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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated whether the known neuroprotective effects of two selective glutamate receptor antagonists, the NMDA antagonist MK-801 and the AMPA antagonist NBQX, are reflected in the regional cerebral protein synthesis rates (CPSR) in rats with middle cerebral artery occlusion (MCAO). Rats treated with either saline, MK-801 (5 mg/kg i.p.) or NBQX (30 mg/kg i.p. x 3) were subjected to permanent MCAO. Regional CPSR and volumes of gray matter structures displaying normal CPSR were measured in coronal cryosections of the brain by quantitative autoradiography following an i.v. bolus injection of 35S-labelled L-methionine 2 h after occlusion. MCAO completely inhibited protein synthesis in the lateral part of striatum and part of the adjacent frontoparietal cortex corresponding to the ischemic focus. Surrounding this, a metabolic penumbra with approximately 50% reductions in CPSR was present. Treatment with MK-801 significantly increased the volume of tissue with normal CPSR in the ischemic hemisphere compared to controls, whereas this was not seen with NBQX treatment. The results suggest that MK-801 and NBQX have different effects on peri-infarct protein synthesis after MCAO. Since both compounds reduce infarct size, it is questionable that acute inhibition of protein synthesis in focal ischemia is of significant importance to the final outcome of a stroke lesion.
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PMID:Differential effect of NMDA and AMPA receptor blockade on protein synthesis in the rat infarct borderzone. 874 Nov 37

Veratridine blocks Na(+)-channel inactivation and causes a persistant Na(+)-influx. Exposure of hippocampal slices to 10 microM veratridine led to a failure of synaptic transmission, repetitive spreading depression (SD)-like depolarizations of increasing duration, loss of Ca(+)-homeostasis, a large reduction of membrane potential, spongious edema and metabolic failure. Normalization of the amplitude of the negative DC shift evoked by high K+ ACSF 80 min after veratridine exposure was taken as the primary endpoint for neuroprotection. Compounds whose mechanisms of action includes Na(+)-channel modulation were neuroprotective (IC50-values in microM): tetrodotoxin 0.017, verapamil 1.18, riluzole 1.95, lamotrigine > or = 10, and diphenylhydantoin 16.1. Both NMDA (MK-801 and PH) and non-NMDA (NBQX) excitatory amino acid antagonists were inactive, as were NOS-synthesis inhibitor (nitro-L-arginine and L-NAME) Ca(2+)-channel blockers (cadmium, nimodipine) and a K(+)-channel blocker (TEA). Lubeluzole significantly delayed in time before the slices became epileptic, postponed the first SD-like depolarization, allowed the slices to better recover their membrane potential after a larger number of SD-like DC depolarizations, preserved Ca2+ and energy homeostasis, and prevented the neurotoxic effects of veratridine (IC50-value 0.54 microM). A concentration of lubeluzole, which was 40 x higher than its IC50-value for neuroprotection against veratridine, had no effect on repetitive Na(+)-dependent action potentials induced by depolarizing current in normal ACSF. The ability of lubeluzole to prevent the pathological consequences of excessive Na(+)-influx, without altering normal Na(+)- channel function may be of benefit in stroke.
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PMID:Altered Na(+)-channel function as an in vitro model of the ischemic penumbra: action of lubeluzole and other neuroprotective drugs. 903 12

Central nervous system dysfunction continues to represent significant morbidity and associated mortality in patients undergoing cardiac surgery. Neurological dysfunction is most exaggerated in patients undergoing hypothermic circulatory arrest (HCA). Although surgical techniques, anesthetic management, and postoperative care have significantly improved over the past two decades, the incidence of stroke and other neurocognitive deficits remains problematic. Understanding the mechanisms of cell death associated with HCA may provide information that is germane to all types of cerebral injury involved in cardiac surgery. Using a closed-chest cardiopulmonary bypass model, dogs underwent 2 hours of circulatory arrest at 18 degrees C followed by resuscitation and recovery for 3 days. Animals were assessed functionally by a species-specific behavioral scale, histologically for patterns of selective neuronal necrosis and receptor autoradiography for NMDA glutamate receptor subtype expression. Using a selective NMDA (-glutamate) receptor antagonist (MK801), an AMPA-antagonist (NBQX) and a nonspecific neuroprotectant (GM1-ganglioside), the role of glutamate excitotoxicity in the development of HCA-induced brain injury was documented and validated. Using a similar canine preparation, a microdialysis technique was used to evaluate the role of nitric oxide in neuronal death. Arginine plus oxygen is converted to nitric oxide plus citrulline by the action of nitric oxide synthase. Simultaneous infusion of artificial cerebrospinal fluid containing L-[14C] arginine or L-[14C] arginine and L-NAME (a nitric oxide synthase inhibitor) was performed in contralateral hemispheres. Citrulline recovery in the cerebrospinal fluid, citrulline production in vitro from canine cortical homogenates, and nitric oxide metabolites in the serum were all significantly increased during HCA and reperfusion. These studies demonstrated that neurotoxicity following HCA involves a significant and early induction of neuronal NOS expression and neuronal processes leading to widespread augmented NO production in the brain. Continued research into the pathophysiologic mechanisms involved in cerebral injury will undoubtedly yield a safe and reliable neuroprotectant strategy.
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PMID:Pathophysiology of cerebral injury and future management. 927 60

