Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

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

We studied the effect of a novel alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate antagonist, YM90K [6-(1H-imidazol-1-yl)-7-nitro-2, 3(1H, 4H)-quinoxalinedione monohydrochloride], in a focal cerebral ischemia model using anesthetized cats. Cats were subjected to permanent occlusion of the middle cerebral artery (MCA) for 6 h, then killed and examined histologically. The amount of ischemic damage was assessed in 12 stereotaxic coronal sections. Treatment with YM90K (i.v. infusion of 0.5 mg/5 ml/kg/h) starting 10 min after MCA occlusion markedly reduced the volume of ischemic damage (from 2823 +/- 164 mm3 of the cerebral hemisphere in saline-treated cats to 1737 +/- 305 mm3 in YM90K-treated cats). No essential differences were observed between YM90K-and saline-treated cats concerning physiological variables or brain temperature. These results further support the notion that the AMPA/kainate receptor plays an important role in the pathogenesis of focal cerebral ischemia. This evidence for the neuroprotective efficacy of YM90K in a gyrencephalic species suggests its therapeutic potential in the treatment of human stroke.
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PMID:Neuroprotective effect of YM90K, a novel AMPA/kainate receptor antagonist, in focal cerebral ischemia in cats. 878 40

The in-vitro pharmacological properties of (2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydro-1-quinoxal inyl)-acetic acid monohydrate, YM872, a novel and highly water-soluble alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-receptor antagonist were investigated. YM872 is highly water soluble (83 mg mL(-1) in Britton-Robinson buffer) compared with 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(F)quinoxaline (NBQX), 6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione hydrochloride (YM90K) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). YM872 potently inhibits [3H]AMPA binding with a Ki (apparent equilibrium dissociation constant) value of 0.096 +/- 0.0024 microM. However, YM872 had very low affinity for other ionotropic glutamate receptors, as measured by competition with [3H]kainate (high-affinity kainate binding site, concentration resulting in half the maximum inhibition (IC50) = 4.6 +/- 0.14 microM), [3H]glutamate (N-methyl-D-aspartate (NMDA) receptor glutamate binding site, IC50 > 100 microM) and [3H]glycine (NMDA receptor glycine-binding site, IC50 > 100 microM). YM872 competitively antagonized kainate-induced currents in Xenopus laevis oocytes which express rat AMPA receptors, with a pA2 value of 6.97 +/- 0.01. In rat hippocampal primary cultures, YM872 blocked a 20-microM AMPA-induced increase of intracellular Ca2+ concentration with an IC50 value of 0.82 +/- 0.031 microM, and blocked 300-microM kainate-induced neurotoxicity with an IC50 value of 1.02 microM. These results show that YM872 is a potent and highly water-soluble AMPA antagonist with great potential for treatment of neurodegenerative disorders such as stroke.
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PMID:In-vitro characterization of YM872, a selective, potent and highly water-soluble alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonist. 972 Jun 30

The neuroprotective effect of an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist YM90K [6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione monohydrochloride] has been examined in a rat middle cerebral artery occlusion model. Intravenous infusion of YM90K (2.5-20mgkg(-l)h(-l) for 4h) starting immediately after occlusion of the middle cerebral artery significantly reduced the cortical infarct volume 24h after occlusion compared with the control group. The protection at the highest dose was 39% (P < 0.05). Similar protective effects were observed when YM90K (20mgkg(-1)h(-1) for 4h) was delayed up to 2h after middle cerebral artery occlusion (45% reduction, P < 0.05). CNS1102 [N-(1-naphthyl)-N'-(3-ethylphenyl)-N'-methylguanidine hydrochloride], a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, also reduced the cortical infarct volume when 1.13mgkg(-1) was administered by intravenous bolus injection immediately after middle cerebral artery occlusion, followed by intravenous infusion at 0.785mgkg(-l)h(-1) for 4h (35% reduction, P<0.05). This neuroprotective effect was not observed when administration was delayed lh after middle cerebral artery occlusion. These results suggest that AMPA receptors might play a more important role than NMDA receptors in the late development of neuronal cell damage after focal cerebral ischaemia and that AMPA receptor blockade would be one beneficial strategy in treating acute stroke.
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PMID:Delayed treatment with YM90K, an AMPA receptor antagonist, protects against ischaemic damage after middle cerebral artery occlusion in rats. 975 54

