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)

The present study examined whether anti-inflammatory drugs can ameliorate the postponed neuronal damage which has been observed following treatment of ischemic animals with 2,3-dihydro-6-nitro-7-sulfamoyl-benz (F) quinoxaline (NBQX). Global cerebral ischemia was induced in male Wistar rats by four-vessel occlusion for 20 min. The animals were treated either with NBQX, rolipram, doxycycline or a combination of NBQX and rolipram or doxycycline. Four weeks after ischemia neuronal damage in the hippocampus was assessed. Treatment with NBQX or doxycycline did not affect ischemic neuronal damage whereas rolipram alone or combination of NBQX with either rolipram or doxycycline reduced neuronal damage. The present study shows that combining NBQX with an anti-inflammatory drug leads to long-lasting protection. These results suggest that inflammation contributes to the postponed neuronal damage following treatment with NBQX.
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PMID:Inflammation contributes to the postponed ischemic neuronal damage following treatment with a glutamate antagonist in rats. 1116 88

Increased levels of extracellular excitatory amino acids and failure of energy metabolism are two conditions associated with brain ischemia. In the present study we have combined the simultaneous inhibition of glutamate uptake and mitochondrial electron transport chain to simulate neuronal damage associated with brain ischemia. Results show that cerebellar granule neurons are not vulnerable to transient glutamate uptake inhibition by L-trans-pyrrolidine-2,4-dicarboxylate (PDC) despite the increase in the extracellular concentration of glutamate, unless they are simultaneously exposed to the mitochondrial toxins 3-nitropropionic acid (3-NP) or sodium azide. Cell damage was assessed by light microscopy observation, by reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and by the fluorescent markers for live and dead cells, calcein and ethidium homodimer, respectively. The protective effect of alternative energy substrates, such as pyruvate, acetoacetate, and beta-hydroxybutyrate against PDC-induced neuronal death during 3-NP exposure was studied and compared to the effects of the antioxidant vitamin E, the spin trapper alpha-phenyl-N-tert-butylnitrone (PBN), voltage-dependent calcium channel antagonists, and glutamate receptor antagonists. Results show that neuronal damage can be efficiently prevented in the presence of pyruvate and the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801, whereas the non-NMDA receptor antagonist NBQX, acetoacetate, vitamin E, and PBN showed partial protection. In contrast, beta-hydroxybutyrate and voltage-dependent calcium channels blockers did not show any protective effect at the concentrations tested.
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PMID:Strategies for neuroprotection against L-trans-2,4-pyrrolidine dicarboxylate-induced neuronal damage during energy impairment in vitro. 1134 Jun 49

Though the AMPA receptor has been implicated in several neurodegenerative processes (epilepsy, ischemia, spasticity), its role in cognition is yet to be clarified. The aim of this study was to assess in the rat the effects of the AMPA receptor antagonist NBQX (3.5, 7, 10, 20 and 30 mgkg(-1), i.p.) on learning and memory. For this purpose, the object recognition task was chosen. NBQX, at the higher doses used (20 and 30 mgkg(-1)) caused respectively, depression of motility and ataxia, while given at lower doses (3.5, 7 and 10 mgkg(-1)) it did not influence animals performance in the object recognition paradigm. All rats acquired similarly well the task. In conclusion, these results would support and broaden previous observations on the lack of major involvement of AMPA receptors in the rat working memory mechanisms.
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PMID:The non-NMDA receptor antagonist NBQX does not affect rats performance in the object recognition task. 1182 Aug 60

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

Neurons and glia reacting to ischemic injury exhibit delayed expression of heat shock proteins (HSPs). We tested the hypothesis that glutamate receptor antagonists alter neuronal and glial activation during focal cerebral ischemia, as shown by spatio-temporal changes in HSP immunoreactivity. Rats underwent focal ischemia by permanent occlusion of the middle cerebral artery. All animals were pre-treated with NBQX (30 mg kg-1), a competitive antagonist of the AMPA/kainate receptor, or CGS-19755 (10 mg kg-1), a competitive NMDA receptor antagonist, and euthanatized after 6 or 24 h of ischemia to demonstrate regional immunoreactivity of HSP-72 or 32 in brain. Neurons immunolabeled for HSP-72 appeared in the penumbral region adjacent to the infarct at 24 h and increased in number and distribution after pretreatment with NBQX or CGS-19755. Immunolabeling for HSP-32 revealed that pre-treatment with CGS-19755 caused ramified glia to infiltrate the ischemic cortex at 6 h, a pattern that was not seen in ischemic controls until 24 h. Blockade of the NMDA or AMPA/kainate receptor modulates cellular stress responses in both neurons and glia within the developing infarct. We conclude that early, rather than delayed, expression of HSP-32 is a sensitive indicator of glial activation induced specifically by CGS-19755.
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PMID:Glutamate receptor antagonists modulate heat shock protein response in focal brain ischemia. 1263 23