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

We performed real-time monitoring of the extracellular glutamate dynamics in the rat striatum in vivo using the microdialysis electrode technique, during an experimental penumbral condition of moderate global cerebral ischemia and activated glutamate receptors. The local cerebral blood flow (CBF) was measured with a laser-Doppler probe. One minute after bilateral common carotid artery occlusion (BCAO), CBF was reduced to approximately 60% of the pre-ischemic value and it remained at this level during the period of occlusion. After BCAO, a transient depolarization and a transient increase in extracellular glutamate concentration ([Glu]e) were seen. In other rats, 500 microM N-methyl-D-aspartate (NMDA) was locally micro-transfused for 30 min prior to BCAO. Upon induction of BCAO, an anoxic depolarization-like depolarization and a gradual increase in [Glu]e that continued over the duration of BCAO were seen. After BCAO was terminated, the direct current (DC) rapidly recovered to the basal level, while [Glu]e gradually decreased to the basal level. In rats that were locally micro-transfused with 500 microM Kainate prior to BCAO, DC and [Glu]e did not differ significantly from control. Pretreatment with MK-801 prior to NMDA treatment completely inhibited the NMDA-induced changes in DC and [Glu]e. Pretreatment with NBQX prior to NMDA treatment did not inhibit the NMDA-induced changes in DC and [Glu]e. Consequently, we found that activation of NMDA receptors by elevated [Glu]e exerts an important effect on [Glu]e dynamics in the spreading stroke region very early in the acute stage of cerebral ischemia in vivo.
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PMID:Effects of glutamate receptor agonist on extracellular glutamate dynamics during moderate cerebral ischemia. 1174 86

NMDA glutamate receptor antagonists are used in clinical anesthesia, and are being developed as therapeutic agents for preventing neurodegeneration in stroke, epilepsy, and brain trauma. However, the ability of these agents to produce neurotoxicity in adult rats and psychosis in adult humans compromises their clinical usefulness. In addition, an NMDA receptor hypofunction (NRHypo) state might play a role in neurodegenerative and psychotic disorders, like Alzheimer's disease and schizophrenia. Thus, understanding the mechanism underlying NRHypo-induced neurotoxicity and psychosis could have significant clinically relevant benefits. NRHypo neurotoxicity can be prevented by several classes of agents (e.g. antimuscarinics, non-NMDA glutamate antagonists, and alpha(2) adrenergic agonists) suggesting that the mechanism of neurotoxicity is complex. In the present study a series of experiments was undertaken to more definitively define the receptors and complex neural circuitry underlying NRHypo neurotoxicity. Injection of either the muscarinic antagonist scopolamine or the non-NMDA antagonist NBQX directly into the cortex prevented NRHypo neurotoxicity. Clonidine, an alpha(2) adrenergic agonist, protected against the neurotoxicity when injected into the basal forebrain. The combined injection of muscarinic and non-NMDA Glu agonists reproduced the neurotoxic reaction. Based on these and other results, we conclude that the mechanism is indirect, and involves a complex network disturbance, whereby blockade of NMDA receptors on inhibitory neurons in multiple subcortical brain regions, disinhibits glutamatergic and cholinergic projections to the cerebral cortex. Simultaneous excitotoxic stimulation of muscarinic (m(3)) and glutamate (AMPA/kainate) receptors on cerebrocortical neurons appears to be the proximal mechanism by which the neurotoxic and psychotomimetic effects of NRHypo are mediated.
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PMID:Receptor mechanisms and circuitry underlying NMDA antagonist neurotoxicity. 1180 44

This review focuses on the in vitro and in vivo neuropharmacology of YM872, a potential neuroprotective agent currently undergoing clinical trials in the United States (trial name: AMPA Receptor Antagonist Treatment in Ischemic Stroke - ARTIST). Its neuroprotective properties in rats and cats with induced focal cerebral ischemia are described. YM872, [2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl]-acetic acid monohydrate, is a selective, potent and highly water-soluble competitive alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist. YM872 has a potent inhibitory effect on [(3)H]AMPA binding with a K(i) value of 0.096 microM. In contrast, YM872 has very low affinity for other ionotropic glutamate receptors. The solubility of YM872 is approximately 500 to 1000 times higher than that of the other competitive AMPA antagonists: YM90K, NBQX, or CNQX. The neuroprotective efficacy of YM872 was investigated in rats and cats subjected to permanent occlusion of the left middle cerebral artery. The animals were assessed either histologically or neurologically following ischemia. In rats with occluded middle cerebral artery (MCAO) YM872, by i.v. infusion, significantly reduced infarct volume measured at 24 h and 1 week after ischemia. Significant neuroprotection was maintained even when drug administration was delayed for up to 2 h after ischemia. In addition, YM872 significantly improved neurological deficit measured at 1 week after ischemia. In cats with MCAO YM872, by i.v. infusion, dose-dependently reduced infarct volume at 6 h after ischemia. YM872 produced no behavioral abnormalities and was not nephrotoxic. The evidence for the neuroprotective efficacy of YM872 suggests its therapeutic potential in the treatment of acute stroke in humans.
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PMID:YM872: a selective, potent and highly water-soluble alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist. 1248 Nov 90

