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)

We investigated the pharmacological properties and neuroprotective actions of a novel alpha-amino-3-hydroxy-5-methylisoxazole-y-propionate (AMPA)/kainate receptor antagonist, [6-(1H-imidazol-1-yl)-7-nitro-2,3-(1H,4H)-quinoxalinedione hydrochloride (YM90K); formerly YM900], in comparison with those of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX). YM90K selectively displaced [3H]-AMPA binding (Ki = 0.084 microM) and was less potent in inhibiting [3H]-kainate (Ki = 2.2 microM), [3H]-L-glutamate (N-methyl-D-aspartate-sensitive site; Ki > 100 microM) and [3H]-glycine (strychnine-insensitive site; Ki = 37 microM) binding to rat brain membranes. YM90K co-injected with AMPA or kainate into the rat striatum protected cholinergic neurons against AMPA- or kainate-induced neurotoxicity. YM90K showed potent suppressive activity against audiogenic seizure in DBA/2 mice; ED50 values of YM90K and NBQX against tonic seizure were 2.54 and 7.17 mg/kg (i.p.), respectively. The duration of the anticonvulsant effects of YM90K and NBQX was 30 min, indicating that both compounds possess short action. In a global ischemia model, YM90K (15 mg/kg i.p. x 3), NBQX (30 mg/kg i.p. x 3) and CNQX (60 mg/kg i.p. x 3) significantly prevented the delayed neuronal death in the hippocampal CA1 region in Mongolian gerbils when administered 1 h after 5-min ischemia. In addition, the therapeutic time window for the neuroprotective effect of YM90K (30 mg/kg i.p. x 3) was 6 h. In a focal ischemia model, YM90K (30 mg/kg i.v. bolus+10 mg/kg/h for 4 h) reduced the volume of ischemic damage in the cerebral cortex in F344 rats. Thus, YM90K was shown to be a potent and selective antagonist for AMPA/kainate receptors in vitro and in vivo. This compound may provide a therapeutic effect in various neurodegenerative disorders such as ischemic stroke in which glutamate neurotoxicity is thought to play a critical role in neuronal damage.
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PMID:YM90K: pharmacological characterization as a selective and potent alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptor antagonist. 855 60

The purpose of the present study was to compare the characteristics of the photochemical-induced thrombotic occlusion model and the thermocoagulated occlusion model of the middle cerebral artery in rats. We evaluated the neuroprotective effects of a NMDA receptor antagonist, (+)-MK-801 (dizocilpine, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptan-5,10-imine), an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist, YM90K (6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione monohydrochloride), a Ca2+ channel antagonist, S-312-d (S-(+)-methyl-4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)-thieno[2 ,3-b]pyridine-5-carboxylate), the radical scavengers, MCI-186 (3-methyl-1-phenyl-2-pyrazolin-5-one) and EPC-K1 (L-ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyl-tridecyl)-2H-1-be nzopyran-6yl-hydrogen phosphate] potassium salt), and a calcineurin inhibitor, FK506 (tacrolimus, Prograf). Although all tested agents in the present study attenuated the brain damage in the photochemical-induced thrombotic occlusion model, the radical scavengers did not attenuate the brain damage in the thermocoagulated occlusion model. The time course of brain damage and brain edema formation in the two models was examined. The time course of brain damage was not different in the two models, but the time course of brain edema was quite different. Brain edema formation in the photochemical-induced thrombotic occlusion model was significantly greater (P < 0.01) than that in the thermocoagulated occlusion model at all time point studied until 24 h after occlusion of the middle cerebral artery. The present study suggests that the photochemical-induced thrombotic occlusion model has characteristics of both permanent ischemia and ischemia-reperfusion.
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PMID:Neuroprotective effects depend on the model of focal ischemia following middle cerebral artery occlusion. 987 63

