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)

Transient forebrain ischemia of 30 min duration was produced in anaesthetized rats by four-vessel occlusion. After survival periods of 3 h to three days brains were perfusion-fixed and sections through the mid-dorsal hippocampus were processed for conventional staining and immunohistochemical analysis. Neuronal damage in the hilus was manifested 3-8 h after ischemia; neurons in the CA1 and CA2 sector suffered delayed neuronal death after 48-72 h whereas the dentate gyrus and the CA3 sector were normal. Vasogenic edema formation was visualized using antibodies against rat serum-proteins, serum albumin and immunoglobulins. By 3 h after ischemia, only faint and diffuse serum-staining was detected. At 8 h survival, weak astrocytic-staining was present. After 24-72 h CA1-CA2 exhibited massive serum extravasation. The molecular layer of the dentate gyrus showed edema formation in the absence of granule cell damage. The glial reaction was studied using antibodies against glial fibrillary acidic protein, vimentin and S-100 protein. Glial fibrillary acidic protein and S-100 protein-staining increased in areas with either edema or neuronal damage. In contrast, changes in vimentin were only detected in areas with neuronal necrosis. The observations demonstrate that following 30 min of ischemia neuronal damage is accompanied by changes in blood-brain barrier function and reactive glial alterations. The dissociation between neuronal necrosis and astroglial hypertrophy and hyperplasia reflects differences in cellular responsiveness which constitute inherent features of postischemic hippocampal injury.
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PMID:Immunohistochemical study of glial reaction and serum-protein extravasation in relation to neuronal damage in rat hippocampus after ischemia. 170 95

Release of the excitatory amino acid (EAA) neurotransmitter glutamate has been implicated in secondary tissue damage following central nervous system (CNS) trauma and ischemia. The present study evaluated the neuroprotective actions of 619C89, a sodium channel blocker that inhibits ischemia-induced glutamate release, on traumatic brain injury (TBI) in rats using a lateral fluid percussion model. Various motor-related behavioral outcomes were used to evaluate neurologic function. Glial fibrillary acidic protein (GFAP) immunostaining and Cresyl violet staining were used to assess the histological changes. Treatment with 619C89, at a dose of 30 mg/kg administered intravenously 15 min before brain injury, significantly attenuated behavioral deficits at 24 h and 1 week. At 2 weeks, neuronal loss in the CA1 and CA3 pyramidal cell layers of the hippocampus was significantly decreased by 619C89 administration. Treatment with this compound also significantly attenuated increases in GFAP-immunoreactivity in both ipsilateral and contralateral CA1 regions. The present results suggest a potential therapeutic role for sodium channel blockade and/or glutamate release inhibition in the treatment of TBI.
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PMID:Neuroprotective effects of 619C89, a use-dependent sodium channel blocker, in rat traumatic brain injury. 775 66

B/A4 is the major component of brain amyloid plaque, one of the hallmarks of Alzheimer's disease (AD). B/A4 is a product of proteolytic processing of its precursor, the Alzheimer amyloid precursor protein (APP). Recently, apolipoprotein E (APO-E) has also been shown to be associated with Alzheimer's disease pathology because it is localized to plaques and tangles, and the gene encoding one of the isoforms of APO-E (E4) is associated with late-onset familial and sporadic AD. In addition, APO-E exhibits high affinity for binding to the B-peptide (B/A4). In this study, we have investigated changes in the steady state levels of APP, APO-E, and the astrocyte-specific marker, glial fibrillary acidic protein (GFAP) mRNA in the gerbil hippocampal CA1 region after a 10-min period of bilateral carotid occlusion-induced forebrain ischemia. Following this insult, we observed a loss of 90% of the CA1 neurons by 72 h post-ischemia. The mRNA levels on day 1 through day 7 post-ischemia were quantitated using an image analyzer. There was an increase in the transcription of APO-E and GFAP mRNAs, with the levels of APO-E mRNA being the highest (3-fold increase on day 7 post-ischemia) (P < 0.005). However, we did not see an increase in APP mRNA. In a parallel study [Hall, E.D. et al., Exp. Neurol., 135(1995) 17-27], we have also seen an increase in levels of APO-E and GFAP protein measured by immunocytochemistry. However, in contrast to the lack of an increase in APP mRNA, immunocytochemical measurement of APP did show an increase, perhaps due to delayed translation of previously formed mRNA. We suggest that neuronal injury or insult results in the induction of certain genes (and, therefore, protein synthesis) in the surrounding reactive astrocytes, and these proteins may contribute to post-injury amyloidogenesis.
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PMID:Induction of apolipoprotein E mRNA in the hippocampus of the gerbil after transient global ischemia. 873 65

