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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The changes in excitatory amino acid receptor ligand binding induced by transient cerebral ischemia were studied in the rat hippocampal subfields. Ten minutes of ischemia was induced by common carotid artery occlusion combined with hypotension, and the animals were allowed variable periods of recovery ranging from 1 day to 4 weeks. The binding of 3H-AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) to quisqualate receptors, 3H-kainic acid (KA) to kainate receptors, and 3H-glutamate to N-methyl-D-aspartate (NMDA) receptors as determined by quantitative autoradiography. One week following ischemia the CA1 region of the hippocampus displayed a severe (90%) dendrosomatic lesion with preservation of presynaptic terminals. This was associated with a 60% decrease in AMPA binding and a 25% decrease in glutamate binding to NMDA receptors. At 4 weeks postischemia, both AMPA and NMDA sites were greatly reduced. Although the dentate gyrus granule cells are resistant to an ischemic insult of this magnitude, this region showed marked changes in receptor binding. One week following ischemia, the AMPA and NMDA binding decreased by approximately 40 and 20%, respectively. Following 2 weeks of recovery, the NMDA binding was not significantly different from control level, while the AMPA binding remained depressed up to 4 weeks postischemia. The high density of KA binding sites in the inner molecular layer of the dentate gyrus was unaffected by the ischemic insult, despite an extensive degeneration of cells in the hilus of dentate gyrus which projects glutamatergic afferents to this area.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dynamic changes of excitatory amino acid receptors in the rat hippocampus following transient cerebral ischemia. 253 82

Stroke is a major cause of morbidity and mortality in the United States with 250,000 cases per year. Cerebral ischemia is the largest category of stroke with cardiac arrest, profound hypotension, and vascular occlusion the principal causes. Traditional approaches to the treatment of ischemic stroke focus on maintaining cardiac output, blood pressure, cerebral blood flow, and on preventing thrombosis. Recently, attention has been focused on developing new therapies that are directed toward abnormal biochemical events at excitatory synapses. Ischemia causes impairment of brain energy metabolism and the release of excessive amounts of glutamate into the extracellular space. This process secondarily excites neurons and further depletes energy stores. The excitotoxic hypothesis of brain injury proposes that glutamate is a principal cause of damage in ischemia. Three components of this hypothesis have been tested and largely proved in experimental studies in tissue culture and in animal models of stroke. First, elevated concentrations of glutamate cause excessive excitation at a subset of glutamate receptors, the N-methyl-D-aspartate (NMDA) receptor. Second, excitation at this receptor leads to excessive influx of sodium chloride and water which causes acute neuronal damage, and calcium which causes delayed and more permanent damage. Third, pharmacologic blockade at the NMDA receptor-ion channel complex prevents ischemic neuronal damage. Studies using specific pharmacologic compounds that block glutamate's action hold particular promise for treating stroke in humans, including competitive antagonists at the NMDA glutamate binding site (for example, 2-amino-5-phosphonovalerate, AP5), noncompetitive antagonists at the calcium channel (for example, MK-801, dextromethorphan, ketamine), and agents that might be directed at the glycine, zinc, and magnesium sites.
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PMID:Selective vulnerability of the brain: new insights into the pathophysiology of stroke. 254 55

Excitatory amino acid receptor antagonists show potential for the treatment of ischemic stroke and head trauma. In search of novel antagonists, a series of alkyl- and alkoxyl-substituted 1, 4-dihydro-2,3-quinoxalinediones were synthesized and assayed for inhibition of glutamate receptors. We report on the pharmacological characterization of one such compound, 7-chloro-6-methyl-5-nitro-1,4-dihydro-2, 3-quinoxalinedione (ACEA-1416). Electrophysiological assays showed that ACEA-1416 is a potent antagonist of rat brain NMDA receptors expressed in Xenopus oocytes, and NMDA receptors expressed by cultured rat cortical neurons. Antagonism is via competitive inhibition at glycine co-agonist sites (Kb = 7.9 nM in oocytes, Kb = 11 nM in neurons). ACEA-1416 also antagonizes AMPA receptors, though potency is considerably lower (Kb = 3.5 microM in oocytes, Kb = 1.6 microM in neurons). Oocyte assays indicated that ACEA-1416 is weak or inactive as an antagonist at NMDA receptor glutamate binding sites (Kb > 5.9 microM) and metabotropic glutamate receptors (Kb > 57 microM). Many NMDA receptor glycine site antagonists show poor penetration of the blood-brain barrier. Systemic bioavailability of ACEA-1416 was assessed by measuring the ability of the compound to protect against electroshock-induced seizures in mice. Protective effects of ACEA-1416 had rapid onset following i.v. administration. Peak efficacy was at approximately 2 min and the biological half-time of protection was approximately 60 min. The ED50 measured at peak efficacy was approximately 1.5 mg/kg. Our results show that ACEA-1416 is a high potency systemically active NMDA receptor glycine site antagonist and a moderate potency AMPA receptor antagonist. Separate studies indicate that ACEA-1416 is efficacious as a neuroprotectant in a rat model of focal cerebral ischemia. Taken together, our results suggest that ACEA-1416 has potential for clinical development as a neuroprotectant.
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PMID:Pharmacology of ACEA-1416: a potent systemically active NMDA receptor glycine site antagonist. 888 5

