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

In culture the protracted and abusive stimulation of glutamate (GLU) receptors results in neuronal death through a mechanism involving the persistent translocation of PKC and the destabilization of (Ca2+)i homeostasis [(Ca2+)i HD]. In contrast, intermittent GLU receptor use elicits a coordinated expression of immediate early genes (IEG) acting as nuclear third messenger. Brain ischemia also is known to result in the paroxysmal abusive stimulation of glutamate receptors. The glutamate receptive elements in turn degenerate largely as a function of their inability to control homeostatic Ca2+ due to the irreversible translocation of PKC. In the present study we employed an in vivo model of focal brain ischemia using the photosensitive dye, Rose bengal. With this model we sought to determine the neuroprotective actions of MK-801, a noncompetitive blocker of GLU at the NMDA-sensitive receptor and of the semisynthetic gangliosides LIGA 4 and LIGA 20 which in vitro have been demonstrated to block PKC translocation. Moreover, we sought to establish whether the persistent stimulation of ionotropic glutamate receptors would led to a change in ionotropic glutamate expression in the focal and perifocal area. Importantly, the perifocal area (i. e., the region surrounding the area of primary insult) is a region in which profound cellular reorganization occurs including neuronal death and glial proliferation and is a key region to target various neuroprotective drugs aimed at ameliorating the neurodegeneration following stroke. Receptor abuse dependent antagonists (RADA) drugs such as gangliosides selectively curtail the amplification steps that specifically differentiate signal transduction following physiological receptor use from that following pathological receptor abuse.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Sequelae of biochemical events following photochemical injury of rat sensory-motor cortex: mechanism of ganglioside protection. 130 98

Glutamatergic transmission is an important factor in the development of neuronal death following transient cerebral ischemia. In this investigation the effects of N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists on neuronal damage were studied in rats exposed to 10 min of transient cerebral ischemia induced by bilateral common carotid occlusion combined with hypotension. The animals were treated with a blocker of the ionotropic quisqualate or alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptor, 2.3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX), given postischemia as an intraperitoneal bolus dose of 30 mg kg-1 followed by an intravenous infusion of 75 micrograms min-1 for 6 h, or with the noncompetitive NMDA receptor blocker dizocilpine (MK-801) given 1 mg kg-1 i.p. at recirculation and 3 h postischemia, or with the competitive NMDA receptor antagonist DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 40116), 5 mg kg-1, given intraperitoneally at recirculation. Treatment with NBQX provided a significant reduction of neuronal damage in the hippocampal CA1 area by 44-69%, with the largest relative decrease in the temporal part of the hippocampus. In neocortex a significant decrease in the number of necrotic neurons was also noted. No protection could be seen following postischemic treatment with dizocilpine or CGP 40116. Our data demonstrate that AMPA but not NMDA receptor antagonists decrease neuronal damage following transient severe cerebral ischemia in the rat and that the protection by NBQX may be dependent on the severity of the ischemic insult. We propose that the AMPA receptor-mediated neurotoxicity could be due to ischemia-induced changes in the control mechanisms of AMPA receptor-coupled processes or to changes of AMPA receptor characteristics.
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PMID:Postischemic blockade of AMPA but not NMDA receptors mitigates neuronal damage in the rat brain following transient severe cerebral ischemia. 134 57

In order to characterize the regional and cellular distribution patterns of individual ionotropic excitatory amino acid receptor subunits in the human hippocampus we performed an immunohistochemical analysis using the monoclonal antibody 3A11 to the AMPA GluR2(4) subunit. The study was based on paraffin embedded hippocampal specimens of five human brains obtained at autopsy. GluR2(4) immunoreactivity was consistently higher in hippocampus as compared to the adjacent areas of the mesial temporal lobe. Virtually all neurons showed intracytoplasmic staining of the perikarya and dendritic profiles with well defined laminar patterns. The most intense GluR2(4) immunoreactivity was observed in the target structures of mossy fibers, thus indicating that GluR2(4) AMPA subunits may be involved in NMDA-independent synaptic transmission pathways and long-term potentiation. Glial cells were not immunoreactive. These findings may provide basic information for studies of the GluR2(4) subunit in human hippocampus during various neuropathological conditions, such as temporal lobe epilepsy, ischemia and Alzheimer's disease.
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PMID:Regional distribution of the AMPA glutamate receptor subunits GluR2(4) in human hippocampus. 755 21

