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)

Two glutamate antagonists were tested in a rat model of complete, transient cerebral ischemia. Six days after 10 min ischemia the mean loss of hippocampal CA1 pyramidal neurones was 73%. Administration of the AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) antagonist NBQX (2,3-dihydro-6-nitro-7-sulfamoyl-benzo(F)quinoxaline) reduced the pyramidal neurone loss to 1%, 11% and 15%, when given before, immediately after or 1 h after ischemia, respectively. MK-801 (dizocilpine), a competitive NMDA antagonist gave no protection in this model. We suggest that the AMPA receptor transduction mechanisms are sensitized by ischemia and that the postischemic blockade of the main glutamatergic input to the CA1 cells with NBQX impairs the deleterious effect of "normal" postischemic excitatory transmission.
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PMID:Protection against ischemic hippocampal CA1 damage in the rat with a new non-NMDA antagonist, NBQX. 132 29

Glutamatergic transmission is an important factor in the development of neuronal death following transient cerebral ischemia. In this investigation the effects of N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists on neuronal damage were studied in rats exposed to 10 min of transient cerebral ischemia induced by bilateral common carotid occlusion combined with hypotension. The animals were treated with a blocker of the ionotropic quisqualate or alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptor, 2.3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX), given postischemia as an intraperitoneal bolus dose of 30 mg kg-1 followed by an intravenous infusion of 75 micrograms min-1 for 6 h, or with the noncompetitive NMDA receptor blocker dizocilpine (MK-801) given 1 mg kg-1 i.p. at recirculation and 3 h postischemia, or with the competitive NMDA receptor antagonist DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 40116), 5 mg kg-1, given intraperitoneally at recirculation. Treatment with NBQX provided a significant reduction of neuronal damage in the hippocampal CA1 area by 44-69%, with the largest relative decrease in the temporal part of the hippocampus. In neocortex a significant decrease in the number of necrotic neurons was also noted. No protection could be seen following postischemic treatment with dizocilpine or CGP 40116. Our data demonstrate that AMPA but not NMDA receptor antagonists decrease neuronal damage following transient severe cerebral ischemia in the rat and that the protection by NBQX may be dependent on the severity of the ischemic insult. We propose that the AMPA receptor-mediated neurotoxicity could be due to ischemia-induced changes in the control mechanisms of AMPA receptor-coupled processes or to changes of AMPA receptor characteristics.
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PMID:Postischemic blockade of AMPA but not NMDA receptors mitigates neuronal damage in the rat brain following transient severe cerebral ischemia. 134 57

Increased extracellular concentrations of glutamate during episodes of cerebral ischemia may be due in part to a positive glutaminergic feedback loop. We evaluated the effect of selective AMPA or NMDA receptor antagonists on hippocampal extracellular concentrations of excitatory amino acids during ischemia and reperfusion. Thirteen New Zealand white rabbits were subjected to 10 min of global cerebral ischemia produced by neck tourniquet inflation (20 psi) combined with systemic hypotension during halothane (1-1.5%) anesthesia. Hippocampal extracellular concentrations of glutamate, aspartate, and glycine were monitored using in vivo microdialysis. NBQX (a selective AMPA receptor antagonist), MK801 (a noncompetitive NMDA receptor antagonist), or 5% dextrose was administered starting 1 h before ischemia. The NBQX group (n = 4) received 5 mg.kg-1 of NBQX intravenously (dissolved in 5% dextrose) over 5 min followed by an infusion of 5 mg.kg-1.h-1. The 5% dextrose group (n = 4) received an equivalent volume of 5% dextrose. The peak concentrations of glutamate, aspartate, and glycine in the early reperfusion period were 5-8-fold, 9-10-fold, and 4-5-fold higher than preischemic values, respectively. There were no significant differences, however, among the three groups in the concentrations of glutamate, aspartate, or glycine at any time during the study. These results do not support the existence of a positive feedback loop for glutamate mediated via AMPA or NMDA autoreceptors in the hippocampus during transient global ischemia or reperfusion.
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PMID:AMPA and NMDA receptor antagonists do not decrease hippocampal glutamate concentrations during transient global ischemia. 135 5

