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 neuroprotective effects of theanine and catechins contained in green tea are discussed. Although the death of cultured rat cortical neurons was induced by the application of glutamic acid, this neuronal death was suppressed with exposure to theanine. The death of hippocampal CA1 pyramidal neurons caused by transient forebrain ischemia in the gerbil was inhibited with the ventricular preadministration of theanine. The neuronal death of the hippocampal CA3 region by kainate was also prevented by the administration of theanine. Theanine has a higher binding capacity for the AMPA/kainate receptors than for NMDA receptors, although the binding capacity in all cases is markedly less than that of glutamic acid. The results of the present study suggest that the mechanism of the neuroprotective effect of theanine is related not only to the glutamate receptor but also to other mechanisms such as the glutamate transporter, although further studies are needed. One of the onset mechanisms for arteriosclerosis, a major factor in ischemic cerebrovascular disease, is probably the oxidative alteration of low-density lipoprotein (LDL) by active oxygen species. The oxidative alterations of LDL were shown to be prevented by tea catechins. Scavenging of *O(2)(-) was also exhibited by tea catechins. The neuroprotective effects of theanine and catechins contained in green tea are a focus of considerable attention, and further studies are warranted.
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PMID:Neuroprotective effects of the green tea components theanine and catechins. 1249 31

Simulated ischemic conditions (hypoxia-hypoglycaemia) in vitro enhanced glutamate efflux from rat cerebrocortical prisms. Here we characterised efflux mechanisms using pharmacological tools. The Na(+) channel blocker TTX (1 microM) did not affect ischemia-induced efflux, while sipatrigine (100 microM), a Na(+)/Ca(2+) channel blocker and omega-conotoxin MVIIC (2 microM), an N/P/Q type Ca(2+) channel blocker, inhibited efflux by fractions of 0.53 and 0.46, respectively (1.00 corresponding to total inhibition). Omission of extracellular Ca(2+) and addition of EGTA (2 mM) inhibited ischemia-induced efflux only during the first 25 min of incubation. A similar result was observed on omission of extracellular Ca(2+) together with addition of La(3+) (10 microM) and Mg(2+) (6 mM). TTX, sipatrigine and La(3+)/Mg(2+) all inhibited control efflux. Ischemia-induced efflux was sensitive to the volume activated anion channel inhibitor NPPB (100 microM) only after the first 25 min of incubation, with the maximal fraction inhibited being 0.54. The glutamate transporter inhibitor D,L-TBOA reduced ischemia-induced efflux throughout a 45-min incubation period, and enhanced efflux from control tissue. D,L-TBOA inhibited efflux at 30 min by a maximum fraction of 0.49, at 50 microM. These data indicate that the early phase of ischemia-induced glutamate efflux is in part Ca(2+) dependent, while the later phase involves volume activated anion currents and both phases involve excitatory amino acid transporters.
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PMID:Pharmacology of ischemia-induced glutamate efflux from rat cerebral cortex in vitro. 1257 7

Glutamate transport is central to neurotransmitter functions in the brain. Impaired glutamate transport induces neurotoxicity associated with numerous pathological processes, including stroke/ischemia, temporal lobe epilepsy, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, HIV-1-associated dementia, and growth of malignant gliomas. Excitatory amino acid transporter-2 (EAAT2) is a major glutamate transporter in the brain expressed primarily in astrocytes. We presently describe the cloning and characterization of the human EAAT2 promoter, demonstrating elevated expression in astrocytes. Regulators of EAAT2 transport, both positive and negative, alter EAAT2 transcription, promoter activity, mRNA, and protein. These findings imply that transcriptional processes can regulate EAAT2 expression. Moreover, they raise the intriguing possibility that the EAAT2 promoter may be useful for targeting gene expression in the brain and for identifying molecules capable of modulating glutamate transport that could potentially inhibit, ameliorate, or prevent various neurodegenerative diseases.
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PMID:Insights into glutamate transport regulation in human astrocytes: cloning of the promoter for excitatory amino acid transporter 2 (EAAT2). 1257 75