The neonatal striatum degenerates after hypoxia-ischemia (H-I). We tested the hypothesis that damage to astrocytes and loss of glutamate transporters accompany striatal neurodegeneration after H-I. Newborn piglets were subjected to 30 minutes of hypoxia (arterial O2 saturation, 30%) and then 7 minutes of airway occlusion (O2 saturation, 5%), producing cardiac arrest, followed by cardiopulmonary resuscitation. Piglets recovered for 24, 48, or 96 hours. At 24 hours, 66% of putaminal neurons were injured, without differing significantly thereafter, but neuronal densities were reduced progressively (21-44%). By DNA nick-end labeling, the number of dying putaminal cells per square millimeter was increased maximally at 24 to 48 hours. Glial fibrillary acidic protein-positive cell body densities were reduced 48 to 55% at 24 to 48 hours but then recovered by 96 hours. Early postischemia, subsets of astrocytes had fragmented DNA; later postischemia, subsets of astrocytes proliferated. By immunocytochemistry, glutamate transporter 1 (GLT1) was lost after ischemia in the astroglial compartment but gained in cells appearing as neurons, whereas neuronal excitatory amino acid carrier 1 (EAAC1) dissipated. By immunoblotting, GLT1 and EAAC1 levels were 85% and 45% of control, respectively, at 24 hours of recovery. Thus, astroglial and neuronal injury occurs rapidly in H-I newborn striatum, with early gliodegeneration and glutamate transporter abnormalities possibly contributing to neurodegeneration.
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PMID:Hypoxia-ischemia causes abnormalities in glutamate transporters and death of astroglia and neurons in newborn striatum. 930 55

Insulin-like growth factor-1 (IGF-1) is known to be important for oligodendrocyte survival and myelination. In the current study, the authors examined the hypothesis that exogenous IGF-1 could reduce postischemic white matter injury. Bilateral brain injury was induced in near-term fetal sheep by 30 minutes of reversible carotid artery occlusion. Ninety minutes after ischemia, either vehicle (n = 8) or a single dose of 3 microg IGF-1 (n = 9) was infused intracerebroventricularly over 1 hour. White matter changes were assessed after 4 days recovery in the parasagittal intragyral white matter and underlying corona radiata. Proteolipid protein (PLP) mRNA staining was used to identify bioactive oligodendrocytes. Glial fibrillary acidic protein (GFAP) and isolectin B-4 immunoreactivity were used to label astrocytes and microglia, respectively. Myelin basic protein (MBP) density and the area of the intragyral white matter tracts were determined by image analysis. Insulin-like growth factor-1 treatment was associated with significantly reduced loss of oligodendrocytes in the intragyral white matter (P < 0.05), with improved MBP density (P < 0.05), reduced tissue swelling, and increased numbers of GFAP and isolectin B-4 positive cells compared with vehicle treatment. After ischemia there was a close association of PLP mRNA labeled cells with reactive astrocytes and macrophages/microglia. In conclusion, IGF-1 can prevent delayed, postischemic oligodendrocyte cell loss and associated demyelination.
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PMID:Insulin-like growth factor-1 reduces postischemic white matter injury in fetal sheep. 1133 59