Normothermic rats with 12 min, complete cerebral ischemia were treated with the AMPA antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo (F) quinoxalinedione (NBQX) [10], which prevents CA1 pyramidal neuron loss. Twenty hours after ischemia, cerebral protein synthesis rate (CPSR) was measured autoradiographically using [35S]methionine. Ischemia caused a 38% decrease of CPSR in CA1, and postischemic treatment with NBQX caused a 66% decrease in this region. Also treatment with NBQX alone resulted in a decrease (22% in CA1) of the CPSR. Since some evidence exists that the neuroprotective effect of NBQX is related to blockade of the fast AMPA-mediated transmission, the further decrease of the postischemic CPSR in CA1 could be a mere side effect.
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PMID:Regional cerebral protein synthesis after transient ischemia in the rat: effect of the AMPA antagonist NBQX. 138 88

We examined the effect of an AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole) antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo (F) quinoxaline (NBQX), on rat cerebellar Purkinje cell loss and hippocampal pyramidal CA1 cell loss, after 10 minutes of global cerebral ischemia. NBQX was given intraperitoneally in a dose of 30 mg kg-1 at the end of ischemia, and 10 and 25 minutes later. Rats subjected to ischemia without post-ischemic administration of NBQX served as controls. Four days after ischemia the cerebellar Purkinje cell density was higher and the density of acidophilic (dead) Purkinje cells lower in the NBQX treated animals compared with the control animals (p = 0.01 and p less than 0.005 respectively). There was partial to total loss of pyramidal neurons in the CA1 region of the dorsal hippocampus in control animals, but no CA1 pyramidal neuron loss in the NBQX treated animals (p = 0.001).
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PMID:The AMPA antagonist, NBQX, protects against ischemia-induced loss of cerebellar Purkinje cells. 138 70

Central neuroexcitatory receptors (N-methyl-D-aspartate [NMDA], non-NMDA) may affect outcome from cerebral ischemia by altering sympathetic nervous system activity. We tested whether ketamine, an NMDA antagonist, and NBQX, a non-NMDA antagonist, improve outcome from incomplete cerebral ischemia in the rat and whether a change in outcome is related to changes in plasma catecholamines. There were five treatment groups: group 1 (control, n = 10) received a fentanyl infusion at a rate of 25 microgram.kg-1.h-1 and ventilation with 70% N2O in O2. Group 2 (n = 10) received the same anesthetic treatment and were given an intraperitoneal injection of 30 mg/kg NBQX 15 min prior to ischemia. Group 3 (n = 10) received a ketamine infusion of 1.0 mg.kg-1.min-1 and ventilation with room air. Group 4 (n = 10) received a ketamine infusion of 1.5 mg.kg-1.min-1. Group 5 received a ketamine infusion of 1 mg.kg-1.min-1 plus a 6 ml/kg intraperitoneal injection of 40% glucose solution 15 min before the start of ischemia. Ischemia was produced by right common carotid ligation combined with hemorrhagic hypotension to 35 mmHg for 30 min. Blood gases, pH, and skull temperature were controlled during ischemia. Plasma glucose increased during ischemia in all groups but was lower in ketamine-anesthetized rats (groups 3 and 4). Glucose-loaded ketamine-anesthetized rats (group 5) had plasma glucose concentrations similar to the control group. Plasma epinephrine and norepinephrine concentrations were significantly less in ketamine-anesthetized rats (groups 3, 4, and 5) during ischemia compared to controls (P less than 0.05). Neurologic outcome was significantly better (P less than 0.05) in all ketamine-treated rats (groups 3, 4, and 5) compared to the control group, regardless of plasma glucose concentration during ischemia. NBQX did not improve neurologic outcome. These results suggest that ketamine improves neurologic outcome from incomplete cerebral ischemia by a mechanism related to a decrease in plasma catecholamine activity.
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PMID:Ketamine decreases plasma catecholamines and improves outcome from incomplete cerebral ischemia in rats. 157 44

The potent and selective AMPA receptor antagonist NBQX was tested for cytoprotective properties in an adult rat model of transient focal neocortical ischemia. Nineteen spontaneously hypertensive rats sustained 2 h of middle cerebral artery occlusion, followed by 22 h of recirculation. Ninety minutes following the onset of ischemia, at the time of, and 30 min following reperfusion, they received i.p. injections of either saline (n = 10) or 30 mg kg-1 of NBQX (n = 9). Saline-treated rats had a mean volume of neocortical infarction ( +/- s.d.) of 181 +/- 31 mm3, while NBQX-treated rats sustained significantly less damage, 125 +/- 19 mm3 (p less than 0.001). Regional cerebral blood flows during ischemia and reperfusion were not affected by the drug. We suggest that the AMPA receptor may play an important role in ischemic cerebral infarction.
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PMID:Delayed AMPA receptor blockade reduces cerebral infarction induced by focal ischemia. 165 10