By analyzing histological damages and the regional N-acetylaspartate (NAA) level simultaneously, we evaluated the effect of an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate receptor antagonist, YM90K [6-(1H-imidazol-1-yl)-7-nitro-2,3-(1H,4H)-quinoxalinedione monohydrochloride], in unilateral forebrain ischemia in gerbils. The right common carotid artery was clipped for 5 min under ether anesthesia, and reperfused for 7 days. The frozen brain sections were lyophilized and the hippocampal CA1 area was dissected out for HPLC assay of NAA. An adjacent section was stained with hematoxylin-eosin for counting survived neurons per 1 mm pyramidal layer of the hippocampal CA1 area. Postischemic administration of YM90K at 20 mg/kg and 25 mg/kg attenuated the decrease of both the number of survived neurons and the NAA level on the ischemic side in a dose-dependent manner. A significant linear correlation was observed between the NAA level and the number of intact neurons. These results indicated that the NAA level could be used as an index of neuroprotective effects of pharmacological agents in global cerebral ischemia.
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PMID:A potent AMPA/kainate receptor antagonist, YM90K, attenuates the loss of N-acetylaspartate in the hippocampal CA1 area after transient unilateral forebrain ischemia in gerbils. 1158 13

The induction of nitric oxide (NO) synthase in astrocytes by endotoxin and/or cytokine treatment is associated with increased glucose consumption and glycolysis, but the mechanism whereby this phenomenon occurs remains obscure. In this work, we have addressed this issue and found that incubation of cultured rat astrocytes with lipopolysaccharide (LPS; 1 microg/mL) for 24 h increased the level of constitutively expressed GLUT1 glucose transporter mRNA, and triggered GLUT3 mRNA expression, which was absent in normal astrocytes. The occurrence of GLUT3 protein after LPS treatment was corroborated by western blotting and immunocytochemistry. A 4-h incubation of astrocytes in the absence of glucose, or under an oxygen-poor (3%) atmosphere also resulted in GLUT3 mRNA overexpression. Experiments performed with 2-deoxy-D-[U-14C]glucose (at 0.1 mM of D-glucose) confirmed that LPS (0.1-10 microg/mL) dose-dependently increased the rate of glucose uptake (by a factor of 1.6 at 1 microg/mL of LPS), which was paralleled with the increase in NO synthesis. Furthermore, blockade of NO synthase with 2-amino-5,6-dihydro-6-methyl-(4H)-1,3-thiazine (AMT; 50 microM) partially (by 45%) prevented the LPS-mediated increase in glucose uptake. Finally, incubation of astrocytes with the NO donor 1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA; 100 microM) increased by a factor of 1.4 the rate of glucose uptake. We conclude that the increase in GLUT3-driven glucose uptake in astrocytes would have a neuroprotective role under conditions in which NO formation is combined with hypoglycaemia, such as in brain ischemia.
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PMID:Expression of glucose transporter GLUT3 by endotoxin in cultured rat astrocytes: the role of nitric oxide. 1159 53

Recent studies suggest that nuclear factor NF-kappaB may be involved in excitotoxin-induced cell apopotosis. To analyze the variation of NF-kappaB, levels of NF-kappaB were measured after the rats were subjected to 30 min of four-vessel occlusion and sacrificed in selected reperfusion time points. Induction of NF-kappaB consisting mainly of p65 and p50 subunits was detected by Western blot with anti p65, p50 antibodies, respectively. DNA binding activity of NF-kappaB was performed by electrophoretic mobility-shift analysis. Our studies indicate that ischemia-induced NF-kappaB nuclear translocation is time-dependent. Inductions or binding activity of NF-kappaB in nucleus increased about 10-fold from 6 to 12 h as compared with that of the control group, then gradually declined in the following 24, 72 h. To further analyze the regulation by ionotropic glutamate receptor and L-type voltage-gated Ca(2+) channel (L-VGCC) in vivo, N-methyl-D-aspartate (NMDA) receptor antagonist ketamine, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate/kainate receptor antagonist 6,7-dinitroquinoxaline-2,3 (1H,4H)-dione and L-VGCC antagonist nifedipine were given 20 min prior to 30 min of ischemia. The NF-kappaB nuclear translocation was completely blocked by these three antagonists in a dose-dependent manner after ischemia/reperfusion 6 h. Increased phosphorylation of the NF-kappaB regulatory unit IkappaB-alpha was detected by Western blot. Decrement of IkappaB-alpha was found after 3 h reperfusion in the cytoplasm following global ischemia, which was also blocked by such three antagonists. These results illustrate that glutamate-gated ionotropic NMDA or non-NMDA receptors and voltage-gated Ca(2+) channels are important routes to mediate NF-kappaB activation during brain ischemic injury. Active NF-kappaB may attend the excitotoxin-induced cell death in turn. Our studies also suggest that IkappaB-alpha is an important regulatory unit that controls the activation of NF-kappaB after its phosphorylation and degradation and resynthesis in rat hippocampus following global ischemia.
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PMID:Nuclear factor kappaB activation is mediated by NMDA and non-NMDA receptor and L-type voltage-gated Ca(2+) channel following severe global ischemia in rat hippocampus. 1192 32

