuroprotective role in ischemic cerebral damage.
 ...
PMID:Low endogenous G-protein-coupled receptor kinase 2 sensitizes the immature brain to hypoxia-ischemia-induced gray and white matter damage. 1836 99

Hypoxic-ischemic brain injury in the perinatal period is a major cause of chronic disability and acute mortality in newborns. Despite numerous therapeutic strategies that reduce hypoxia-ischemia-induced damage in different experimental animal models, most of them have failed to translate to clinical therapies. This challenge calls for an urgent need to explore novel approaches to develop effective therapies for the clinical management of perinatal hypoxia-ischemia brain injury. This review focuses on studies that investigate neuroprotective related events during mammalian hibernation, characterized by dramatic reductions in several parameters including body temperature, oxygen consumption and heart rate, such that it is difficult to tell if the hibernating animal is dead or alive. The first part of this article reviews the mechanisms of metabolic suppression related events during hibernation. In the second part, hypoxic-ischemic events in the perinatal brain are discussed, and in turn, contrasted with brains experiencing metabolic suppression during mammalian hibernation. In the last part of this article, the diverse neuroprotective adaptations of hibernators and the mechanisms that might be involved in mammalian hibernation, and how they could in turn, contribute to neurprotection during perinatal hypoxia-ischemia related injuries are discussed. This article appraises the novel idea that knowledge of the central mechanisms involved in the regulatory metabolic suppression, during which; hibernators switch themselves off without dissolving their brains could represent brain neuroprotective strategy for the clinical management of perinatal hypoxia-ischemia brain injuries in newborns.
 ...
PMID:Brain-regulated metabolic suppression during hibernation: a neuroprotective mechanism for perinatal hypoxia-ischemia. 1870 3

Hypoxic-Ischemic Encephalopathy (HIE) is the consequence of systemic asphyxia occurring at birth. Twenty five percent of neonates with HIE develop severe and permanent neuropsychological sequelae, including mental retardation, cerebral palsy, and epilepsy. The outcomes of HIE are devastating and permanent, making it critical to identify and develop therapeutic strategies to reduce brain injury in newborns with HIE. To that end, the neonatal rat model for hypoxic-ischemic brain injury has been developed to model this human condition. The HIE model was first validated by Vannucci et al and has since been extensively used to identify mechanisms of brain injury resulting from perinatal hypoxia-ischemia and to test potential therapeutic interventions. The HIE model is a two step process and involves the ligation of the left common carotid artery followed by exposure to a hypoxic environment. Cerebral blood flow (CBF) in the hemisphere ipsilateral to the ligated carotid artery does not decrease because of the collateral blood flow via the circle of Willis; however with lower oxygen tension, the CBF in the ipsilateral hemisphere decreases significantly and results in unilateral ischemic injury. The use of 2,3,5-triphenyltetrazolium chloride (TTC) to stain and identify ischemic brain tissue was originally developed for adult models of rodent cerebral ischemia, and is used to evaluate the extent of cerebral infarctin at early time points up to 72 hours after the ischemic event. In this video, we demonstrate the hypoxic-ischemic injury model in postnatal rat brain and the evaluation of the infarct size using TTC staining.
 ...
PMID:The hypoxic-ischemic encephalopathy model of perinatal ischemia. 1906 30

Hypoxic-ischemic brain injury is an important cause of neonatal mortality and subsequent serious neurological sequel. In neonatal brain the severity of hypoxic injury varies most probably due to the effects of multiple protective or deleterious factors. But the mechanisms under this difference are still not full understood. In recent years, some evidence has been found supporting the involvement of epigenetic mechanisms in many neurodegenerative diseases and stroke. We hypothesised that epigenetic mechanisms have been also involved in neonatal hypoxic-ischemic brain injury possibly by suppression of ischemia-induced cerebral inflammation and changing the expression of proapoptotic-antiapoptotic genes.
 ...
PMID:Role of epigenetic regulatory mechanisms in neonatal hypoxic-ischemic brain injury. 1926 50

Hypoxic-ischemic brain injury is often delayed and involves both apoptotic and immunoregulatory mechanisms. In this study, we used a neonatal model of hypoxia-ischemia to examine the effect of the mixed lineage kinase (MLK) inhibitor CEP-1347 on brain damage, apoptosis and inflammation. The tissue volume loss was reduced by 28% (p = 0.019) in CEP-1347-treated versus vehicle-treated rats and CEP-1347 significantly attenuated microgliosis at 7 days (p = 0.038). CEP-1347 decreased TUNEL-positive staining as well as cleaved caspase 3 immunoreactivity. CEP-1347 did not affect the expression of pro-inflammatory cytokines IL-1 beta, IL-6 and MCP-1, nor did it affect the expression of OX-42 (CR3) and OX-18 (MHC I) 24 h after the insult. In conclusion, the MLK inhibitor CEP-1347 has protective effects in a neonatal rat model of hypoxia-ischemia, which is mainly related to reduced apoptosis.
 ...
PMID:Role of mixed lineage kinase inhibition in neonatal hypoxia-ischemia. 1967 71


1 2 3 Next >>