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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Severe forebrain ischemia induces a large increase in expression of NMDA receptor subunits in rat brain. One week after ischemia, levels of NMDA-R1 mRNAs in the CA1 pyramidal cells of hippocampus are 7 times higher than those observed in control rats. At 7 days postischemia, an enhanced immunostaining of the NMDA-R1 subunit was observed in all hippocampal structures indicating that changes in mRNA levels are accompanied by changes in receptor protein level. Riluzole, a potent inhibitor of glutamate release and CNQX, a selective AMPA/kainate antagonist, drastically reduced the ischemia-induced expression of mRNAs for the three NMDA receptor subunits while D-AP5, a selective NMDA antagonist, had essentially no effect. Therefore ischemia-induced expression of NMDA receptor subunits is associated with glutamate release and proceeds via an AMPA/kainate pathway. These results together with those of other groups concerning ischemia effects on AMPA and GABAA receptor levels, suggest an important role of the induced expression of NMDA receptor subunits in the deleterious effects of ischemia.
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PMID:Glutamate-induced overexpression of NMDA receptor messenger RNAs and protein triggered by activation of AMPA/kainate receptors in rat hippocampus following forebrain ischemia. 782 Jun 82

Excitatory amino acids may cause neuronal damage and death in cerebral hypoxia and ischemia, through the activation of different subtypes of glutamate receptors, in particular of the N-methyl-D-aspartate (NMDA) receptor. In the present work, the effect of hypoxia on the component of the field excitatory postsynaptic potential (fepsp) mediated by the NMDA receptor was studied in the hippocampal CA1 area of the rat. A period of 15 min of hypoxia induced virtual abolition of the NMDA receptor-mediated fepsp and a 94.8 +/- 0.7% maximal decrease in the fepsp. A period of 3 min of hypoxia induced a 89.3 +/- 12.3% maximal decrease in the NMDA receptor-mediated component of the fepsp and only a 50.8 +/- 11.5% maximal decrease in the fepsp. Both periods of hypoxia thus induced a more pronounced depression of the NMDA receptor-mediated component of the fepsp than of the fepsp. We found that 48.5 +/- 9.1% decrease (about half of the total decrease) in the NMDA receptor-mediated fepsp, and 51.6 +/- 19.6% decrease (approximately all decrease) in the fepsp induced by hypoxia (3 min) were reversed in the presence of the selective adenosine A1 receptor antagonist, 1,3-dipropyl-8- cyclopentylxanthine (DPCPX) (50 nM), and thus likely to be mediated by endogenous adenosine, through the activation of adenosine A1 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:1,3-Dipropyl-8-cyclopentylxanthine attenuates the NMDA response to hypoxia in the rat hippocampus. 783 77

6,11-Ethano-12,12-diaryl-6,11-dihydrobenzo[b]quinolizinium cations 8, a novel class of N-methyl-D-aspartate (NMDA) antagonists acting at the phencyclidine site, have been identified. Structure-activity relationship studies around the lead compound 8a led to the identification of 12g (WIN 67870-2), one of the most potent compounds in this series. Compound 12g has a Ki = 1.8 +/- 0.2 nM vs [3H]TCP binding, has 700-fold selectivity for binding to the open state of the NMDA receptor-ionophore, and was devoid of MK-801- and PCP-like behavioral effects in rats. Compound 12g was neuroprotective in cultured mouse cortical neurons and exhibited antiischemic activity in a rat middle cerebral artery occlusion/reperfusion model of focal ischemia.
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PMID:Discovery of 6,11-ethano-12,12-diaryl-6,11-dihydrobenzo[b]quinolizinium cations, a novel class of N-methyl-D-aspartate antagonists. 783 34

Glutamate (Glu), the major excitatory neurotransmitter in the nervous system, is toxic to neurons when it accumulates at high concentrations in the extracellular space. Even though Glu is a mixed agonist, capable of activating N-methyl-D-aspartate (NMDA) receptors and non-NMDA receptors, in many preparations Glu neurotoxicity is prevented by selective blockade of NMDA receptors. In cultures of hippocampal neurons, treatment with 500 microM Glu for 30 min killed more than 90% of the neurons. The simultaneous addition of the selective NMDA agonist methyl-10,11-dihydro-5-H-dibenzocyclo-hepten-5,10-imine (MK-801) reduced the cell loss to less than 30%. However, when Glu was combined with either diazoxide or cyclothiazide, two thiazides which dramatically diminish rapid Glu desensitization, MK-801 was no longer very protective and neuronal loss exceeded 80%. However, the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), in combination with MK-801, was able to prevent most Glu neurotoxicity in the presence of these thiazides. These experiments show that there are circumstances under which Glu neurotoxicity is produced by overactivation of non-NMDA receptors. Our observations offer a possible explanation for the recent finding that blockade of non-NMDA receptors is much more beneficial than NMDA receptor blockade in protecting the brain in some in vivo models of global ischemia.
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PMID:Rapid desensitization determines the pharmacology of glutamate neurotoxicity. 784 51