Global ischemia, induced in Mongolian gerbils by bilateral occlusion of the carotid arteries for 5 min, produced a significant increase in locomotor activity at 1 day post-occlusion and a severe loss of hippocampal CA1 neurons at 4 days post-occlusion. To explore the pharmacological relationship between ischemia-induced hypermotility and CA1 cell death in the hippocampus, we evaluated the efficacy of diverse classes of putative neuroprotective agents for preventing hypermotility and delayed neuronal death. Administration of any drug 30 min before global ischemia dose-dependently, and with similar potency, ameliorated both hippocampal delayed neuronal death and locomotor hyperactivity, with a rank order: tacrolimus (FK506)>nizofenone>clonindine>dizocilpine (MK-801)>6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione hydrochloride (YM90K)>phencyclidine>pentobarbital>2-(4-(p-fluorobenzoyl)-piperidin-1-yl)-2'-acetonaphthone hydrochloride (E-2001)>cis-(+/-)-4-phosphonomethyl-2-piperidine carboxylic acid (CGS19755)>3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide (U-50,488H)>piroxicam>eliprodil>vinpocetine. Furthermore, potencies of the protective effect on delayed neuronal death and inhibitory effects on hypermotility were closely correlated (r=0.98). These results suggest that post-ischemic CA1 injury and hypermotility share common mechanisms, and further imply that it is possible to predict the neuroprotective efficacy of drugs more easily by examining the inhibitory effects on post-ischemic hypermotility in global ischemia model in gerbils.
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PMID:Pharmacological evidence for a correlation between hippocampal CA1 cell damage and hyperlocomotion following global cerebral ischemia in gerbils. 1270 62

c-Jun N-terminal kinase-3 (JNK3), the only neural-specific isoform, may play an important role in excitotoxicity and neuronal injury. To analyze the variation of JNK3 activation, levels of phospho-JNK3 were measured at various time points of ischemia and selected time points of reperfusion, respectively. Our study illustrated that JNK3 was rapidly activated and translocated from cytosol to nucleus during ischemia. During reperfusion, two peaks of JNK3 activation occurred at 30 min and 3 days, respectively. To further define the mechanism of JNK3 activation, antioxidant N-acetylcysteine (NAC), alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate (KA) receptor antagonist 6,7-dinitro-quinoxaline-2,3(1H,4H)-dione (DNQX), N-methyl-D-aspartate (NMDA) receptor antagonist ketamine and L-type voltage-gated Ca(2+) channel (L-VGCC) antagonist nifedipine were given to the rats 20 min prior to ischemia. The results showed that NAC obviously inhibited JNK3 activation during the early reperfusion, whereas DNQX preferably attenuated JNK3 activation during the latter reperfusion. Ketamine and nifedipine had no significant effects on JNK3 activation during reperfusion. Consequently, reactive oxygen species (ROS) and AMPA/KA receptor were closely associated with JNK3 activation following global ischemia.
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PMID:Antioxidant NAC and AMPA/KA receptor antagonist DNQX inhibited JNK3 activation following global ischemia in rat hippocampus. 1276 82