Although stroke is a major cause of death and disability in the elderly, the inhibitory effects of neuroprotectants in acute stroke have been investigated using experimental cerebral ischemic models of young animals. Recent clinical trials have found that few neuroprotectants are effective. These observations indicate that effects in the clinical setting do not always reflect data from young animals. Thus, we compared the effects of the NMDA receptor antagonist MK-801 and of the AMPA receptor antagonist NBQX [2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinixaline] on ischemic cerebral damage in the photothrombosis model of aged and young rats. MK-801 administered immediately after MCA occlusion significantly (P<0.05) reduced the extent of cerebral damage in young, but not in aged, rats and the effects of NBQX were similar. In separate experiments, we evaluated brain damage after microinjecting NMDA or kainic acid into the cortex using a stereotaxic apparatus. We found no significant differences in focal cerebral damage caused by NMDA between young and aged rats. On the other hand, kainic acid caused all of the aged rats tested to die, but none of the young rats. Our observations indicate that NMDA and AMPA receptor antagonists are less effective in aged, than in young, rats and that cerebral damage by receptor agonists depends on the type of receptor, such as NMDA and AMPA.
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PMID:Ability of NMDA and non-NMDA receptor antagonists to inhibit cerebral ischemic damage in aged rats. 1257 19

Signal transduction via ionotropic glutamate receptors is found in many life forms, from protozoa to mammals. Glutamate is the main excitatory neurotransmitter in the mammalian CNS, were fast postsynaptic depolarisation is induced by the activation of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors. In addition to their important physiological role, excessive AMPA receptor stimulation is also a hallmark of excitotoxicity-related diseases, like ischaemic stroke. Conversely, AMPA receptor inhibitors were proposed to be useful neuroprotective drugs. First generation AMPA receptor blockers were competitive antagonists, like NBQX, which showed robust neuroprotection in a variety of disease-related animal models. Its clinical use, however, was restricted by the very low solubility, inducing kidney precipitaton in vivo. Second generation competitive antagonists are available, which do not possess this property. None of those, however, up to now is in clinical use. Competitive AMPA receptor antagonists are not the first choice for neuroprotective drugs, since due to receptor kinetics they preferently suppress the physiological relevant component of the postsynaptic glutamate response. Non-competitive blockers, like 2,3-benzodiazepines or the novel neuroprotectant BIIR 561 should be suited better for the treatment of stroke. The latter compound is also described as blocker of voltage-gated sodium channels. Targetting more than one mechanism in the excitotoxicity cascade might be a fruitful approach for the development of neuroprotective drugs.
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PMID:AMPA receptor antagonists for the treatment of stroke. 1585

Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory diseases of the central nervous system (CNS) characterized by localized areas with demyelination. Disease is believed to be an autoimmune disorder mediated by activated immune cells such as T- and B-lymphocytes and macrophages/microglia. Lymphocytes are primed in the peripheral tissues by antigens, and clonally expanded cells infiltrate the CNS. They produce large amounts of inflammatory cytokines, nitric oxide (NO) that lead to demyelination and axonal degeneration. Although several studies have shown that oligodendrocytes (OLGs), the myelin-forming glial cells in the CNS, are sensitive to cell death stimuli, such as cytotoxic cytokines, anti-myelin antibodies, NO, and oxidative stress, in vitro, the mechanisms underlying injury to the OLGs in MS/EAE remain unclear. The central role of glutamate receptors in mediating excitotoxic neuronal death in stroke, epilepsy, trauma and MS has been well established. Glutamate is the major excitatory amino acid transmitter within the CNS and it's signaling is mediated by a number of postsynaptic ionotropic and metabotropic receptors. Inflammation can be blocked with anti-cell adhesion molecules MAb, simultaneously protected oligodendrocytes and neurons against glutamate-mediated damage with the AMPA/kainate antagonist NBQX, and the NMDA receptor antagonist GPE, could thus be effective therapies for multiple sclerosis.
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PMID:Anti-inflammatory immunotherapy for multiple sclerosis/experimental autoimmune encephalomyelitis (EAE) disease. 1637 98


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