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

The bilateral carotid occlusion model and a polyclonal antibody to the carboxyl terminus of the rat brain/human hepatoma glucose transporter were used to examine quantitatively changes in the transporter in gerbil hippocampal microvessels following 6-7.5 min of ischemia. The optical densities of immunocytochemically stained microvessels in the stratum lacunosum-moleculare (SLM) below the CA1 subfield were determined using image analysis of frozen sections from gerbils killed 2 h, 3 days, 6 days, 4 weeks, and 7 weeks after the ischemic episode. Microvessels were sparsely distributed in the stratum oriens, stratum pyramidale, and stratum radiatum. In contrast, the SLM was relatively well vascularized, and this distribution of microvessels persisted following ischemia. The SLM was identifiable based solely on microvessel distribution both in control gerbils and in gerbils that exhibited complete destruction of CA1 pyramidal cells. The abundance of the glucose transporter in SLM microvessels remained constant, suggesting that down-regulation of this protein cannot account for reported declines in brain glucose utilization and cell death following ischemia. Conversely, the presence and metabolic activity of CA1 pyramidal cells do not appear to be determinants of glucose transporter abundance in hippocampal microvessels. The brain/hepatoma glucose transporter was abundant in brain microvessels and the epithelial cells of the choroid plexus of gerbil and rat. Staining of hippocampal neuropil was less intense, poorly localized, and, at the light microscope level, not clearly associated with a particular cell type.
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PMID:Quantitative immunocytochemistry (image analysis) of glucose transporters in the normal and postischemic rodent hippocampus. 201 51

Expression of vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen and a potent angiogenic factor, is upregulated in response to a hypoxic or hypoglycemic stress. Here we show that the increase in steady-state levels of VEGF mRNA is partly due to transcriptional activation but mostly due to increase in mRNA stability. Both oxygen and glucose deficiencies result in extension of the VEGF mRNA half-life in a protein synthesis-dependent manner. Viewing VEGF as a stress-induced gene, we compared its mode of regulation with that of other stress-induced genes. Results showed that under nonstressed conditions, VEGF shares with the glucose transporter GLUT-1 a relatively short half-life (0.64 and 0.52 h, respectively), which is extended fourfold and more than eightfold, respectively, when cells are deprived of either oxygen or glucose. In contrast, the mRNAs of another hypoxia-inducible and hypoglycemia-inducible gene, grp78, as well as that of HSP70, were not stabilized by these metabolic insults. To show that VEGF and GLUT-1 are coinduced in differentially stressed microenvironments, multicell spheroids representing a clonal population of glioma cells in which each cell layer is differentially stressed were analyzed by in situ hybridization. Cellular microenvironments conducive to induction of VEGF and GLUT-1 were completely coincidental. These findings show that two different consequences of tissue ischemia, namely, hypoxia and glucose deprivation, induce VEGF and GLUT-1 expression by similar mechanisms. These proteins function, in turn, to satisfy the tissue needs through expanding its vasculature and improving its glucose utilization, respectively.
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PMID:Stabilization of vascular endothelial growth factor mRNA by hypoxia and hypoglycemia and coregulation with other ischemia-induced genes. 756 86

Because neurons are postmitotic, they are irreplaceable once they succumb to necrotic insults such as hypoglycemia, ischemia, and seizure. A paucity of energy can exacerbate the toxicities of these insults; thus, a plausible route to protect neurons from necrotic injury would be to enhance their glucose uptake capability. We have demonstrated previously that defective herpes simplex virus (HSV) vectors overexpressing the rat brain glucose transporter (GT) gene (gt) can enhance glucose uptake in adult rat hippocampus and in hippocampal cultures. Furthermore, we have observed that such vectors can maintain neuronal metabolism during hypoglycemia and reduce kainic acid-induced seizure damage. In this study, we have developed bicistronic vectors that coexpressed gt and Escherichia coli lacZ as a reporter gene, which allows us to identify directly neurons that are infected with the vectors. Overexpression of GT from these vectors protected cultured hippocampal, spinal cord, and septal neurons against various necrotic insults, including hypoglycemia, glutamate, and 3-nitropropionic acid. Our observations demonstrate the feasibility of using HSV vectors to protect neurons from necrotic insults. Although this study has concentrated on the delivery of gt, other genes with therapeutic or protective capability might also be used.
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PMID:Defective herpes simplex virus vectors expressing the rat brain glucose transporter protect cultured neurons from necrotic insults. 761 44

