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 drugs that act against excitotoxic damage, caused by glutamate, are well described in focal ischemia, but behavioral effects, and apparent failure in clinical trials of "first-generation" competitive N-methyl D-aspartate (NMDA) antagonists, such as Selfotel (CGS19755), has led to interest in evaluating newer NMDA antagonists with fewer behavioral effects. We have therefore evaluated the neuroprotective effect of a new forebrain-selective polyamine site NMDA antagonist, CP101,606 in a rat subdural hematoma (SDH) model. An SDH was produced by slow injection of 0.4 ml autologous blood into the parietal subdural space. Brain damage was assessed histologically at eight coronal planes, in animals sacrificed 4 h after induction of hematoma. The drug was infused 30 min after induction of SDH. The reductions of ischemic brain damage achieved by CP101,606, was 29% for the low dose and 37% for the high dose. This novel glutamate antagonist has shown a magnitude of neuroprotection which is comparable with that seen with "first-generation" NMDA antagonists such as MK801, D-CPP-ene and CGS19755, in this same model. This new agent is claimed to have fewer psychomotor and behavioral effects than MK801, D-CPP-ene, and CGS19755.
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PMID:The neuroprotective effect of the forebrain-selective NMDA antagonist CP101,606 upon focal ischemic brain damage caused by acute subdural hematoma in the rat. 921 55

Anesthetized rats exposed to a high ambient temperature develop heatstroke with brain ischemia. Since nitric oxide (NO) plays an important role during normothermic ischemia, its cortical and cerebellar production were continuously assessed in pentobarbital anesthetized rats exposed to heat by using differential pulsed voltammetry. After 60 min at thermoneutrality, the rats were submitted to an ambient temperature of 40 degrees C until death. After 60 min in the heat, the rats were injected intraperitoneally with saline, MK801 (1 mg.kg(-1)), an antagonist of N-methyl-D-aspartate (NMDA) receptors, or L-arginine p-nitroanilide (L-ANA; 100 mg.kg(-1)), an inhibitor of NO synthase. Just before death, a 70% increase in NO production was observed in both the cerebellum and the cortex of saline-treated rats. The cortical increase in NO was not modified by MK801 while the NO signal was suppressed by L-ANA.
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PMID:Voltametric assessment of brain nitric oxide during heatstroke in rats. 929 Nov 42

In the present study we investigated the effects of NMDA and non-NMDA glutamate receptor antagonists on the ischemia-evoked release of [3H]noradrenaline from rat spinal cord slices. An in vitro ischemia model (oxygen and glucose deprivation) was used to simulate the ischemic conditions known to cause neuronal injury. Spinal cord slices were loaded with [3H]noradrenaline and superfused with Krebs solution in a micro-organ bath. Both axonal stimulation and ischemia increased the release of [3H]noradrenaline, but the release in response to glucose and oxygen deprivation was [Ca2+]o independent. Dizocilpine (MK-801), an NMDA receptor antagonist, suppressed the release of [3H]noradrenaline produced by ischemia, while it enhanced the release of [3H]noradrenaline evoked by electrical field stimulation. In contrast, LY300168 (GYKI-53655) [(+/-)-3-N-methylcarbamyde-1-(4-aminophenyl)-4-methyl-1.8-methylen e-dioxy-5H-2.3-benzodiazepine] and its (-)isomer LY303070 (GYKI-53784) [(-)-3-N-methylcarbamyde-1-(4-aminophenyl)-4-methyl-1.8-methylene- dioxy-5H-2.3-benzodiazepine] AMPA receptor antagonists, had no effect on the release of [3H]noradrenaline evoked by either electrical stimulation or ischemia. Desipramine, a noradrenaline uptake inhibitor, potentiated the release of [3H]noradrenaline evoked by ischemia, while in the absence of [Ca2+]o but under conditions when [3H]noradrenaline release was further increased, it reduced the release. Dizocilpine also decreased glutamate and aspartate release, measured by high performance liquid chromatography, during ischemia. It is concluded that glutamate release and NMDA receptors, but not AMPA receptors, are involved in the acute effect of oxygen and glucose deprivation on the excessive release of noradrenaline and that this release is not related to physiological axonal conduction.
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PMID:Excessive release of [3H]noradrenaline and glutamate in response to simulation of ischemic conditions in rat spinal cord slice preparation: effect of NMDA and AMPA receptor antagonists. 1008 94