Functional neurological outcome after transient ischemia might be improved by timely therapeutic intervention. To determine if restorative behavioral therapy influences damage, improves task learning, or alters astrocyte metabolic activity after ischemia, rats (food-restricted to 85% of free-feeding weight) were (a) first trained to respond on one of two levers under a fixed-ratio 20 schedule of food presentation (FR20), then (b) subjected to sham manipulation of carotid arteries or 10 min ischemia by four-vessel occlusion, followed by (c) 4 days of operant testing or inactivity, (d) then all rats were tested under a FR20 lever reversal task for 4 weeks, and (e) 3 days after the last behavioral session astrocyte metabolism was assayed by local uptake of [2-14C]acetate. Mild loss of hippocampal neurons occurred in ischemic rats with or without training after ischemia. Glial fibrillary acidic protein-positive astrocytes were present in similar numbers throughout brains of sham control and ischemic rats. Mild ischemia did not impair learning, and no changes in FR20 reversal learning were detected in sham vs. ischemic rats. Net [14C]acetate uptake was unaffected by ischemia but [14C]acetate uptake increased 15-24% (P<0.05; n=12-15/group) in specific structures (caudate, primary motor and sensorimotor cortex, CA1 hippocampus, subcortical white matter) in the pooled groups of rats that had 4 days FR20 testing vs. inactivity before reversal learning. 'Behavioral therapy' (operant testing on the 4 days immediately following either sham manipulation or ischemia) did not alter ischemic outcome, but was associated with higher acetate utilization in regions involved in motor activities.
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PMID:Behavioral training increases local astrocytic metabolic activity but does not alter outcome of mild transient ischemia. 1253 87

Distinctive cerebral lesions with disruptions to the developing white matter are found in very low birth weight (VLBW) infants. Although hypoxia-ischemia (HI) is a causal pathway, the pathogenesis of cerebral white matter injury in the VLBW infant is not fully understood. Pertinent murine models would facilitate the investigation of the processes leading to these cerebral lesions and enable the evaluation of therapeutic strategies. Postnatal d 3 (P3) rats are at a stage of cortical oligodendroglial maturation and axonal outgrowth similar to very preterm infants. Our aim was to characterize the effects of a focal hypoxic-ischemic injury at P3 on subsequent cerebral development. Three groups of P3 Wistar rats were investigated: group I underwent right carotid ligation followed by 6% hypoxia for 30 min (HI), group 2 had carotid ligation only, and group 3 had no intervention. At P21, in the HI group, the right cortical area was reduced compared with controls (p < 0.01). There were no significant alterations in the size of the dorsal hippocampus, striatum, and thalamus. The cortical myelinated area was reduced in the HI animals compared with controls (p < 0.01). There was a corresponding loss of myelinated axons extending up into the cortex, with deep cortical neuronal and axonal architecture markedly disrupted. Glial fibrillary acidic protein immunohistology showed a reactive gliosis in the deep parietal cortex (p < 0.01). Moderate HI injury in the immature rat brain compromised cortical growth and led to a selective alteration of cortical myelinated axons with persistent gliosis. These alterations induced at P3 by unilateral HI share neuropathological similarities with the diffuse white matter lesions found in VLBW infants.
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PMID:Selective cortical alteration after hypoxic-ischemic injury in the very immature rat brain. 1273 86

Induction of heat shock protein (HSP72) has been implicated in the development of ischemic tolerance in several tissue organs including brain and spinal cord. In the present study, using an aortic balloon occlusion model in rats, we characterized the effect of transient noninjurious (3 or 6 min) or injurious intervals (10 min) of spinal ischemia followed by 4-72 h of reflow on spinal expression of HSP72 and GFAP protein. In a separate group of animals, the effect of ischemic preconditioning (3 or 6 min) on the recovery of function after injurious interval of spinal ischemia (10 min) was studied. After 3 min of ischemia, there was a modest increase in HSP72 protein immunoreactivity in the dorsal horn neurons at 12 h after reperfusion. After 6 min of ischemia, a more robust and wide spread HSP72 protein expression in both dorsal and ventral horn neurons was detected. The peak of the expression was seen at 24 h after ischemia. At the same time point, a significant increase in spinal tissue GFAP expression was measured with Western blots and corresponded morphologically with the presence of activated astrocytes in spinal segments that had been treated similarly. After 10 min of ischemia and 24 h of reflow, a significant increase in spinal neuronal HSP72 expression in perinecrotic regions was seen. Behaviorally, 3 min preconditioning ischemia led to the development of a biphasic ischemic tolerance (the first at 30 min and the second at 24 h after preconditioning) and was expressed as a significantly better recovery of motor function after exposure to a second 10-min interval of spinal ischemia. After 6 min ischemic preconditioning, a more robust ischemic tolerance at 24 h after preconditioning then seen after 3-min preconditioning was detected. These data indicate that 3 min of spinal ischemia represents a threshold for spinal neuronal HSP72 induction, however, a longer sublethal interval (6 min) of preconditioning ischemia is required for a potent neuronal HSP72 induction. More robust neurological protection, seen after 6 min of preconditioning ischemia, also indicates that HSP72 expression in spinal interneurons seen at 24 h after preconditioning may represent an important variable in modulating ischemic tolerance observed during this time frame.
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PMID:Characterization of spinal HSP72 induction and development of ischemic tolerance after spinal ischemia in rats. 1469 21