Defective glutamate uptake has been implicated as a pathogenic event of neuronal damage related to cerebral ischemia and hypoxia. In several models of ischemia-hypoxia, a reduced immunoreactivity and altered RNA expression of excitatory amino acid transporter 2 (EAAT2), the major excitatory amino acid transporter, have been reported. However, the gene regulation of EAAT2 under these conditions is incompletely understood. In this study, we investigated alternative splicing of EAAT2 in an in vivo mouse model of chemical hypoxia as induced by 3-nitropropionic acid (3-NP). The neurotoxin 3-NP is an inhibitor of mitochondrial energy production. Furthermore, it is known to inhibit glutamate reuptake directly, representing at least one of the mechanisms responsible for 3-NP-induced neurodegeneration. Here we report an expression analysis of five known (mEAAT2/5UT1-5) and two novel (mEAAT2/5UT6, -7) 5' splice variants of EAAT2 using semiquantitative PCR. The RNA expression was studied at 2, 12, 24, 48, and 72 hr and 7 days after 3-NP administration. mEAAT2/5UT4 and mEAAT2/5UT5 were up-regulated in the frontal cortex and down-regulated in the hippocampus 12-72 hr after chemical hypoxia. In the cerebellum, there was an increased expression of mEAAT2/5UT4 and a down-regulation of mEAAT2/5UT5. mEAAT2/5UT3 show a different regional expression pattern, being regulated in the cerebellum only. mEAAT2/5UT1-7 encoded distinct 5' regulatory sequences, including conserved elements of translational control. It is easily conceivable that expression alterations of 5' splice variants of EAAT2 are related to glutamate transporter malfunction after chemical hypoxia. Our findings contribute to the hypothesis that RNA splicing events can serve as a molecular mechanism of posthypoxic gene regulation.
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PMID:Differential regulation of 5' splice variants of the glutamate transporter EAAT2 in an in vivo model of chemical hypoxia induced by 3-nitropropionic acid. 1260 8

We investigated changes of immunoreactivities of N-methyl-D-aspartate receptor (NR) and of excitatory amino acid carrier 1 (EAAC-1), the neuronal glutamate transporter, in the vulnerable CA1 area and the less vulnerable subiculum of the gerbil hippocampus at various times following transient forebrain ischemia. At 30 min after ischemia-reperfusion, the intensity of NR immunoreactivity increased markedly in neurons of CA1 and subiculum, particularly NR2A/B, while EAAC-1 immunoreactivity was reduced in CA1. At 3 hr after reperfusion, the density of NR1 immunoreactivity markedly decreased in CA1. In contrast EAAC-1 immunoreactivity increased in CA1 and in the subiculum. At 12 hr after reperfusion, the decrease of NR1 immunoreactivity was not detected whereas EAAC-1 immunoreactivities in the CA1 area were intensified. In the subiculum, both NR subunits immunoreactivities decreased significantly, in contrast to the maintenance of EAAC-1 immunoreactivity. At 24 hr after reperfusion, both NR2A/B and EAAC-1 immunoreactivities decreased markedly in CA1 and subiculum. We tentatively suggest that the increase of NR immunoreactivity in CA1 at early times after ischemia-reperfusion may increase the delayed neuronal death, and that the increase or maintenance of EAAC-1 immunoreactivity at early times after ischemia-reperfusion may be an important factor in survival of neurons.
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PMID:Chronological changes of N-methyl-D-aspartate receptors and excitatory amino acid carrier 1 immunoreactivities in CA1 area and subiculum after transient forebrain ischemia. 1262 76