Maintenance of low extracellular glutamate ([Glu](O)) preventing excitotoxic cell death requires fast removal of glutamate from the synaptic cleft. This clearance is mainly provided by high affinity sodium-dependent glutamate transporters. These transporters can, however, also be reversed and release glutamate to the extracellular space in situations with energy failure. In this study the cellular localisation of the glutamate transporters GLAST and GLT-1 in organotypic hippocampal slice cultures was studied by immunofluorescence confocal microscopy, under normal culture conditions, and after a simulated ischemic insult, achieved by oxygen and glucose deprivation (OGD). In accordance with in vivo findings, GLAST and GLT-1 were primarily expressed by astrocytes under normal culture conditions, but after OGD some damaged neurons also expressed GLAST and GLT-1. The potential damaging effect of inhibition of the glutamate transporters by DL-threo-beta-benzyloxyaspartate (DL-TBOA) was studied using cellular uptake of propidium iodide (PI) as a quantitative marker for the cell death. Addition of DL-TBOA for 48 h was found to induce significant cell death in all hippocampal regions, with EC(50) values ranging from 38 to 48 microM for the different hippocampal subregions. The cell death was prevented by addition of the glutamate receptor antagonists NBQX and MK-801, together with an otherwise saturating concentration of DL-TBOA (100 microM). Finally, the effect of inhibition of glutamate release, via reverse operating transporters during OGD, was investigated. Addition of a sub-toxic (10 microM) dose of DL-TBOA during OGD, but not during the subsequent 48 h recovery period, significantly reduced the OGD-induced PI uptake. It is concluded: (1) that the cellular expression of the glutamate transporters GLAST and GLT-1 in hippocampal slice cultures in general corresponds to the expression in vivo, (2) that inhibition of the glutamate transporters induces cell death in the slice cultures, and (3) that partial inhibition during simulation of ischemia by OGD protects against the induced PI uptake, most likely by blocking the reverse operating transporters otherwise triggered by the energy failure.
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PMID:Neurotoxic and neuroprotective effects of the glutamate transporter inhibitor DL-threo-beta-benzyloxyaspartate (DL-TBOA) during physiological and ischemia-like conditions. 1274 81

Ischemic depolarizing events, such as repetitive spontaneous periinfarct spreading depolarizations (PIDs), expand the infarct size after experimental middle cerebral artery (MCA) occlusion. This worsening may result from increased metabolic demand, exacerbating the mismatch between cerebral blood flow (CBF) and metabolism. Here, we present data showing that anoxic depolarization (AD) and PIDs caused vasoconstriction and abruptly reduced CBF in the ischemic cortex in a distal MCA occlusion model in mice. This reduction in CBF during AD increased the area of cortex with 20% or less residual CBF by 140%. With each subsequent PID, this area expanded by an additional 19%. Drugs that are known to inhibit cortical spreading depression (CSD), such as N-methyl-D-aspartate receptor antagonists MK-801 and 7-chlorokynurenic acid, and sigma-1 receptor agonists dextromethorphan and carbetapentane, did not reduce the frequency of PIDs, but did diminish the severity of episodic hypoperfusions, and prevented the expansion of severely hypoperfused cortex, thus improving CBF during 90 mins of acute focal ischemia. In contrast, AMPA receptor antagonist NBQX, which does not inhibit CSD, did not impact the deterioration in CBF. When measured 24 h after distal MCA occlusion, infarct size was reduced by MK-801, but not by NBQX. Our results suggest that AD and PIDs expand the CBF deficit, and by so doing negatively impact lesion development in ischemic mouse brain. Mitigating the vasoconstrictive neurovascular coupling during intense ischemic depolarizations may provide a novel hemodynamic mechanism of neuroprotection by inhibitors of CSD.
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PMID:Vasoconstrictive neurovascular coupling during focal ischemic depolarizations. 1634 Sep 58