The recreational use of the psychoactive drug, methamphetamine has increased markedly over the last three decades. It has long been known that this drug has detrimental effects upon the mammalian brain monoaminergic system, but the long- or short-term effects on the retina, a neurological extension of the central nervous system, have received little attention. The aim of this study was, therefore, to determine whether intraocular injection of methamphetamine (MA) is toxic to the healthy adult rat retina and to analyse its effects on the compromised retina after an injection of the ionotropic glutamate receptor agonist, kainate, which is known to cause retinal neuropathology. The equivalent of 1 mM (in the vitreous humour) MA and/or kainate (40 microM) were injected intravitreally. Flash electroretinograms (ERGs) were recorded before and 2 and 4 days after treatment. Five days after treatment, animals were killed and the retinas analysed either for the immunohistochemical localisation of various antigens or for electrophoresis/Western blotting. Some animals were kept for 19 days after treatment and the retinas analysed for tyrosine hydroxylase immunoreactivity. No differences could be found between vehicle- and MA-treated retinas with respect to the nature or localisation of either tyrosine hydroxylase immunoreactivity after 5 or 19 days or other antigens after 5 days. Moreover, the normal ERG and GFAP and calretinin protein antigens were unaffected by MA. Kainate treatment, however, caused a change in the ERGs after 2 and 4 days, an alteration in every antigen localised by immunohistochemistry and an increase in the retinal levels of calretinin and GFAP proteins. Significantly, the changes seen in the b-wave amplitude and implicit time of the ERG after 4 days and the increased level of GFAP protein after 5 days following kainate treatment were enhanced when MA was co-injected. Intravitreal injection of methamphetamine had no detectable detrimental effect on the normal adult rat retina but exacerbated the damaging effects of kainic acid. Such data suggest that a neurotoxic effect of MA may be more obviously illustrated when the tissue is already compromised as occurs in, for example, ischemia.
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PMID:Methamphetamine exacerbates the toxic effect of kainic acid in the adult rat retina. 1538 Jun 23

Moderate focal brain hypoxic-ischemic (HI) injury in the immature P3 rat leads to loss of cortical volume and disruptions of cortical myelination. In this study, we characterized the time course and pattern of cellular degeneration, axonal disruption, astrogliosis, and microglia activation. After moderate transient unilateral hypoxia-ischemia, brains were collected at set time points and positive staining was assessed. Cellular degeneration stained with Fluoro-Jade B (FJ-B) was distributed in a columnar pattern, primarily within the deep cortical layers V-VII extending up to layer IV of the parietal cortex (pCx). FJ-B staining increased in the ipsilateral pCx 12 and 24 h (p < 0.05) after the injury. Beta-amyloid precursor protein immunoreactivity indicating axonal disruption increased at 24 h (p < 0.05) and showed the same distribution as FJ-B. Glial fibrillary acidic protein-positive astrocytes increased dramatically within the ipsilateral pCx from 24 h (p < 0.05) to 18 d (p < 0.001) after HI injury and displayed a columnar pattern extending from the deep cortical layers to layers IV. Isolectin-B4 and ED1-labeled microglia were also increased within the ipsilateral deep pCx and underlying white matter between 12 and 24 h (p < 0.01), and increased Isolectin-B4 lasted up to 7 d after injury. These observations are consistent with the hypothesis that neuronal loss, astrogliosis, and microglia activation precede the subsequent disruption of cortical growth and myelination. This model offers new possibilities for investigating the cellular and molecular mechanisms of damage and repair after neonatal HI injury.
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PMID:Distinctive neuropathologic alterations in the deep layers of the parietal cortex after moderate ischemic-hypoxic injury in the P3 immature rat brain. 1577 44


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