We monitored survival of Purkinje cells in rat cerebellar slices to test the hypothesis that isoflurane preconditioning reduces ischemia-induced neuronal death. Preconditioning the brain slices with isoflurane, a volatile anesthetic commonly used in clinical practice, at 1-4% for 15 min at 37 degrees C significantly decreased Purkinje cell injury and death caused by a 20-min ischemia (simulated by oxygen-glucose deprivation, OGD). The effective concentration for half of the maximal effect (EC(50)) for this isoflurane preconditioning-induced neuroprotection was 1.17+/-0.31% and the maximal protective effects were achieved at 3% or higher concentrations of isoflurane. In addition, preconditioning the cells with isoflurane for 15-30 min was needed for the preconditioning to be maximally protective. Although farnesyl protein transferase inhibitor III blocked the protective effects of OGD preconditioning (a 3-min OGD 15 min before the 20-min OGD), this inhibitor did not affect the neuroprotection induced by isoflurane preconditioning. While DL-threo-beta-hydroxyaspartic acid (THA), a specific glutamate transporter inhibitor, did not change basal OGD-induced cell death rate, THA blocked the neuroprotection induced by isoflurane preconditioning but not by OGD preconditioning. Glybenclamide, a K(ATP) channel inhibitor, did not block the neuroprotection induced by either isoflurane or OGD preconditioning. Our results suggest that isoflurane preconditioning is neuroprotective. The isoflurane concentrations and times needed for the preconditioning to be neuroprotective are clinically relevant. The mechanisms of this protection seem to involve modulation of glutamate transporter activity.
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PMID:Isoflurane preconditioning reduces purkinje cell death in an in vitro model of rat cerebellar ischemia. 1267 41

Adenosine released during cerebral ischemia is considered to act as a neuroprotectant, possibly through the inhibition of glutamate release. The involvement of A(1) and A(2A) receptors in the control of the rise of extracellular glutamate during ischemia was investigated by monitoring the effects of selective A(1) and A(2A) receptor antagonists on ischemia-evoked glutamate release in rat cerebrocortical slices.Slices were superfused with oxygen- and glucose-deprived medium and [(3)H]D-aspartate or endogenous glutamate was measured in the superfusate fractions. Withdrawal of Ca(2+) ions or addition of tetrodotoxin more than halved the ischemia-evoked efflux of [(3)H]D-aspartate or glutamate, compatible with a vesicular-like release. The glutamate transporter inhibitor DL-TBOA prevented the ischemia-evoked efflux of [(3)H]D-aspartate by about 40%, indicating a carrier-mediated efflux. The ischemia-evoked efflux of [(3)H]D-aspartate or glutamate was increased by the A(1) receptor antagonist DPCPX. The A(2A) antagonist SCH 58261 decreased [(3)H]D-aspartate or endogenous glutamate efflux (50 and 55% maximal inhibitions; EC(50): 14.9 and 7.6 nM, respectively); the drug was effective also if added during ischemia. No effect of either the A(1) or the A(2A) receptor antagonist was found on the ischemia-evoked efflux of [(3)H]D-aspartate in Ca(2+)-free medium. Our data suggest that adenosine released during cerebral ischemia can activate inhibitory A(1) and stimulatory A(2A) receptors that down- or up-regulate the vesicular-like component of glutamate release.
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PMID:Sensitivity to selective adenosine A1 and A2A receptor antagonists of the release of glutamate induced by ischemia in rat cerebrocortical slices. 1284 26

Glutamate transporters remove glutamate from the extracellular space and maintain it below neurotoxic levels under normal conditions. However, the dynamics under ischemic conditions remain to be determined. In the present study, we evaluated the function of the glial glutamate transporter (GLT-1) during brain ischemia by using an in vivo brain microdialysis technique in GLT-1 mutant mice. A microdialysis probe was placed in the hippocampal CA1 of GLT-1 mutant and wild-type mice, and glutamate levels were measured during 5 and 20 min ischemia. The glutamate levels in mice lacking GLT-1 were significantly higher than the corresponding glutamate levels in wild-type mice during 5 min ischemia. Delayed neuronal death was induced in the CA1 of the mice lacking GLT-1 but not in the CA1 of the wild-type mice. When ischemia was elongated to the duration of 20 min, the glutamate levels in wild-type mice were significantly higher than the corresponding glutamate levels in mice lacking GLT-1 during the last 12.5 min of 20 min ischemia. Acute neuronal death was also observed in the CA1 of wild-type mice. These results suggest that GLT-1 takes up extracellular glutamate to protect neurons in the early stage of ischemia and then releases glutamate, triggering acute neuronal death, when ischemic conditions are elongated. The function of GLT-1 may change from neuroprotective to neurodegenerative during ischemia.
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PMID:Functional changes of glial glutamate transporter GLT-1 during ischemia: an in vivo study in the hippocampal CA1 of normal mice and mutant mice lacking GLT-1. 1290 78