The neuroprotective activity of the novel glycine receptor antagonist (E)-3[(phenylcarbamoil)ethenil]-4,6-dichloroindole-2-c arboxylic acid sodium salt) (GV150526) was recently reported in a model of focal ischemia in the rat. Here it was investigated whether GV150526 treatment results in any of the adverse side effects commonly detected after injection of NMDA (N-methyl-D-aspartate) receptor antagonists. First, it was found that neuronal vacuolization in the posterior cingulate/retrosplenial area of the cortex was not induced by GV150526 (200 mg/kg, i.v.), but was evident after injection of the NMDA receptor antagonist dizocilpine (MK801) (1 mg/kg, s.c.). In a second set of experiments, the effects of GV150526 were examined on perforant path-dentate gyrus long-term potentiation in rats. GV150526 (3 mg/kg, i.v.) injected 30 min or 150 min prior to tetanization did not block potentiation of the e.p.s.p. slope and population spike amplitude. In contrast, in animals treated with MK801 (1 mg/kg, i.p.) 150 min before tetanization there was a clear block of long-term potentiation of the e.p.s.p. slope and population spike amplitude. The effects of GV150526 were also examined in the Morris Water Maze. Rats injected with GV150526 (10 mg/kg or 60 mg/kg, p.o.) did not show any impairment in learning when compared to control. MK801 (0.08 mg/kg, i.p.), on the other hand, significantly affected the ability to locate the escape platform in the Water Maze. These findings show that GV150526 is devoid of adverse side effects even at doses well above those producing a neuroprotective effect. This, drug has therapeutic potential with a much greater margin of safety than NMDA channel blockers or competitive NMDA receptor antagonists.
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PMID:The neuroprotective glycine receptor antagonist GV150526 does not produce neuronal vacuolization or cognitive deficits in rats. 1047 27

Use-dependent N-methyl-D-aspartate (NMDA) receptor antagonists protect neurons from the lethal consequences of excessive stimulation by excitatory amino acids. Clinical development of high-affinity compounds such as MK801 have been limited due to untoward side effects. Toward this end, the lower-affinity use-dependent NMDA antagonists have greater margins of safety and have advanced to clinical trials for stroke, epilepsy, head trauma and chronic neurodegenerative disorders. AR-R 15896AR is currently in Phase II trials for stroke and has been repeatedly demonstrated to afford neuroprotection in a variety of in vivo and in vitro models associated with ischemia/excitotoxic conditions.
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PMID:The low-affinity, use-dependent NMDA receptor antagonist AR-R 15896AR. An update of progress in stroke. 1066 46

Dopamine released from the lateral olivocochlear efferent system is thought to inhibit the toxic effect of the extreme glutamate outflow from the inner hair cells during ischemia or acoustic trauma. Using in vitro microvolume superfusion, we have studied the release of [(3)H]dopamine from the lateral olivocochlear efferent bundle of guinea pig in response to accumulation of [Na(+)](i), under condition characteristics of ischemia. Veratridine, that acts only on excitable membranes as a specific activator of voltage-sensitive sodium channels, significantly increased the electrically evoked release of [(3)H]dopamine, which was completely inhibited by tetrodotoxin. Dizocilpine (MK-801), a non-competitive NMDA-receptor antagonist, and GYKI-52466, a selective non-NMDA-receptor antagonist, had no effect on veratridine-induced [(3)H]dopamine release. Our data provide further evidence that the cochlear release of dopamine is of neural origin and possibly independent on a local effect of glutamate. The veratridine-induced transmitter release in the cochlea will be a very useful method in studying the effect of drugs on ischemic injury.
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PMID:Veratridine-evoked release of dopamine from guinea pig isolated cochlea. 1083 68

We, and others, have previously demonstrated that N-methyl-D-aspartate (NMDA) receptor is involved in hypoxia or ischemia-mediated responses. We found that the NMDA antagonist ketamine attenuates cortical nitric oxide release during cerebroischemia. It has been reported that ethanol (EtOH) antagonizes NMDA-induced responses in various systems. In the present study, the interaction of EtOH and KCl-evoked striatal dopamine release in vivo during acute hypoxia was examined. High-speed chronoamperometric recording techniques, using Nafion-coated carbon fiber electrodes, were used to evaluate extracellular dopamine (DA) concentration in the striatum of urethane-anesthetized Sprague-Dawley rats. KCl was directly applied to the striatum to evoke release of DA. These anesthetized animals were paralyzed with d-tubocurarine and connected to a respirator to allow controlled respiration. Systemic concentrations of oxygen were altered by changing the rate of the respirator. We previously reported that lowering the respiratory rates from 90 to 20 times/min for 5 min decreased arterial PO(2) and facilitated KCl-induced DA release in the striatum. In this study, we found that application of NMDA antagonist MK801 attenuates hypoxic DA release, suggesting that NMDA receptor is involved in this hypoxic reaction. In contrast, EtOH dose dependently enhanced KCl-evoked DA release during hypoxia. To further examine the interactions of excitatory amino acid and EtOH on DA release, glutamate was locally applied to the striatum. Glutamate-induced DA release was not affected by the systemic application of EtOH. Taken together, these data suggest that EtOH enhances DA release in vivo during short-term hypoxia, possibly through mechanisms other than excitatory amino acid pathways.
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PMID:Ethanol potentiates dopamine release during acute hypoxia in rat striatum. 1097 3