In a model of perinatal hypoxic-ischemic brain damage, we examined the neuroprotective efficacy of posttreatment with the NMDA receptor antagonist MK-801 and the AMPA receptor antagonist NBQX. Unilateral brain damage developed in 95% of rat pups subjected to hypoxia-ischemia with a 27.8 +/- 1.2% weight deficit of the damaged hemisphere. MK-801 in doses of 0.3 and 0.5 mg/kg i.p. reduced the brain damage by 61% (p < 0.001) and 43% (p < 0.001), respectively. A higher dose of MK-801 (0.75 mg/kg) did not offer neuroprotection. Treatment with NBQX (40 mg/kg) reduced the hemispheric lesion by 28% (p < 0.05). In conclusion, posttreatment with both NBQX and low doses of MK-801 reduced perinatal brain damage. The NMDA receptor antagonist offered stronger neuroprotection which is in agreement with a proposed NMDA receptor hyperactivity around postnatal day 7 in rats.
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PMID:Hypoxia-ischemia in the neonatal rat brain: histopathology after post-treatment with NMDA and non-NMDA receptor antagonists. 786 35

The local redox milieu of a biological system is of critical importance in understanding the actions of the nitrogen monoxide (NO) moiety, as disparate chemical pathways involving distinct redox-related congeners of NO may trigger neurotoxic or neuroprotective pathways. The reactions of nitric oxide (NO.) with superoxide can lead to neurotoxicity through formation of peroxynitrite, whereas NO. alone does not, at least under certain conditions. Reaction (or transfer) of NO+ equivalents to thiol(s) on the NMDA receptor can lead to neuroprotection by inhibiting Ca2+ influx. These findings suggest that cell function can be controlled by, or through, protein S-nitrosylation, and raise the possibility that the NO group may initiate signal transduction in or at the plasma membrane. Neuroprotective effects of NO- suggest that acceleration of disulfide bond formation at the NMDA receptor is of mechanistic importance in the attenuation of Ca2+ influx. Our findings suggest novel therapeutic strategies. For example, downregulation of NMDA receptor activity can be obtained via sulfhydryl oxidation by S-nitros(yl)ation with NO+ donors (to form an RSNO at a cysteine residue on the receptor), or with NO- donors (with intermediate formation of RSNHOH). Pharmacologic intervention with these forms of NO donors could be implemented in the treatment of focal ischemia, neuropathic pain, Huntington's disease, AIDS dementia, and other neurological disorders associated, at least in part, with excessive activation of NMDA receptors.
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PMID:Actions of redox-related congeners of nitric oxide at the NMDA receptor. 787 Feb 83

The pharmacological inhibition of excitatory amino acid neurotransmission has evolved to be a major topic in neuropharmacology since enhanced synaptic action of glutamate and possibly other related neurotransmitters has been suggested to play a role both in acute neurological conditions such as ischemia and epilepsy and in chronic degenerative neurological diseases including Parkinson's disease, Huntington's disease and Alzheimer's disease. While antagonists at N-methyl-D-aspartate (NMDA) type glutamate receptors include psychotomimetic and neurotoxic agents such as phencyclidine and MK-801, the aminoadamantanes represent a class of drugs which may be largely free of such actions and which have already been used clinically as antiviral and antiparkinsonian agents. Multiple in vitro studies have recently delineated the neuroprotective properties of amantadine, and of its more potent congener, memantine, which appear to mediate neuroprotection via inhibition of NMDA receptor-dependent glutamate activity. Thus, neuroprotection targeting glutamate receptors does apparently not have to be associated with prominent psychotogenicity, and the development and evaluation of new neuroprotective drugs will have to performed in consideration both of the relative safety and of the good clinical effect of the already known and established aminoadamantanes.
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PMID:Amantadine and memantine are NMDA receptor antagonists with neuroprotective properties. 788 11

