Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Drugs that dissolve clots, such as streptokinase and rTPA, and drugs that promote vasodilation are undergoing clinical testing for the treatment of hyperacute stroke, but an adjuvant therapy that either prolongs temporal thresholds before irreversible injury occurs or actually protects the brain from ischemia would transform these trials. Mild hypothermia, either intraischemically or at the onset of reperfusion, provides us with a gold standard for cytoprotection against which new pharmacologic strategies can be measured. The cytoprotective effects of the voltage-sensitive calcium channel blockers and the NMDA antagonists have been relatively less compelling than more recent findings with non-NMDA or AMPA antagonists. Their ability to inhibit SINN or reduce neocortical infarction is remarkable. Future randomized clinical trials for both resuscitated cardiac arrest victims and patients sustaining embolic stroke are predicted by this major advance in the field of stroke medicine.
 ...
PMID:Advances in cerebral ischemia: experimental approaches. 131 34

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.
 ...
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.
 ...
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.
 ...
PMID:AMPA and NMDA receptor antagonists do not decrease hippocampal glutamate concentrations during transient global ischemia. 135 5

By using primary cultures of cerebral cortical neurons, it has been demonstrated that the antihyperthermia drug dantrolene protects against cytotoxicity induced by the excitatory amino acids quisqualate (QA) and N-methyl-D-aspartate (NMDA), whereas no effect was observed on cell damage mediated by kainate (KA) or 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionate (AMPA). In parallel it was shown that KA and AMPA increased the concentration of intracellular free calcium ([Ca2+]i) mainly by influx, whereas the increase in [Ca2+]i stimulated by NMDA and QA predominantly was caused by release of Ca2+ from intracellular stores, which for NMDA seemed to be mediated at least partly by Ca2+ influx. In accordance with the effects on cytotoxicity, dantrolene blocked the increase in [Ca2+]i elicited by QA and NMDA leaving the increase induced by KA and AMPA unaffected. The finding that 2-amino-3-[3-(carboxymethoxy)-5-methylisoxazol-4-yl]propionate, which regarding toxicity is a selective KA antagonist, only reduced the KA-stimulated increase in [Ca2+]i by 30% may suggest that the elevation of [Ca2+]i is not the only element in KA-induced cytotoxicity. On the other hand, the present study underlines the importance of Ca2+ for cytotoxicity induced by some excitatory amino acids (glutamate, NMDA, and QA) and supports the current proposal that multiple mechanisms are operating, even concerning calcium homeostasis. Because excitatory amino acid-induced cytotoxicity is thought to be involved in neuropathological conditions such as ischemia, it is possible that dantrolene might be of therapeutic interest.
 ...
PMID:Mobilization of dantrolene-sensitive intracellular calcium pools is involved in the cytotoxicity induced by quisqualate and N-methyl-D-aspartate but not by 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionate and kainate in cultured cerebral cortical neurons. 137 82

The delayed neuronal death (DND) resulting from brief forebrain ischemia has recently been reported to be markedly attenuated by parenteral administration of the reversible protein synthesis inhibitor, anisomycin. Previous work suggests that ischemia-induced DND is mediated by glutamate acting at one or more glutamate receptors, since glutamate receptor antagonists have been reported to reduce ischemia-induced DND. Consequently, we tested whether anisomycin could modify DND induced by direct intracerebral administration of the excitotoxins, N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxasole (AMPA) or kainic acid. Anisomycin, administered parenterally, in multiple doses did not alter DND induced by any of these excitotoxins, nor did combined parenteral and direct intracerebral injection of anisomycin protect against DND induced by AMPA. Thus, neurotoxicity induced by direct intracerebral administration of NMDA, AMPA or kainic acid does not appear to require de novo protein synthesis, and, therefore, is not likely to be mediated by the expression of a programmed cell death cascade.
 ...
PMID:Failure of a protein synthesis inhibitor to modify glutamate receptor-mediated neurotoxicity in vivo. 137 68

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.
 ...
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).
 ...
PMID:The AMPA antagonist, NBQX, protects against ischemia-induced loss of cerebellar Purkinje cells. 138 70

Severe, transient global ischemia of the brain induces delayed damage to specific neuronal populations. Sustained Ca2+ influx through glutamate receptor channels is thought to play a critical role in postischemic cell death. Although most kainate-type glutamate receptors are Ca(2+)-impermeable, Ca(2+)-permeable kainate receptors have been reported in specific kinds of neurons and glia. Recombinant receptors assembled from GluR1 and/or GluR3 subunits in exogenous expression systems are permeable to Ca2+; heteromeric channels containing GluR2 subunits are Ca(2+)-impermeable. Thus, altered expression of GluR2 in development or following a neurological insult or injury to the brain can act as a switch to modify Ca2+ permeability. To investigate the molecular mechanism underlying delayed postischemic cell death, GluR1, GluR2, and GluR3 gene expression was examined by in situ hybridization in postischemic rats. Following severe, transient forebrain ischemia GluR2 gene expression was preferentially reduced in CA1 hippocampal neurons at a time point that preceded their degeneration. The switch in expression of kainate/AMPA receptor subunits coincided with the previously reported increase in Ca2+ influx into CA1 cells. Timing of the switch indicates that it may play a causal role in postischemic cell death.
 ...
PMID:Switch in glutamate receptor subunit gene expression in CA1 subfield of hippocampus following global ischemia in rats. 143 39

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.
 ...
PMID:Delayed AMPA receptor blockade reduces cerebral infarction induced by focal ischemia. 165 10


1 2 3 4 5 6 7 8 9 10 Next >>