The effect of N-methyl-D-aspartate (NMDA) and 2-(aminomethyl)phenylacetic acid/kainate (AMPA/kainate) glutamate receptors on dentate cell proliferation and hippocampal synapsin-I induction was examined after global ischemia. Cell proliferation was assessed using BrdU labeling, and synaptic responses were assessed using synapsin-I expression. Systemic glutamate receptor antagonists (MK-801 and NBQX) increased BrdU-labeled cells in the dentate subgranular zone (SGZ) of control adult gerbils (30% to 90%, P < 0.05). After global ischemia (at 15 days after 10 minutes of ischemia), most CA1 pyramidal neurons died, whereas the numbers of BrdU-labeled cells in the SGZ increased dramatically (>1000%, P < 0.0001). Systemic injections of MK801 or NBQX, as well as intrahippocampal injections of either drug, when given at the time of ischemia completely blocked the birth of cells in the SGZ and the death of CA1 pyramidal neurons at 15 days after ischemia. Glutamate receptor antagonists had little effect on cell birth and death when administered 7 days after ischemia. The induction of synapsin-I protein in stratum moleculare of CA3 at 7 and 15 days after global ischemia was blocked by pretreatment with systemic or intrahippocampal MK-801 or NBQX. It is proposed that decreased dentate glutamate receptor activation--produced by glutamate receptor antagonists in normal animals and by chronic ischemic hippocampal injury--may trigger dentate neurogenesis and synaptogenesis. The synapsin-I induction in mossy fiber terminals most likely represents re-modeling of dentate granule cell neuron presynaptic elements in CA3 in response to the ischemia. The dentate neurogenesis and synaptogenesis that occur after ischemia may contribute to memory recovery after hippocampal injury caused by global ischemia.
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PMID:NMDA and AMPA/kainate glutamate receptors modulate dentate neurogenesis and CA3 synapsin-I in normal and ischemic hippocampus. 1112 83

Using sodium (NaN3)-induced anoxia plus aglycaemia as a model of chemically-induced ischemia, we have characterized the endogenous release of excitatory and inhibitory amino acids from superfused hippocampal slices. Chemical ischemia produced an azide (1-30 mM) dose-dependent increase in the efflux of glutamate, aspartate and GABA. These increases were attenuated to varying degrees by removal of Ca2+, or the addition of the voltage dependent Na+-channel blocker tetrodotoxin (TTX), the selective Ca2+ channel blockers conotoxin MVIIA, MVIIC, and nifedipine, the NMDA antagonist MK801, the AMPA antagonist GYKI-52466. Similarly, addition of the GLT-1 glutamate transport inhibitor dihydrokainate (DHK) and the anti-estrogen/anion channel blocker tamoxifen also attenuated the efflux of glutamate and GABA. It would therefore appear that the increases in amino acid efflux induced by chemical ischemia originates from both the neuronal pool, via conventional exocytotic release, and glial sources via reversal of the GLT-1 transporter and anion channel regulated cell swelling.
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PMID:Characterization of endogenous amino acid efflux from hippocampal slices during chemically-induced ischemia. 1147 40

Although accumulating evidence indicates that cAMP response element-binding protein (CREB) phosphorylation mediates not only synaptic plasticity but also survival of certain neurons, it remains uncertain whether CREB phosphorylation induced after metabolic insult leads to CRE-mediated gene transcription and is involved in cell survival or not. In the present study, we clarified that (1) CREB phosphorylation and ischemic tolerance induced after preconditioning ischemia in the hippocampal neurons was abolished by MK801 administration in gerbil global ischemia model, (2) CREB phosphorylation induced after exposure to glutamate in cultured neurons was inhibited by removal of extracellular calcium, by MK801 and by an inhibitor of calcium-calmodulin-dependent protein kinase (CaMK) II and IV, (3) inhibitor of CaMK II-IV or CRE-decoy oligonucleotide suppressed upregulation of BCL-2 expression and accelerated neuronal damage after exposure to glutamate, and (4) CREB phosphorylation induced in the hippocampal neurons after ischemia and in cultured neurons after exposure to glutamate was followed by CRE-mediated gene transcription in transgenic mice with a CRE-LacZ reporter. Our results suggest that CREB phosphorylation in neurons after ischemia and exposure to glutamate is induced by NMDA receptor-gated calcium influx and subsequent activation of CaMK II-IV and that CREB phosphorylation after metabolic stress might show a neuroprotective response through CRE-mediated gene induction.
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PMID:Phosphorylation of cAMP response element-binding protein in hippocampal neurons as a protective response after exposure to glutamate in vitro and ischemia in vivo. 1171 54


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