Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cytoprotective effects of MK-801 and NBQX, selective N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonists, respectively, were compared both singularly and in combination in models of transient severe forebrain and transient focal cerebral ischemia. After 10 minutes of four-vessel occlusion ischemia, the sodium salt of NBQX (30 mg/kg IP) given at the time of reperfusion and, subsequently, 15 and 30 minutes later produced a dramatic reduction in CA1 hippocampal necrosis at 7 days. This effect was not obtained with the intraperitoneal administration of either MK-801 (1 mg/kg x 3) or the combination of both NBQX and MK-801 given at the same time intervals. This effect of intraperitoneal NBQX alone was reproduced in a two-vessel occlusion/hypotension model using this same drug administration. Delayed treatment with both NBQX and GYKI 52466, but neither MK-801 nor the combination of NBQX and MK-801 given after a delay, produced a significant reduction in the mean volume of neocortical infarction after transient focal ischemia. We conclude that the AMPA receptor may play a more important role than the NMDA receptor in both selective ischemic necrosis of hippocampal neurons and in neocortical infarction. AMPA antagonists should be subjected to clinical stroke trials.
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PMID:AMPA antagonists: do they hold more promise for clinical stroke trials than NMDA antagonists? 750 38

The development of selective, systemically active alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate antagonists over the last 4 years has enabled the role of this excitatory amino acid receptor subtype to be scrutinised in the different models of ischaemia. The animal models of cerebral ischaemia can be subdivided into two major categories: focal ischaemia, in which the resulting infarct resembles the clinical condition of stroke; and models of severe forebrain ischaemia, in which there is delayed neuronal degeneration of hippocampal CA1 neurones. The neuropathology in the latter models resembles the clinical condition seen following a cardiac arrest, for example. It is well established that N-methyl-D-aspartate (NMDA) antagonists such as MK-801, 3-(2-carboxypiperazine-4-yl)-propenyl-1-phosphonate (CPPene), DL-(E)-2-amino-4-methyl-5-phosphono-3-pentanoic acid (CGP 37849), and N-(1-naphthyl)-N'-(3-ethylphenyl)-N'-methylguanidine hydrochloride (CNS 1102) are neuroprotective in animal models of focal ischaemia. However, in models of severe forebrain ischaemia NMDA antagonists produced only partial protection. The discovery of 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX) as a systemically active AMPA receptor antagonist enabled the role of this receptor subtype in ischaemia to be investigated. NBQX was shown to be neuroprotective against delayed neuronal degeneration of hippocampal CA1 neurones in animal models of severe forebrain ischaemia. Recent studies have demonstrated that NBQX administration can be delayed by up to 12 h and amelioration of delayed neuronal degeneration of hippocampal CA1 neurones can still be seen. NBQX has also been shown to be neuroprotective in animal models of permanent and temporary middle cerebral artery occlusion. 1-(Aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466), a systemically active noncompetitive AMPA/kainate antagonist, was neuroprotective against focal ischaemia but was unable to attenuate hippocampal CA1 neuronal degeneration. Whilst the newer compounds such as (3SR,4aRS,6RS,8aRS)-6-[2-(1H-tetrazol-5-yl )-ethyl]-1,2,3,4,4a,5,6,7,8a-decahydroisoquinoline-3-carboxylic acid (LY 215490) and 6-(1-imidazolyl)-7-nitroquinoxaline-2,3(1H,4H)-dione (YM900) have been demonstrated to be neuroprotective in focal ischaemia models, there is still a lack of information with regard to their efficacy in models of severe forebrain ischaemia. It appears from initial studies that AMPA/kainate antagonists have a better behavioural profile than NMDA antagonists in terms of a lack of phychostimulant and phychotomimetic effects. However, these antagonists have their own problems in that they cause severe depression of glucose utilisation in the central nervous system at neuroprotective doses.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The pharmacology of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate antagonists and their role in cerebral ischaemia. 752 37