Brain damage after global forebrain ischemia is worsened by prior hyperglycemia and ameliorated by antecedent hypoglycemia. To assess whether GLUT3, the neuron specific glucose transporter and its mRNA, are affected by cerebral ischemia, we investigated the hippocampal pattern of GLUT3 immunoreactivity and GLUT3 gene expression 1, 4 and 7 days after global forebrain ischemia in a rat 2-vessel occlusion model. We used a newly generated, specific, C-terminally directed polyclonal antiserum against GLUT3 to stain coronal frozen sections. Thionin staining and the microglial marker, OX42, indicated the extent of ischemic damage in hippocampus and correlated with GLUT3 loss. One day after ischemia, no significant change in hippocampal GLUT3 immunoreactivity was observed; by 4 days however, there was consistent and pronounced loss; and at 7 days the loss of GLUT3 staining was maximal. The greatest loss of GLUT3 staining was in the CA1 region, especially the strata oriens and radiatum of Ammon's horn. By contrast, GLUT3 staining was undiminished in the stratum lacunosum moleculare, in the mossy fibers of the lateral aspect of CA3 and in all but the inner-most portion of the molecular layer of the dentate gyrus, immediately adjacent to the granule cells. GLUT3 mRNA levels were not significantly altered at 24 hours and significantly declined at 4 and 7 days after ischemia in the CA1 pyramidal layer. These data are consistent with the pattern of neuronal loss and microglial activation in hippocampus. Loss of GLUT3 may affect the availability of glucose, and possibly the viability of ischemically damaged neurons.
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PMID:Progressive hippocampal loss of immunoreactive GLUT3, the neuron-specific glucose transporter, after global forebrain ischemia in the rat. 771 21

GLUT1 and GLUT3 mRNAs in normal and post-ischemic gerbil brains were examined qualitatively and semi-quantitatively using in situ hybridization in conjunction with image analysis. Coronal brain sections at the level of the anterior hippocampus were prepared three hours, one day, and three days after animals were subjected to six min of ischemia. The sections were hybridized with vector- and PCR-generated RNA probes labeled with 35S. Microscopic evaluation of hybridized brain sections coated with autoradiographic emulsion indicated that GLUT1 mRNA was associated with brain microvessels, choroid plexus, and some ependymal cells. GLUT1 mRNA was not observed in neurons, except that one day following ischemia, this mRNA was induced in neurons of the dentate gyrus. GLUT3 mRNA was detected only in neurons. Image analysis of film autoradiograms revealed that both the GLUT1 and GLUT3 messages increased following ischemia but returned nearly to control levels by day three. In the CA1 region of the hippocampus the increase in GLUT3 mRNA was not statistically significant, and by day three the level had fallen significantly below the control, coinciding with the degeneration of the CA1 neurons. Our results suggest that the brain possesses mechanisms for induction and up-regulation of glucose transporter gene expression.
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PMID:GLUT1 and GLUT3 gene expression in gerbil brain following brief ischemia: an in situ hybridization study. 780 30