The vulnerability of brain cells to neurologic insults varies greatly, depending on their neuronal subpopulation. However, cells surviving pathological insults such as ischemia or brain trauma may undergo structural changes, e.g., altered process growth, that could compromise brain function. In this study, we examined the effect of glutamate excitotoxicity on dendrite growth from surviving cortical GABAergic neurons in vitro. Glutamate exposure did not affect GABAergic neuron viability, however, it significantly reduced dendrite growth from GABAergic neurons. This effect was blocked by the AMPA receptor antagonists NBQX and CFM-2, and mimicked by AMPA, but not NMDA. Glutamate excitotoxicity also caused an NMDA receptor-mediated decrease in the GABA synthesizing enzyme glutamic acid decarboxylase (GAD65/67) immunoreactivity from GABAergic neurons, measured using immunocytochemical and Western blot techniques. GAD is necessary for GABA synthesis; however, reduction of GABA by 3-mercaptopropionic acid (3-MPA), which inhibits GABA synthesis, did not alter dendrite growth. These results suggest that GABAergic cortical neurons are relatively resistant to excitotoxic-induced cell death, but they can display morphological and biochemical alterations which may impair their function.
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PMID:Reduced dendrite growth and altered glutamic acid decarboxylase (GAD) 65- and 67-kDa isoform protein expression from mouse cortical GABAergic neurons following excitotoxic injury in vitro. 1743 99

Dark neurons have plagued the interpretation of brain tissue sections, experimentally and clinically. Seen only when perturbed but living tissue is fixed in aldehydes, their mechanism of production is unknown. Since dark neurons are seen in cortical biopsies, experimental ischemia, hypoglycemia, and epilepsy, we surmised that glutamate release and neuronal transmembrane ion fluxes could be the perturbation leading to dark neuron formation while the fixation process is underway. Accordingly, we excised biopsies of rat cortex to simulate neurosurgical production of dark neurons. To ascertain the role of glutamate, blockade of N-methyl-D-aspartate (NMDA) and non-NMDA receptors was done prior to formaldehyde fixation. To assess the role of transmembrane sodium ion (and implicitly, water) fluxes, tetraethylammonium (TEA) was used. Blockade of NMDA receptors with MK-801 and non-NMDA receptors with the quinoxalinediones (CNQX and NBQX) abolished dark neuron formation. More delayed exposure of the tissue to the antagonist, CNQX, by admixing it with the fixative directly, allowed for some production of dark neurons. Aminophosphonoheptanoate (APH), perhaps due to its polarity, and TEA, did not prevent dark neurons, which were abundant in control formaldehyde fixed material unexposed to either receptor or ion channel antagonists. The results demonstrate a role for the pharmacologic subtypes of glutamate receptors in the pathogenetic mechanism of dark neuron formation. Our results are consistent with the appearance of dark neurons in biopsy where the cerebral cortex has been undercut, and rendered locally ischemic and hypoglycemic, as well as in epilepsy, hypoglycemia, and ischemia, all of which lead to glutamate release. Rather than a pressure-derived mechanical origin, we suggest that depolarization, glutamate release or receptor activation are more likely mechanisms of dark neuron production.
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PMID:Pharmacologic analysis of the mechanism of dark neuron production in cerebral cortex. 1869 90

The biology of cerebral white matter injury has been woefully understudied, in part because of the difficulty of reliably modeling this type of injury in rodents. Periventricular leukomalacia (PVL) is the predominant form of brain injury and the most common cause of cerebral palsy in premature infants. PVL is characterized by predominant white matter injury. No specific therapy for PVL is presently available, because the pathogenesis is not well understood. Here we report that two types of mouse PVL models have been created by hypoxia-ischemia with or without systemic coadministration of lipopolysaccharide (LPS). LPS coadministration exacerbated hypoxic-ischemic white matter injury and led to enhanced microglial activation and astrogliosis. Drug trials with the antiinflammatory agent minocycline, the antiexcitotoxic agent NBQX, and the antioxidant agent edaravone showed various degrees of protection in the two models, indicating that excitotoxic, oxidative, and inflammatory forms of injury are involved in the pathogenesis of injury to immature white matter. We then applied immunoelectron microscopy to reveal fine structural changes in the injured white matter and found that synapses between axons and oligodendroglial precursor cells (OPCs) are quickly and profoundly damaged. Hypoxia-ischemia caused a drastic decrease in the number of postsynaptic densities associated with the glutamatergic axon-OPC synapses defined by the expression of vesicular glutamate transporters, vGluT1 and vGluT2, on axon terminals that formed contacts with OPCs in the periventricular white matter, resulted in selective shrinkage of the postsynaptic OPCs contacted by vGluT2 labeled synapses, and led to excitotoxicity mediated by GluR2-lacking, Ca(2+) -permeable AMPA receptors. Overall, the present study provides novel mechanistic insights into the pathogenesis of PVL and reveals that axon-glia synapses are highly vulnerable to white matter injury in the developing brain. More broadly, the study of white matter development and injury has general implications for a variety of neurological diseases, including PVL, stroke, spinal cord injury, and multiple sclerosis.
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PMID:Axon-glia synapses are highly vulnerable to white matter injury in the developing brain. 2181 16


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