Major interest is currently focused on the development and evaluation of effective strategies for the pharmacological therapy of human stroke and cerebral ischemia, as well as some neurodegenerative disorders in which increased production of free oxygen radicals and the neurotoxic effect of excitatory amino acids may take place. Selected N-methyl-D-aspartate (NMDA) antagonists and antioxidants in the model of experimental oxidative stress induced by hypoxia and reoxygenation in rat hippocampal slices were tested. The putative antiglutamatergic effect of the antioxidant stobadine and its neuroprotective effect during oxidative stress was studied. NMDA antaonists 2-amino-5-phosphonovaleric acid (APV) and Mg2+, as well as the antioxidants stobadine and trolox, prevented the decrease of NMDA binding site number induced by hypoxia/reoxygenation in rat hippocampal slices. Moreover, stobadine, APV and Mg2+ prevented the decrease of NMDA binding site number due to glutamic acid incubation. Stobadine does not inhibit [3H]-glutamate binding and therefore does not seem to interact directly with glutamate binding sites. Thus, its neuroprotective effect in rat hippocampus exposed to hypoxia/reoxygenation does not seem to be based on a direct antiglutamatergic effect. The protective action of stobadine against the decrease of NMDA binding site number elicited by hypoxia/reoxygenation in rat hippocampus could rather be due to its antioxidant and antiradical effect.
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PMID:Effect of antioxidants and NMDA antagonists on the density of NMDA binding sites in rat hippocampal slices exposed to hypoxia/reoxygenation. 1269 Jul 2

Ischemic stroke is known to cause the accumulation of misfolded proteins and loss of calcium homeostasis leading to impairment of endoplasmic reticulum (ER) function. The unfolded protein response (UPR) is an ER-located and cytoprotective pathway that aims to resolve ER stress. Transmembrane BAX inhibitor-1 motif-containing (TMBIM) protein family member TMBIM3/GRINA is highly expressed in the brain and mostly located at the ER membrane suppressing ER calcium release by inositol-1,4,5-trisphosphate receptors. GRINA confers neuroprotection and is regulated by erythropoietin (EPO) after murine cerebral ischemia. However, the role of GRINA and the impact of EPO treatment on the post-ischemic UPR have not been elucidated yet. We subjected GRINA-deficient (Grina-/-) and wildtype mice to transient (30 min) middle cerebral artery occlusion (tMCAo) followed by 6 h or 72 h of reperfusion. We administered EPO or saline 0, 24 and 48 h after tMCAo/sham surgery. Oxygen-glucose deprivation (OGD) and pharmacological stimulation of the UPR using Tunicamycin and Thapsigargin were carried out in primary murine cortical mixed cell cultures. Treatment with the PERK-inhibitor GSK-2606414, IRE1a-RNase-inhibitor STF-083010 and EPO was performed 1 h prior to either 1 h, 2 h or 3 h of OGD. We found earlier and larger infarct demarcations in Grina-/- mice compared to wildtype mice, which was accompanied by a worse neurological outcome and an abolishment of EPO-mediated neuroprotection after ischemic stroke. In addition, GRINA-deficiency increased apoptosis and the activation of the corresponding PERK arm of the UPR after stroke. EPO enhanced the post-ischemic activation of pro-survival IRE1a and counteracted the pro-apoptotic PERK branch of the UPR. Both EPO and the PERK-inhibitor GSK-2606414 reduced cell death and regulated Grina mRNA levels after OGD. In conclusion, GRINA plays a crucial role in post-ischemic UPR and the use of both GSK-2606414 and EPO might lead to neuroprotection.
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PMID:EPO and TMBIM3/GRINA Promote the Activation of the Adaptive Arm and Counteract the Terminal Arm of the Unfolded Protein Response after Murine Transient Cerebral Ischemia. 3168 19