The cytoprotective effect of NBQX, a selective AMPA receptor antagonist, was tested following 10 min of severe forebrain ischemia using the 4-vessel occlusion model. Immediately, and at 15 and 30 min following reperfusion, adult Wistar rats received intraperitoneal injections of either saline (n = 5), 1 mg lithium chloride (n = 17) or 30 mg/kg of the lithium salt of NBQX (n = 18). In saline-treated animals 82 +/- 12% of CA1 hippocampal neurons were lost. Of those treated with lithium 70 +/- 23% were injured, while those given NBQX sustained only 40 +/- 34% CA1 necrosis (P less than 0.01). Twelve of 18 NBQX-treated animals had less than 30% CA1 injury as compared with 1 of 17 lithium-treated animals. The AMPA receptor may play a more important role than the NMDA receptor in selective ischemic necrosis of hippocampal neurons.
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PMID:Blockade of the AMPA receptor prevents CA1 hippocampal injury following severe but transient forebrain ischemia in adult rats. 166 5

The neuroprotective effects of NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline) were assessed on hippocampal CA1 neuronal loss and locomotor hyperactivity following transient bilateral carotid artery occlusion (BCAO) in the gerbil. NBQX, a selective blocker of the AMPA glutamate receptor subtype, was injected 1 h after 5 or 10 min BCAO, or sham surgery. Both 5 and 10 min ischemia produced equivalent hyperactivity 3 days post ischemia and CA1 neuronal loss on Day 4, while activity was unchanged in the sham-operated group. NBQX protected from both hippocampal damage and post-ischemic hyperactivity. These results demonstrate that NBQX can protect from behavioral pathology induced by global cerebral ischemia.
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PMID:Protection against post-ischemic behavioral pathology by the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX) in the gerbil. 166 18

Recent data suggest that brain damage in ischemia, hypoglycemia, and several other brain diseases is caused by excitotoxic mechanisms which are triggered by presynaptic release of glutamate and related excitatory amino acids, and which involve an abnormal postsynaptic influx of calcium into cells containing a high density of glutamate receptors. This contention is supported by results demonstrating reduction of infarct size in focal ischemia due to middle cerebral artery (MCA) occlusion, and amelioration of neuronal necrosis in hypoglycemic coma, by antagonist which block the NMDA type of glutamate receptor. These results underscore the pathogenetic role of calcium influx into energy-compromised cells since the NMDA receptor-linked ion channel has a high conductance to calcium. The issue has been clouded by the inability of NMDA antagonists to ameliorate brain damage due to cardiac arrest, or to forebrain ischemia in rats and gerbils. In these conditions, however, an AMPA receptor blocker (NBQX) has been found efficacious. These results demonstrate that the pathophysiology of ischemic lesions is different in the cardiac arrest type of ischemia and in lesions due to MCA occlusion, and demand an explanation of the differences in therapeutic response. Tentatively, the cardiac arrest type of ischemia is so dense that multiple calcium conductances are activated in the energy-deprived tissue, explaining why any drug which acts on only one of them (such as an NMDA antagonist) cannot prevent cellular calcium overload. Furthermore the ultimate brain damage, which is often conspicuously delayed, may be secondary to upregulation of synaptic efficacy, causing increased calcium cycling and calcium-related damage. In this situation, an AMPA receptor blocker may be efficacious because it blocks "fast" excitation and Na+ influx, an "upstream" event which causes "downstream" calcium influx via multiple pathways. In the perifocal ("penumbra") zone of a stroke lesion, the situation is different since depolarisation is initially moderate and/or intermittent. Furthermore, since ATP is still produced (albeit at a reduced rate) the problem is one of a disturbed pump/leak relationship. Then, blockade of a major calcium-carrying channel by NMDA receptor blockers, or of the trigger to depolarisation by an AMPA receptor antagonist, may improve the pump/leak relationship and carry cells in the penumbra over a critical period.
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PMID:Neurocytotoxicity: pharmacological implications. 168 4


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