Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0917798 (cerebral ischemia)
17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sequential alterations in the binding of [3H]cyclic AMP (cAMP) as an indicator of cAMP-dependent protein kinase (cAMP-DPK) binding activity following transient cerebral ischaemia were studied in the gerbil brain using receptor autoradiography. Transient ischaemia was induced for 10 min. [3H]cAMP binding in the stratum oriens and pyramidale of the hippocampal CA1 sector significantly decreased in the early post-ischaemic stage and showed severe reduction 7 days and 1 month after recirculation. By contrast, [3H]cAMP binding showed no significant alterations in the stratum radiatum of the hippocampal CA1 sector and the stratum pyramidale of the hippocampal CA3 sector up to 48 h after ischaemia. However, the binding in these areas significantly decreased 7 days and 1 month after ischaemia. The stratum lacunosum-moleculare of the hippocampal CA1 sector and dentate gyrus showed no significant changes in [3H]cAMP binding throughout the recirculation period. However, in the dorsolateral part of the striatum, where severe neuronal damage was seen morphologically, [3H]cAMP binding was significantly reduced only one month after ischaemia. These results indicate that marked alteration of intracellular signal transduction precedes neuronal damage in the hippocampal CA1 sector, but not in the striatum. Furthermore, our autoradiographic data suggest that post-ischaemic alteration in [3H]cAMP binding between the hippocampal CA1 sector and striatum may be produced by different mechanisms.
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PMID:Sequential changes of [3H]cyclic AMP binding in the gerbil brain following transient cerebral ischaemia. 810 69

Transient ischemia-induced perturbations in calcium homeostasis have been proposed to lead to pathological activation of the cysteine protease calpain I and subsequent delayed neuronal death in the CA1 region of hippocampus. We report here on the design and characterization of antibodies selective for calpain-generated fragments of brain spectrin, and their use for immunoblot and immunohistochemical analyses of calpain activation following cerebral ischemia in the gerbil. Although spectrin was susceptible to degradation in vitro by many mammalian proteases, only calpain degraded spectrin to generate fragments immunoreactive with the antibodies. Following 5 min of global ischemia, immunoreactivity for calpain-degraded spectrin was rapidly (within 30 min) and markedly elevated in the perikarya and dendrites of several populations of forebrain neurons. The rapid calpain activation was completely prevented by the NMDA receptor antagonist MK-801. At later times postischemia, but prior to frank neuronal necrosis, calpain-degraded spectrin was restricted to hippocampal area CA1 pyramidal neurons. Silver impregnation histochemistry confirmed that neuronal damage was confined to area CA1. The results indicate that while nonpathological NMDA receptor stimulation can activate calpain, only those neurons showing sustained calpain activation are destined to die.
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PMID:Immunolocalization of calpain I-mediated spectrin degradation to vulnerable neurons in the ischemic gerbil brain. 820 97

Receptor autoradiographic and histological techniques were used to investigate sequential alteration of naloxone receptors in the gerbil brain 1 h-7 days after transient cerebral ischemia. Transient ischemia was induced for 10 min. [3H]Naloxone binding showed a transient elevation in the striatum 1 h after ischemia, whereas the hippocampus revealed no significant alteration in the binding. Thereafter, no conspicuous alteration in [3H]naloxone binding was seen in the striatum and hippocampus up to 24 h after ischemia. However, a significant elevation in [3H]naloxone binding was found in the hippocampal region 48 h after ischemia. In contrast, the striatum showed no significant alteration in [3H]naloxone binding. Seven days after ischemia, a severe reduction in [3H]naloxone binding was seen not only in the dorsolateral striatum and hippocampal CA3 pyramidal cell layer, where irreversible neuronal damage was found, but also in the histopathological intact dentate gyrus. However, the hippocampal CA1 sector which was most vulnerable to ischemia, revealed no conspicuous alteration in [3H]naloxone binding. These results demonstrate that alteration of naloxone receptors precedes ischemic neuronal damage to the striatum and hippocampus. They also suggest that the damage between striatum and hippocampus may be produced with different processes.
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PMID:Naloxone receptor binding in gerbil striatum and hippocampus following transient cerebral ischemia. 822 Jan 73

We investigated the long-term changes that occur in the gerbil brain following transient cerebral ischemia using histology and receptor autoradiography. Transient ischemia was induced for 3 and 10 min, and animals were allowed to survive for 8 months. A histological study showed that 3-min ischemia caused neuronal damage and mild atrophy only in the hippocampal CA1 sector, and that 10-min ischemia produced severe neuronal damage and marked shrinkage in the hippocampal CA1 and CA3 sectors. Furthermore, severe neuronal damage was seen in the striatum after 10-min ischemia. Autoradiography study revealed that 3-min ischemia caused a significant reduction in [3H] naloxone binding in the frontal cortex, striatum, dentate gyrus, and thalamus, whereas [3H]SCH 23390 and [3H] forskolin binding was not significantly altered in all regions. In contrast, 10-min ischemia produced marked alteration in these binding sites in the striatum, hippocampus, thalamus, and substantia nigra. The alteration was especially notable in the hippocampal region and substantia nigra. These results indicate that hippocampal damage after transient ischemia, compared with that in other regions, is not static, but particularly progressive. Furthermore, they demonstrate a reduction in adenylate cyclase system in the striatum and substantia nigra after transient ischemia. Moreover, our results suggest that long-term survival after ischemia may induce synaptic modification of neurotransmitter and adenylate cyclase system in the hippocampus.
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PMID:Long-term observations in gerbil brain following transient cerebral ischemia: autoradiographic and histological study. 827 28