The purpose of this study was to quantify the changes of blood-brain barrier glucose transporter kinetics following cerebral ischemia using an in situ brain perfusion technique. Sixty-four adult male Sprague-Dawley rats were divided into control and ischemia groups, and a four-vessel occlusion model was used to provide an ischemic insult. To obtain regional capillary permeability area products of glucose and regional perfusion fluid flow rates, the perfusion fluid was dually labeled with 2-deoxy[14C]glucose and [3H]diazepam, and the brain was perfused at a constant rate via the external carotid artery. After sampling tissues from the brain, dual scintillation counting was performed and both regional perfusion fluid flow rates and regional capillary permeability area products were calculated. We determined kinetic parameters, including Vmax, Km and Kd as described in the Michaelis-Menten equation, by the non-linear least squares method. In the ischemia group, a decrease in Vmax and an increase in Km were recognized, which mean decreases in the affinity and the number of functioning glucose transporters. These results suggest that cerebral ischemia downregulates the blood-brain barrier glucose transporters.
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PMID:Cerebral ischemia alters glucose transporter kinetics across rat brain microvascular endothelium. Quantitative analysis by an in situ brain perfusion method. 783 76

The present study examined the immunocytochemical expression of the blood-brain barrier glucose transporter (GLUT-1) in a series of fetal neocortical transplants, autonomic tissue transplants, and stab wounds to the rat brain. GLUT-1 is one of a family of different glucose transporters and is found exclusively on barrier-type endothelial cells. In the brain it is responsible for the regulated facilitative diffusion of glucose across the blood-brain barrier. This investigation is the first to determine if this important molecule is altered during the process of angiogenesis that occurs following neural transplantation procedures or direct brain injury. Beginning in late fetal brain, e.g., E18 and continuing into maturity, GLUT-1 was strongly and exclusively expressed on normal cerebral vessels. In solid fetal central nervous system (CNS) transplants up to around 3 weeks postoperative, GLUT-1 was only weakly expressed, particularly as exemplified by colloidal gold immunostaining when compared with the host. At later times examined, up to 15 months postoperative, GLUT-1 immunoexpression was comparable with the normal adjacent brain. In autonomic tissue transplants, where the vessels do not have a blood-brain barrier, as expected, GLUT-1 was not expressed. In stab wounds, at 1 week there was extensive gliosis, and the injured vessels appeared fragmented and collapsed but still expressed GLUT-1, although to a somewhat lesser extent than normal brain. Between 3 and 6 weeks, GLUT-1 was expressed on tortuous vessels and in apparently fibrillar processes in the wound vicinity with a similar pattern to astrocyte (GFAP) reactivity. These results suggest the occurrence of a down-regulation of GLUT-1 in early transplants, perhaps related to reduced glycolytic activity or transient ischemia, or possibly due to the utilization of alternative energy sources. That GLUT-1 expression was not entirely lost in stab wounds to the mature brain suggests that the protein may be more labile in fetal or perinatal brain than in the adult and may not be affected by direct injury. Coupled with previous transplantation studies that have shown reduced neuronal glycolysis and potential barrier alterations, the reduction of GLUT-1 activity within nearly the identical time frame could indicate a relatively early critical period in cellular metabolism following transplantation of CNS tissue.
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PMID:Immunocytochemical expression of the blood-brain barrier glucose transporter (GLUT-1) in neural transplants and brain wounds. 788 40