In the Western world, over 350,000 deaths and $30 billion in medical costs are attributed annually to stroke. Head and spinal cord trauma cause an estimated 250,000 deaths annually and result in medical costs of $15 billion. Although stroke and head/spinal cord trauma are leading causes of disability and death in humans, no adequate neuroprotective treatment is available. Glutamate antagonists derived from the quinoxa-linedione scaffold are as drug candidates for neuroprotection in stroke and trauma. Quinoxalinedione derivatives such as 2,3-dihydroxy-6- nitro-7-sulfamoylbenzo(f)quinoxaline and 6-(1H-imidazol-1-yl)-7-nitro-2,3-(1H,4H)-quinoxalinedione failed clinical trials because of insolu-bility and resulting nephrotoxicity. Introduction of a phosphonate group into the quinoxalinedione skeleton improves solubility and leaves potency for the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor unchanged. Phosphonate quinoxalinedione derivatives ZK202000 and ZK200775 protected rodent brain against sequelae of permanent occlusion of the middle cerebral artery and head trauma. No major deleterious effects on motor coordination, cardiovascular, or respiratory systems were detected in doses required for neuroprotection. No psychotomimetic and no neurotoxic side effects, typical for N-methyl-D-aspartate antagonists, were observed following treatment with phosphonate quinoxalinediones.
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PMID:Phosphonate quinoxalinedione AMPA antagonists. 1149 77

1. UK-240,455 ((+) 6,7-dichloro-5-[N-(2-hydroxyethyl)methanesulphonamido]-2,3 (1H,4H)-quinoxalinedione) is a potent, selective N-methyl D-aspartate (NMDA) glycine site antagonist that is being evaluated for the potential treatment of stroke. 2. UK-240,455 is predominately excreted unchanged in urine (58-68%) in rats, dogs and man following intravenous administration. The remainder of the dose is excreted unchanged in the faeces. It is considered that UK-240,455 is predominantly cleared by active renal tubular secretion and active hepatobiliary transport. In man, there is evidence that UK-240,455 undergoes glucuronidation. However, there is no evidence for this in rats and dogs. 3. UK-240,455 has a short elimination half-life in rats, dogs and man (0.4-1.4 h) and clearances of 12, 13 and 6 ml min(-1) kg(-1), respectively. The compound shows limited tissue distribution with volumes of distribution of 0.4-0.8 l kg(-1) in rats, dogs and man. The species' variation in pharmacokinetic parameters was related allometrically when plasma protein binding was taken in to account. Hence, active hepatic or renal clearance processes for this compound were conserved across species. 4. Cerebrospinal fluid and brain concentrations of UK-240,455 were determined in rats. The cerebrospinal fluid/plasma concentration ratio of UK-240,455 was 4.3%, which was similar to the plasma-free fraction of this compound (3%), indicating good blood-brain barrier permeability. Brain tissue concentrations were low (0.7% of the total plasma concentrations).
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PMID:Pharmacokinetics and disposition of a novel NMDA glycine site antagonist (UK-240,455) in rats, dogs and man. 1274 9

The study of ischemic tolerance is critical in the development of strategies for the treatment of ischemic stroke. We used the oxygen and glucose deprivation (OGD) paradigm in cultured cortical neurons as an in vitro approach to elucidate the mechanism of protection conferred by glutamate preconditioning. Pretreatment of neurons with N-methyl-d-aspartate (NMDA) receptor antagonists prevented OGD-induced cell death whereas alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor and voltage-dependent Ca(++) channel (VDCC) blockers were without effect. Neurons preconditioned with glutamate exhibited resistant to damage induced by OGD. The ischemic tolerance depended on the duration of preconditioning exposure and the interval between preconditioning exposure and test challenge. Protective efficacy was blocked by the NMDA or AMPA receptor antagonists but not by the VDCC blocker. Furthermore, neuroprotective effect was not seen if extracellular Ca(++) was omitted or removed with EGTA. Pretreatment with staurosporin and 2-[N-(2-hydroxyethyl)]-N-(4-methoxybenzenesulfonyl)] amino-N-(4-chlorocinnamyl)-N-methylbenzylamine (KN93) but not 2-(4-Morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one (LY294002) or 1,4-diamino-2,3-dicyano-1, 4-bis[2-aminophenylthio] butadiene (U0126) significantly reduced ischemic tolerance. Preconditioning increased phosphorylated levels of cAMP responsive element binding protein (CREB) and pretreatment with CRE-decoy oligonucleotide completely blocked preconditioning-induced increase in cell viability. Importantly, glutamate preconditioning increased Bcl-2 expression that was blocked by KN93, staurosporin and CRE-decoy oligonucleotide. These results suggest that preconditioning with glutamate conferred neuroprotection against subsequent OGD by inducing p-CREB-mediated Bcl-2 expression.
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PMID:Glutamate preconditioning prevents neuronal death induced by combined oxygen-glucose deprivation in cultured cortical neurons. 1858 12