1. The reactions of nitric oxide with superoxide can lead to neurotoxicity through formation of peroxynitrite, and not by NO. alone, at least under our conditions. 2. Transfer of NO+ groups to thiol(s) on the NMDA receptor can lead to neuroprotection by inhibiting Ca2+ influx. These findings suggest that cell function can be controlled by, or through, protein S-nitrosylation, and raise the possibility that the NO group may initiate signal transduction in or at the plasma membrane. 3. The local redox milieu of a biological system is of critical importance in understanding NO actions as disparate chemical pathways involving distinct redox related congeners of NO may trigger neurotoxic or neuroprotective pathways. These claims are highlighted in the CNS by the recent finding that tissue concentrations of cysteine approach 700 microM in settings of cerebral ischemia (Slivka and Cohen, 1993); these levels of thiol would be expected to influence the redox state of the NO group. 4. Finally, our findings suggest novel therapeutic strategies. For example, downregulation of NMDA receptor activity via S-nitrosylation with NO+ donors could be implemented in the treatment of focal ischemia, AIDS dementia, and other neurological disorders associated, at least in part, with excessive activation of NMDA receptors.
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PMID:Nitric oxide in the central nervous system. 788 18

The physiological regulation of the intracellular Ca2+ homeostasis and its pathological alteration has been studied in rat and gerbil hippocampal slices using ion-sensitive electrodes and the fluorescence imaging technique. The ischemia-induced intracellular Ca2+ rise, accentuated in the synaptic/dendritic layer of the vulnerable CA1 neurons was observed in vivo and could be replicated at an accelerated time course in the "ischemic" hippocampal slice superfused with unoxygenated, glucose-free medium. The intracellular Ca2+ loading, thought to be instrumental for the generation of postischemic nerve cell damage, seems to result from an increased Ca2+ release out of intracellular stores as well as from an enhanced synaptic Ca2+ influx. The latter is attributed to a depolarization-induced opening of the voltage-dependent Ca2+ channels and to an uncontrolled influx through "upregulated" NMDA receptor-operated channels. Such an ischemia-induced upregulation which is reported to occur physiologically by the activation of PKC, is reflected by the selective loss of the depressive control of the synaptic NMDA Ca2+ influx by adenosine. Ischemia also leads to a hypertrophy of astrocytes which may go along with an impairment of their physiological function to take up glutamate adding to the extracellular rise of the excitotoxic amino acids. A pathological activation of microglial cells and their transformation into macrophages, known to release oxygen radicals, may further add to neuronal damage. The observed neuroprotection by adenosine can be primarily ascribed to its limiting effect on a pathological membrane depolarization and its deleterious consequences. The more powerful neuroprotection by propentofylline, thought to act analogue to adenosine, seems to be achieved by additional mechanisms. This pharmacon depresses the ischemia-induced neuronal Ca2+ loading in vivo and in vitro, prevents the activation of astrocytes and interferes with the transformation as well as with the free radical formation of microglia-derived macrophages as demonstrated in complementary studies with fluorescence techniques on cell cultures.
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PMID:The use of ion-sensitive electrodes and fluorescence imaging in hippocampal slices for studying pathological changes of intracellular Ca2+ regulation. 789 1

Dynorphin A reduced lumbosacral blood flow, elevated cerebrospinal fluid lactic acid concentrations and caused flaccid hindlimb paralysis and striking neuropathological changes after its injection into the spinal subarachnoid space in rats. Coadministration of the vasodilator hydralazine substantially eliminated the paralytic, anaerobic metabolic and neuropathological responses to dynorphin A. In contrast, in concentrations up to 1 mM, dynorphin A did not alter the viability of cultured rat spinal cord neurons. Thus, it appears that this peptide lacks direct neurotoxic effects and that neuronal injuries in vivo result primarily from ischemia associated with dynorphin A-induced blood flow reductions. NMDA receptor antagonists significantly improved recovery from dynorphin A-induced hindlimb paralysis, and substantially eliminated neuropathological changes without attenuating the acute blood flow reductions or lactic acid elevations. Additionally, glutamate and aspartate concentrations were increased significantly in spinal cord cerebrospinal fluid samples removed during the time that peptide-induced spinal cord blood flow reductions were observed. In contrast, neither amino acid concentration was elevated in media removed after 1-hr exposure of spinal cord neuronal cell cultures to 100 microM concentrations of dynorphin A. These results indicate that the paralysis and spinal cord injuries produced in rats after spinal subarachnoid injection of dynorphin A result predominantly from spinal cord ischemia, and further identify excitatory amino acids and N-methyl-D-aspartate receptor mechanisms as important mediators in this injury model.
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PMID:Dynorphin A-induced rat spinal cord injury: evidence for excitatory amino acid involvement in a pharmacological model of ischemic spinal cord injury. 790 61


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