Receptor autoradiographic and histological techniques were used to investigate the long-term changes that occur in the gerbil brain following the induction of transient cerebral ischemia. Transient ischemia was induced for 3 and 10 min, and animals were allowed to survive for eight months. Autoradiographic analysis of second messenger systems showed that 3-min ischemia caused a significant reduction in [3H]inositol-1,4,5-trisphosphate binding in the hippocampal CA1 sector, whereas the alteration in [3H]phorbol 12,13-dibutyrate, [3H]forskolin and [3H] cyclic-AMP bindings was not found in this region. In the striatum, 3-min ischemia caused no significant alteration in [3H]phorbol 12,13-dibutyrate, [3H]inositol-1,4,5-trisphosphate and [3H]forskolin binding sites, whereas the [3H]cyclic-AMP binding showed a significant elevation. The thalamus exhibited a significant elevation only in the [3H]inositol-1,4,5-trisphosphate binding sites. Following 10-min ischemia, [3H]phorbol 12,13-dibutyrate, [3H]inositol-1,4,5-trisphosphate and [3H]cyclic-AMP binding sites revealed a significant reduction in the hippocampus, whereas the [3H]forskolin binding showed a significant elevation in this area. In the striatum, 10-min ischemia caused no significant alteration in [3H]phorbol 12,13-dibutyrate, [3H]inositol-1,4,5-trisphosphate and [3H]cyclic-AMP binding sites. However, marked reduction in the [3H]forskolin binding was seen in the striatum. Furthermore, the substantia nigra also exhibited a significant reduction in [3H]forskolin binding. Histological studies suggested that 3-min ischemia can produce severe neuronal damage and mild shrinkage to the hippocampal CA1 sector. They also showed that 10-min ischemia can cause severe tissue shrinkage and severe neuronal damage in the hippocampal CA1 sector and hippocampal CA3 sector. Thus, the hippocampal damage following ischemia was not static but progressive.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Postischemic changes of intracellular second messengers in the gerbil brain after long-term survival: an autoradiographic study. 838 52

1. We investigated alterations in dopamine D1 receptors in the striatum and hippocampus after transient cerebral ischemia in gerbils using [3H]SCH 23390 autoradiography. 2. We also examined the effect of vinconate against the alterations in dopamine D1 receptors after transient ischemia. 3. Transient ischemia was induced for 10 min, and vinconate (100 and 300 mg/kg) was given intraperitoneally 10 min before ischemia. 4. [3H]SCH 23390 binding showed no significant alterations in the striatum and hippocampus 5 hr after ischemia, whereas severe reduction in these areas was found after 7 days of recirculation. 5. Vinconate showed no significant alterations in [3H]SCH 23390 binding in the striatum and hippocampus except for a decrease in the hippocampal CA3 sector and dentate gyrus 5 hr after ischemia. By contrast, vinconate prevented a significant reduction in [3H]SCH 23390 binding in the striatum, hippocampal CA3 sector, hilus, and dentate gyrus 7 days after ischemia. 6. Vinconate inhibited lipid peroxidation in rat brain homogenates in a concentration-related manner. 7. These results indicate that free radicals generated from abnormal dopamine metabolism may play a key role in the development of ischemic brain damage. Furthermore, they suggest that vinconate prevents ischemic brain damage by inhibiting lipid peroxidation.
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PMID:Neuroprotective effect of vinconate against postischemic alterations in binding of [3H]SCH 23390 in the gerbil brain. 848 99

Activation of the N-methyl-D-aspartate (NMDA) receptor has been implicated in the events leading to ischemia-induced neuronal cell death. Recent studies have indicated that the properties of the NMDA receptor channel may be regulated by tyrosine phosphorylation. We have therefore examined the effects of transient cerebral ischemia on the tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B in different regions of the rat brain. Transient (15 min) global ischemia was produced by the four-vessel occlusion procedure. The tyrosine phosphorylation of NR2A and NR2B subunits was examined by immunoprecipitation with anti-tyrosine phosphate antibodies followed by immunoblotting with antibodies specific for NR2A or NR2B, and by immunoprecipitation with subunit-specific antibodies followed by immunoblotting with anti-phosphotyrosine antibodies. Transient ischemia followed by reperfusion induced large (23-29-fold relative to sham-operated controls), rapid (within 15 min of reperfusion), and sustained (for at least 24 h) increases in the tyrosine phosphorylation of NR2A and smaller increases in that of NR2B in the hippocampus. Ischemia-induced tyrosine phosphorylation of NR2 subunits in the hippocampus was higher than that of cortical and striatal NR2 subunits. The enhanced tyrosine phosphorylation of NR2A or NR2B may contribute to alterations in NMDA receptor function or in signaling pathways in the postischemic brain and may be related to pathogenic events leading to neuronal death.
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PMID:Transient ischemia differentially increases tyrosine phosphorylation of NMDA receptor subunits 2A and 2B. 928 28