Neural progenitor cells (NPCs) have the potential to survive brain ischemia and participate in neurogenesis after stroke. However, it is not clear how survival responses are initiated in NPCs. Using embryonic mouse NPCs and the in vitro oxygen and glucose deprivation (OGD) model, we found that angiopoietin-1 (Ang1) could prevent NPCs from OGD-induced apoptosis, as evidenced by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and annexin V labeling. Ang1 significantly elevated tunica intima endothelial kinase 2 (Tie2) autophosphorylation level, suggesting the existence of functional Tie2 receptors on NPCs. NPCs under OGD conditions exhibited reduction of Akt phosphorylation, decrease of the Bcl-2/Bax ratio, activation of caspase-3, cleavage of PARP, and downregulation of beta-catenin and nestin. Ang1 reversed the above changes concomitantly with significant rising of survival rates of NPCs under OGD, but all these effects of Ang1 could be blocked by either soluble extracellular domain of Tie2 Fc fusion protein (sTie2Fc) or the phosphoinositide 3-kinase (PI3K) inhibitor 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one (LY294002). Our findings suggest the existence of an Ang1-Tie2-PI3K signaling axis that is essential in initiation of survival responses in NPCs against cerebral ischemia and hypoxia.
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PMID:An Ang1-Tie2-PI3K axis in neural progenitor cells initiates survival responses against oxygen and glucose deprivation. 1940 99

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease and conditions such as ischemic stroke affect millions of individuals annually and exert an enormous financial burden on society. A hallmark of these conditions is the abnormal loss of neurons. Currently, there are no effective strategies to prevent neuronal death in these pathologies. We report that several 2-arylidine and 2-hetarylidin derivatives of the 1,4-benzoxazines class of compounds are highly protective in tissue culture models of neurodegeneration. Results obtained using pharmcalogical inhibitors indicate that neuroprotection by these compounds does not involve the Raf-MEK-ERK or PI-3 kinase-Akt signaling pathways nor other survival-promoting molecules such as protein kinase A (PKA), calcium calmodulin kinase A (CaMK), and histone deacetylases (HDACs). We tested one of these compounds, (Z)-6-amino-2-(3',5'-dibromo-4'-hydroxybenzylidene)-2H-benzo[b][1,4]oxazin-3(4H)-one, designated as HSB-13, in the 3-nitropropionic acid (3-NP)-induced mouse model of Huntington's disease. HSB-13 reduced striatal degeneration and improved behavioral performance in mice administered with 3-NP. Furthermore, HSB-13 was protective in a Drosophila model of amyloid precursor protein (APP) toxicity. To understand how HSB-13 and other 1,4-benzoxazines protect neurons, we performed kinase profiling analyses. These analyses showed that HSB-13 inhibits GSK3, p38 MAPK, and cyclin-dependent kinases (CDKs). In comparison, another compound, called ASK-2a, that protects cerebellar granule neurons against low-potassium-induced death inhibits GSK3 and p38 MAPK but not CDKs. Despite its structural similarity to HSB-13, however, ASK-2a is incapable of protecting cortical neurons and HT22 cells against homocysteic acid (HCA)-induced or Abeta toxicity, suggesting that protection against HCA and Abeta depends on CDK inhibition. Compounds described in this study represent a novel therapeutic tool in the treatment of neurodegenerative diseases.
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PMID:Identification of novel 1,4-benzoxazine compounds that are protective in tissue culture and in vivo models of neurodegeneration. 2014 21


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