We measured the MLK3 expression, activity and backphosphorylation following cerebral ischemia. Our data showed that MLK3 protein levels were unalterable during ischemia and reperfusion. However, during ischemia MLK3 activity gradually increased and reached its peak at 30 min of ischemia. While its backphosphorylation reduced from 5 min of ischemia to 30 min of ischemia. In addition, we also detected MLK3 alteration at various time points of reperfusion after 15 min of ischemia, which showed that MLK3 activity increased twice, whereas MLK3 backphosphorylation was similarly consistent with its activity during reperfusion. To further analyze the reason of MLK3 activation, antioxidant N-acetylcysteine (NAC) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionate (AMPA)/kainate (KA) receptor antagonist 6,7-dinitroquinoxaline-2,3(1H, 4H)-dione (DNQX) were given to the rats 20 min prior to ischemia. The results illustrated that NAC preferably inhibited the MLK3 activation during the ischemia and the early reperfusion, whereas DNQX effectively attenuated the MLK3 activation of the late reperfusion. We think that MLK3 activation is certainly associated with reactive oxygen species (ROS) and AMPA/KA receptor in response to ischemic insult.
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PMID:Antioxidant N-acetylcysteine and AMPA/KA receptor antagonist DNQX inhibited mixed lineage kinase-3 activation following cerebral ischemia in rat hippocampus. 1294 46

The phosphorylation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors subunit GluR1 at Ser831 has been implicated in the regulation of AMPA receptors channel. In this paper, Ser831 phosphorylation of GluR1 in rat hippocampus was investigated, which significantly increased during early global ischemia. To further illustrate the underlying mechanisms, calcium/calmodulin-dependent kinase IIalpha (CaMKIIalpha) inhibitor 1-[N,O-bis-(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (KN62), CaM antagonist trifluoperazine (TFP), N-methyl-D-aspartate (NMDA) receptor antagonist dextromethorphan (DEX), AMPA receptor antagonist 6,7-dinitro-quinoxaline-2,3-(1H,4H)-dione (DNQX) and L-type voltage-gated Ca2+ channel (L-VGCC) blocker nifedipine (NIF), were respectively administrated to the rats 20 min prior to ischemia. The results showed that KN62, TFP and DEX significantly attenuated Ser831 phosphorylation of GluR1, while DNQX and NIF had no obvious effects. Consequently, the studies suggest that early global ischemia induced Ser831 phosphorylation of GluR1 may be closely associated with CaMKIIalpha and the NMDA receptor, while the immediate Ser831 phosphorylation of GluR1 may have been involved in pathogenic events after early global ischemia.
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PMID:NMDA receptor-mediated immediate Ser831 phosphorylation of GluR1 through CaMKIIalpha in rat hippocampus during early global ischemia. 1468 84

Activation (phosphorylation) and the possible mechanism of extracellular signal-regulated kinase 5 (ERK5) were evaluated after cerebral ischemia-reperfusion (I/R) in the hippocampus in a four-vessel occlusion model of Sprague-Dawley rats. Western blotting showed that ERK5 was strongly activated from 10 min to 1 day and peaked at 30 min of reperfusion after 15 min ischemia. Pretreatment with N-acetylcysteine, a free radical scavenger, effectively inhibited ERK5 activation in a dose-dependent manner. Consistently, ERK5 activation was significantly suppressed by genistein (protein-tyrosine kinase inhibitor), PP2 (specific inhibitor of Src family kinases), nifedipine (L-VGCC blocker) and dextromethorphan (NMDA receptor antagonist), but not 6,7-dinitroquinoxaline-2, 3(1H, 4H)-dione (AMPA receptor antagonist). These results suggested that ERK5 could be significantly activated by I/R, which might be mediated by NMDA receptor and L-VGCC through Src kinase pathway involving oxidative stress in rat hippocampus.
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PMID:Activation of ERK5 is mediated by N-methyl-D-aspartate receptor and L-type voltage-gated calcium channel via Src involving oxidative stress after cerebral ischemia in rat hippocampus. 1503 2


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