The solute carrier family 1 (SLC1) includes five high-affinity glutamate transporters, EAAC1, GLT-1, GLAST, EAAT4 and EAAT5 (SLC1A1, SLC1A2, SLC1A3, SLC1A6, and SLC1A7, respectively) as well as the two neutral amino acid transporters, ASCT1 and ASCT2 (SLC1A4 and ALC1A5, respectively). Although each of these transporters have similar predicted structures, they exhibit distinct functional properties which are variations of a common transport mechanism. The high-affinity glutamate transporters mediate transport of l-Glu, l-Asp and d-Asp, accompanied by the cotransport of 3 Na(+) and 1 H(+), and the countertransport of 1 K(+), whereas ASC transporters mediate Na(+)-dependent exchange of small neutral amino acids such as Ala, Ser, Cys and Thr. The unique coupling of the glutamate transporters allows uphill transport of glutamate into cells against a concentration gradient. This feature plays a crucial role in protecting neurons against glutamate excitotoxicity in the central nervous system. During pathological conditions, such as brain ischemia (e.g. after a stroke), however, glutamate exit can occur due to "reversed glutamate transport", which is caused by a reversal of the electrochemical gradients of the coupling ions. Selective inhibition of the neuronal glutamate transporter EAAC1 (SLC1A1) may be of therapeutic interest to block glutamate release from neurons during ischemia. On the other hand, upregulation of the glial glutamate transporter GLT1 (SLC1A2) may help protect motor neurons in patients with amyotrophic lateral sclerosis (ALS), since loss of function of GLT1 has been associated with the pathogenesis of certain forms of ALS.
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PMID:The glutamate/neutral amino acid transporter family SLC1: molecular, physiological and pharmacological aspects. 1453 Sep 74

The solute carrier family 1 (SLC1) is composed of five high affinity glutamate transporters, which exhibit the properties of the previously described system XAG-, as well as two Na+-dependent neutral amino acid transporters with characteristics of the so-called "ASC" (alanine, serine and cysteine). The SLC1 family members are structurally similar, with almost identical hydropathy profiles and predicted membrane topologies. The transporters have eight transmembrane domains and a structure reminiscent of a pore loop between the seventh and eighth domains [Neuron 21 (1998) 623]. However, each of these transporters exhibits distinct functional properties. Glutamate transporters mediate transport of L-Glu, L-Asp and D-Asp, accompanied by the cotransport of 3 Na+ and one 1 H+, and the countertransport of 1 K+, whereas ASC transporters mediate Na+-dependent exchange of small neutral amino acids such as Ala, Ser, Cys and Thr. Given the high concentrating capacity provided by the unique ion coupling pattern of glutamate transporters, they play crucial roles in protecting neurons against glutamate excitotoxicity in the central nervous system (CNS). The regulation and manipulation of their function is a critical issue in the pathogenesis and treatment of CNS disorders involving glutamate excitotoxicity. Loss of function of the glial glutamate transporter GLT1 (SLC1A2) has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), resulting in damage of adjacent motor neurons. The importance of glial glutamate transporters in protecting neurons from extracellular glutamate was further demonstrated in studies of the slc1A2 glutamate transporter knockout mouse. The findings suggest that therapeutic upregulation of GLT1 may be beneficial in a variety of pathological conditions. Selective inhibition of the neuronal glutamate transporter EAAC1 (SLC1A1) but not the glial glutamate transporters may be of therapeutic interest, allowing blockage of glutamate exit from neurons due to "reversed glutamate transport" of EAAC1, which will occur during pathological conditions, such as during ischemia after a stroke.
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PMID:The glutamate and neutral amino acid transporter family: physiological and pharmacological implications. 1461 54


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