Glutamate antagonists have been shown to be neuroprotective in animal models of cerebral ischemia. Global cerebral ischemia in rats leads to selective neuronal damage in the hippocampus and striatum. Following ischemia a deficit in spatial learning and memory occurs. The aim of the present study was to investigate the potential neuroprotective effect of GYKI 52466, an antagonist at the non-N-methyl-D-aspartate receptor, with behavioural and histological measures of global ischemia in rats. Global ischemia was induced by four-vessel-occlusion (4VO) for 20 min in rats. GYKI 52466 (30 mg/kg i.p.) was administered either 20 min before induction of ischemia or immediately after onset of reperfusion. One week after surgery spatial learning was tested in the Morris water maze. After behavioural testing the animals were sacrificed and the neuronal damaged was assessed. GYKI 52466 reduced the increase in escape latency and in swim distance induced by 4VO when given before ischemia but not when applied after ischemia. Neuronal damage in the CA1 sector of the hippocampus produced by 4VO was significantly attenuated by pretreatment but not by posttreatment with GYKI 52466. Striatal neuronal damage was not affected by either treatment with GYKI 52466. GYKI 52466 had neuroprotective effects in a rat model of global cerebral ischemia. Pretreatment with GYKI 52466 protected rats against behavioural deficits and hippocampal neuronal damage induced by 4VO.
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PMID:Pretreatment but not posttreatment with GYKI 52466 reduces functional deficits and neuronal damage after global ischemia in rats. 885 48

Global cerebral ischemia leads to selective neuronal damage in the CA1 sector of the hippocampus and in the striatum. This ischemia leads to a deficit in spatial learning and memory in the water maze. The results of earlier studies that have examined the relationship between neuronal damage and the deficit in the water maze were not clear-cut. It has been observed that neuroprotection reduces both the deficit in the water maze and the neuronal damage. The present study therefore approached the relationship between the neuronal damage and the deficit in the water maze by pharmacological means. Global cerebral ischemia was induced in male Wistar rats by four-vessel occlusion for 20 min. Ischemic rats were then treated with the noncompetitive non-NMDA receptor antagonist GYKI 52466 (30 mg/kg), the radical scavenger LY 231617 (20 mg/kg), the inhibitor of protein kinase C staurosporine (0.1 mg/kg), or solvent. Treatment with GYKI 52466 or LY 231617 reduced the deficit in spatial learning by limiting the increase in swim distance due to ischemia. In addition, LY 231617 reduced the deficit in spatial memory as demonstrated by minimizing the ischemia-induced reduction in time spent in the quadrant of the former platform position during the probe trial. Staurosporine had no influence on the ischemia-induced behavioural changes. Histological examination revealed neuronal damage in the hippocampus and in the striatum in all of the ischemic rats. However, treatment with GYKI 52466 or LY 231617 reduced the hippocampal damage. Correlation analysis demonstrated a correlation between hippocampal damage and total swim distance (r = 0.88, P < 0.001). No correlation was found between hippocampal damage and quadrant time of the probe trial (r = -0.24, p > 0.1). No correlation was observed between striatal damage and either total swim distance of the escape trials (r = 0.28. p > 0.1) or quadrant time of the probe trial (r = -0.08, p > 0.6). It is concluded that a correlation exists between hippocampal damage and the deficit in spatial learning following global cerebral ischemia.
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PMID:Correlation between hippocampal neuronal damage and spatial learning deficit due to global ischemia. 913 Mar 3

AMPA Receptor antagonists have received considerable attention in recent years. Within the class of excitatory amino acid receptor antagonists AMPA receptor antagonists have shown excellent neuroprotection in several models of cerebral ischemia and neuronal injury. However, poor physical properties have been a major limiting factor in developing these as viable drug candidates. The quinoxaline-2,3-dione template has been the backbone of various competitive AMPA receptor antagonists such as NBQX, PNQX, YM-90K and more recently ZK200775. The SAR learned from these have been valuable for developing the AMPA pharmacophore model (Fig. 2) and has been discussed in detail in this review. There have been efforts in this area to design very selective AMPA receptor antagonists by minimizing the interaction at the NMDA associated GlyN receptors. Compounds designed by BASF and Yamanouchi have been successful in these efforts and their compounds show excellent affinity for the AMPA receptors. Efforts by Warner-Lambert and Novartis also highlight significant success in developing balanced AMPA and GlyN receptor antagonists. Non-competitive AMPA receptor antagonists are also being pursued for various neurological disorders including neuroprotection and are divided in two major classes, viz. positive and negative allosteric modulators. The physical properties of negative allosteric modulators such as GYKI 52466, which belong to the 2,3-benzodiazepinyl structural class have been significantly better. However, the in vitro activity of these compounds has been in the micromolar range and the overall class has the disadvantage of not having a high throughput assay. Other classes of compounds such as phthalazines and quinazolines are being developed and have raised hopes for the second generation of compounds in this area.
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PMID:AMPA receptor antagonists. 1117 72