As neurons rely almost exclusively on glucose as an energy substrate, glucose transport is of critical importance to cerebral function. Two specific facilitative glucose transporters, GT1 and -3, predominate in brain, with the latter exclusively expressed by neurons, whereas GT1 is expressed by astrocytes and vascular elements. Little is known about the regulation of these transporters at the genetic level or the extent to which their expression may change in response to acute or chronic changes in metabolic demands. Thus, we employed in situ hybridization to evaluate changes in glucose transporter gene expression in the rat brain in response to ischemia induced by middle cerebral artery occlusion (MCAO). The most remarkable responses were demonstrated by GT1, which within an hour of ischemic insult demonstrated a global increase in gene expression throughout the forebrain. In the ensuing hours, GT1 expression further intensified and became lateralized to the lesioned hemisphere, with normalization of expression contralaterally. Increased GT1 mRNA levels were found in astroglia and microvessels and were also present in distinct neuronal populations, including the piriform cortex, dentate gyrus, and medial habenula, which normally do not express GT1 mRNA. By 24 h post-MCAO, glial cells of the ipsilateral cortex surrounding the infarct zone still demonstrated elevated GT1 mRNA levels, but expression had returned to baseline in neurons. Interestingly, it was not until GT1 expression had subsided (24 h post-MCAO), that there was a modest increase in neuronal GT3 gene expression in the affected hemisphere. GT2 and GT4 mRNAs were not detected in the rat brain under normal conditions or after ischemia. These data demonstrate that ischemia induces an immediate and sustained increase in brain GT1 gene expression in both glial cells and neurons. This augmentation of GT1 expression could represent a defensive strategy aimed at repletion of the brain's energy stores and stabilization of neuronal membrane potential.
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PMID:Ischemic injury induces brain glucose transporter gene expression. 824 75

We assessed the effects of 4 weeks of streptozocin-induced diabetes on regional myocardial glycolytic metabolism during ischemia in anesthetized open-chest domestic swine. Diabetic animals were hyperglycemic (12.0 +/- 2.1 v 6.6 +/- .5 mmol/L), and had lower fasting insulin levels (27 +/- 8 v 79 +/- 19 pmol/L). Myocardial glycolytic metabolism was studied with coronary flow controlled by an extracorporeal perfusion circuit. Left anterior descending coronary artery (LAD) flow was decreased by 50% for 45 minutes and left circumflex (CFX) flow was constant. Myocardial glucose uptake and extraction were measured with D-[6-3H]-2-deoxyglucose (DG) and myocardial blood flow was measured with microspheres. The rate of glucose conversion to lactate and lactate uptake and output were assessed with a continuous infusion of [6-14C]glucose and [U-13C]lactate into the coronary perfusion circuit. Both diabetic and nondiabetic animals had sharp decreases in subendocardial blood flow during ischemia (from 1.21 +/- .10 to 0.43 +/- .08 mL.g-1.min-1 in the nondiabetic group, and from 1.30 +/- .15 to 0.55 +/- .11 in the diabetic group). Diabetes had no significant effect on myocardial glucose uptake or glucose conversion to lactate under either well-perfused or ischemic conditions. Forty-five minutes of ischemia resulted in significant glycogen depletion in the subendocardium in both nondiabetic and diabetic animals, with no differences between the two groups. Glycolytic metabolism is not impaired in hyperglycemic diabetic swine after 1 month of the disease when compared with that in normoglycemic nondiabetic animals. The myocardial content of the insulin-regulatable glucose transporter (GLUT 4) was measured in left ventricular biopsies.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Myocardial glucose transporters and glycolytic metabolism during ischemia in hyperglycemic diabetic swine. 828 77

Cerebral hypoxia-ischemia produces major alterations in energy metabolism and glucose utilization in brain. The facilitative glucose transporter proteins mediate the transport of glucose across the blood-brain barrier (BBB) (55 kDa GLUT1) and into the neurons and glia (GLUT3 and 45 kDa GLUT1). Glucose uptake and utilization are low in the immature rat brain, as are the levels of the glucose transporter proteins. This study investigated the effect of cerebral hypoxia-ischemia in a model of unilateral brain damage on the expression of GLUT1 and GLUT3 in the ipsilateral (damaged, hypoxic-ischemic) and contralateral (undamaged, hypoxic) hemispheres of perinatal rat brain. Early in the recovery period, both hemispheres exhibited increased expression of BBB GLUT1 and GLUT3, consistent with increased glucose transport and utilization. Further into recovery, BBB GLUT1 increased and neuronal GLUT3 decreased in the damaged hemisphere only, commensurate with neuronal loss.
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PMID:Effects of hypoxia-ischemia on GLUT1 and GLUT3 glucose transporters in immature rat brain. 853 May 59


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