1. The aim of this study was to investigate the effect of N-(3-(aminomethyl)benzyl)acetamidine (1400W), a selective inhibitor of inducible calcium-independent nitric oxide synthase (iNOS), on the functional and histopathological outcomes of experimental transient focal cerebral ischaemia in rats. 2. Transient ischaemia was produced by the occlusion for 2 h of both the left middle cerebral artery and common carotid artery. Treatments with 1400W (20 mg kg(-1)) or vehicle were started 18 h after occlusion of the arteries and consisted in seven subcutaneous injections at 8 h interval. Ischaemic outcomes and NOS activities (constitutive and calcium-independent NOS) were evaluated 3 days after ischaemia. 3. 1400W significantly reduced ischaemic lesion volume by 31%, and attenuated weight loss and neurological dysfunction. 4. 1400W attenuated the calcium-independent NOS activity in the infarct by 36% without affecting the constitutive NOS activity. 5. These findings suggest that iNOS activation contributes to tissue damage and that selective inhibitors of this isoform may be of interest for the treatment of stroke.
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PMID:Selective inhibition of inducible nitric oxide synthase prevents ischaemic brain injury. 1038 57

Transient ischemia increases tyrosine phosphorylation of N-methyl-D-aspartate (NMDA) receptor. Several tyrosine kinases are involved in this process. In this study, effect of ischemia and reperfusion (I/R) on tyrosine phosphorylation of NMDA receptor subunit 2A (NR2A) and the interaction of two tyrosine kinases, Src and Pyk2, with NR2A was investigated. Four-vessel occlusion was used to produce transient (15 min) cerebral ischemia in SD rats. Tyrosine phosphorylation of NR2A in hippocampus was enhanced after 15 min of reperfusion and reached its peak level at 6 h of reperfusion. The increase sustained for at least 24 h. Src and Pyk2 co-immunoprecipitated with NR2A and the binding increased after I/R, which also reached a peak at 6 h of reperfusion. Besides, Src and Pyk2 were activated after I/R. These increases were prevented by ketamine, a selective NMDA receptor antagonist, which was administered to the SD rats 20 min before ischemia. Moreover, Src and Pyk2 coprecipitated with each other. These data show that NR2A, Src and Pyk2 might form a protein complex in vivo and the interaction suggests a possible mechanism of signal transduction in the postischemic hippocampus.
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PMID:NMDA receptor activation results in tyrosine phosphorylation of NMDA receptor subunit 2A(NR2A) and interaction of Pyk2 and Src with NR2A after transient cerebral ischemia and reperfusion. 1147 20

Transient global cerebral ischemia triggers suppression of the initiation step of protein synthesis, a process which is controlled by endoplasmic reticulum (ER) function. ER function has been shown to be disturbed after transient cerebral ischemia, as indicated by an activation of the ER-resident eIF2alpha kinase PERK. In this study, we investigated ischemia-induced changes in protein levels and phosphorylation states of the initiation factors eIF2alpha, eIF2B epsilon, and eIF4G1 and of p70 S6 kinase, proteins playing a central role in the control of the initiation of translation. Transient focal cerebral ischemia was induced in mice by occlusion of the left middle cerebral artery. Transient ischemia caused a long-lasting suppression of global protein synthesis. eIF2alpha was transiently phosphorylated after ischemia, peaking at 1-3 h of recovery. eIF2B epsilon and p70 S6 kinase were completely dephosphorylated during ischemia and phosphorylation did not recover completely following reperfusion. In addition, eIF2B epsilon, eIF4G1, and p70 S6 kinase protein levels decreased progressively with increasing recirculation time. Thus, several different processes contributed to ischemia-induced suppression of the initiation of protein synthesis: a long-lasting dephosphorylation of eIF2B epsilon and p70 S6K starting during ischemia, a transient phosphorylation of eIF2alpha during early reperfusion, and a marked decrease of eIF2B epsilon, eIF4G1, and p70 S6K protein levels starting during vascular occlusion (eIF4G1). Study of the mechanisms underlying ischemia-induced suppression of the initiation step of translation will help to elucidate the role of protein synthesis inhibition in the development of neuronal cell injury triggered by transient cerebral ischemia.
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PMID:Mechanisms underlying suppression of protein synthesis induced by transient focal cerebral ischemia in mouse brain. 1242 99


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