GYKI 52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine], a non-competitive AMPA [alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate] and kainate receptor antagonist and its two analogues, GYKI 53405 [1-(4-aminophenyl)-3-acetyl-4-methyl-3,4-dihydro-7,8-methylenedioxy-5H-2,3-benzodiazepine] and GYKI 53655 [1-(4-aminophenyl)-3-methylcarbamyl-4-methyl-3,4-dihydro-7,8-methylenedioxy-5H-2,3-benzodiazepine] were investigated in two seizure models and in MgCl2 induced global cerebral ischaemia, as an acute neuroprotective model. The ED(50) values of GYKI 52466 for suppression of the tonic and clonic phases of sound-induced seizures were 3.6 and 4.3 mg/kg, respectively. The corresponding data for GYKI 53405 were 1.1 and 3.1 mg/kg, while ED(50) values of GYKI 53655 were 1.3 and 2.0 mg/kg, respectively. The inhibition of seizure evoked by maximal electroshock was also found to be remarkable: the ED(50) values of GYKI 52466 and its two analogues were 6.9, 2.6, and 2.2 mg/kg, respectively. All compounds prolonged the survival times in MgCl2 induced global cerebral ischaemia test in a dose-dependent fashion, with PD(50) (dose of 50% prolongation) values of 24.1, 8.3, and 8.2 mg/kg intraperitoneal, respectively. In audiogenic seizure model the duration of anticonvulsant action of 10 mg/kg GYKI 52466 and 5 mg/kg GYKI 53405, GYKI 53655 were examined, too. The effect of GYKI 52466 decreased to 50% after 2 h, while the analogues showed more than 80% seizure suppression 3 h after treatment. After 6 h the effect of GYKI 53655 decreased to zero, while the effect of GYKI 52466, remained on the 50% level.
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PMID:Comparison of anticonvulsive and acute neuroprotective activity of three 2,3-benzodiazepine compounds, GYKI 52466, GYKI 53405, and GYKI 53655. 1148 46

Neurodegeneration induced by excitotoxicity is a common feature in various neurological disorders. This pathological condition is caused by prolonged stimulation of glutamate receptor subtypes, followed by both intracellular Ca2+ overload and activation of specific genes, resulting in synthesis of enzymes involved in cell stress response. Using experimental in vitro models of excitotoxicity, we demonstrated that glutamate exposure up-regulated tissue transglutaminase in primary cultures of both cerebellar granule cells and astrocytes. These changes were consequent to receptor-mediated Ca2+ influx, as demonstrated by the inhibition with selective antagonists, MK-801 and GYKI 52466. Early increases in different transglutaminase isoforms were also observed in global cerebral ischemia, which closely resembles neuronal damage caused by NMDA receptor activation. These findings agree with a postulated role for transglutaminases in molecular mechanisms of several neurodegenerative diseases. Indeed, increased cross-linking reactions could be of pathologic relevance, as part of biochemical changes observed in neurological disorders.
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PMID:Excitotoxic and post-ischemic neurodegeneration: Involvement of transglutaminases. 1536 7

Under pathophysiological conditions, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor activation is considered to play a key role in several disorders of the central nervous system. In the search for AMPA receptor antagonists, the synthesis and pharmacological characterization of a series of novel compounds that are structurally related to GYKI 52466 (1), a well-known selective noncompetitive AMPA receptor antagonist, was performed. In vitro, 2,3-dimethyl-6-phenyl-12H-[1,3]dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine (ZK 187638, 14a) antagonized the kainate-induced currents in cultured hippocampal neurons with an IC(50) of 3.4 microM in a noncompetitive fashion. When tested in a clinically predictive rat model of acute ischemic stroke, this noncompetitive AMPA receptor antagonist significantly reduced brain infarction, indicating that it is neuroprotective after permanent focal cerebral ischemia.
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PMID:Novel alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor antagonists of 2,3-benzodiazepine type: chemical synthesis, in vitro characterization, and in vivo prevention of acute neurodegeneration. 1599 99