The effects of intravitreal injections of excitatory amino acid receptor antagonists have been studied on the ischemic neuronal damage induced by photochemical occlusion of the retinal vessels. Rats were systemically injected with rose bengal fluorescein dye and one of their eyes was exposed to bright light. The activities of the enzymes, choline-acetyltransferase and glutamate decarboxylase, were measured as an index of neuronal loss in the lesioned tissue. Lesioned retinas had a 75 +/- 5% reduction in choline-acetyltransferase activity and a 72 +/- 8% reduction in glutamate-decarboxylase activity, suggesting that the lesion causes a massive loss of retinal neurons, which use acetylcholine or gamma-aminobutyric acid (GABA) as neurotransmitter. A single intravitreal injection of excitatory amino acid receptor antagonists, performed immediately after the lesion, significantly reduced this loss. Both alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate) (NMDA) types of ionotropic glutamate receptor antagonists were active in a dose-dependent manner. Almost complete protection was also obtained with relatively large doses of thiokynurenic acid (400 nmol), a non-selective antagonist of both AMPA and NMDA glutamate receptors, while 7-Cl-thiokynurenic acid, a potent and selective glycine receptor antagonist, was not active up to 200 nmol. These results strongly suggest that excitotoxic mechanisms are involved in ischemia-induced neuronal death in the retina and that appropriate treatments with antagonists of both AMPA and NMDA receptor types may significantly reduce this damage.
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PMID:Glutamate receptor antagonists protect against ischemia-induced retinal damage. 770 49

Vasoactive intestinal peptide (VIP) has been shown to exert vasodilatory action and positive ionotropic effect on the heart and to possess free radical-scavenging ability. Because these properties are likely to make this peptide a suitable agent for myocardial preservation, we examined the role of VIP in myocardial ischemia and reperfusion. Isolated rat heart perfused by the Langendorff technique was subjected to 30 min of normothermic ischemia followed by 60 min of reperfusion. A significant amount of VIP was found to be released from the ischemic reperfused heart. The amount of VIP released from the heart increased progressively with the duration of reperfusion and paralleled the release of creative kinase from the heart. In another set of experiments, hearts were divided into two groups. The experimental group received three different doses of VIP (0.1 microM, 0.3 microM and 1 microM) before ischemia. After perfusing the isolated heart with VIP for 15 min, ischemia was induced for 30 min by terminating the coronary flow, which was followed by 60 min of reperfusion. The results of our study indicated a significant improvement of myocardial functions by VIP (0.3 and 1 microM), as evidenced by enhanced left ventricular functions and coronary flow, and reduction of tissue injury, as judged by the decrease in creatine kinase release (0.3 microM only). Intracellular Ca++ ([Ca++]i) transients increased during ischemia and further increased during reperfusion. The increase in [Ca++]i transients was significantly reduced in the VIP-treated hearts. A significant amount of hydroxyl radical was detected in the ischemic reperfused heart, but the quantity of the hydroxyl radical was much lower in the VIP-treated group.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protective role of intracoronary vasoactive intestinal peptide in ischemic and reperfused myocardium. 811 10

Glutamate antagonists protect neurons from hypoxic injury both in vivo and in vitro, but in vitro studies have not been done under the acidic conditions typical of hypoxia-ischemia in vivo. Consistent with glutamate receptor antagonism, extracellular acidity reduced neuronal death in murine cortical cultures that were deprived of oxygen and glucose. Under these acid conditions, N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate-kainate antagonists further reduced neuronal death, such that some neurons tolerated prolonged oxygen and glucose deprivation almost as well as did astrocytes. Neuroprotection induced by this combination exceeded that induced by glutamate antagonists alone, suggesting that extracellular acidity has beneficial effects beyond the attenuation of ionotropic glutamate receptor activation.
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PMID:Neuroprotective effects of glutamate antagonists and extracellular acidity. 838 56

Excitatory amino acids (EAA) became known as neurotransmitters of the central nervous system (CNS) in the last decade. The most studied EAA are glutamate and aspartate. Both are synthetized by the same mechanism as gamaaminobutyric acid. (Fig. 1). Glutamate is widely distributed in the CNS and the spinal cord, being the areas of higher concentration the cerebral cortex, the hypocampus and the cerebellum. There have been identified two type of receptors for glutamate: ionotropic and metabotropic. The former includes three different types: NMDA, AMPA and KA. NMDA receptor is coupled to a Na+ and Ca2+ channel being the second ion the most important one. This receptor has several sites of binding for various substances. Along with the site for N-methyl-D-aspartate, which binds glutamate and/or aspartate, there have been identified a site for the binding of glycine (which is different from the strychnine sensitive one), a site for poliamines such as spermine and spermidine, and a site for the binding of Zn2+ (Table 1). AMPA receptor is associated to a Ca(2+)-Na+ channel, being in this case the Na+ the most important ion. There are two metabotropic type receptors: L-AP4 and trans-ACPD. Both are coupled to a G protein and agonists exert their action increasing phospholipase C activity which in turn induces an increment of IP3 and diacyl-glicerol, and a consecutive releasing of Ca2+ from intracellular stores. EAA play a role in some physiological processes. One of them is long-term potentiation (LTP), an electrochemical phenomenon involved in memory consolidation. Antagonists of NMDA and AMPA receptor prevent the development of LTP, and conversely, the agonist of glycine site of NMDA receptor--D-cycloserine--facilitates memory consolidation. Since 1957, EAA are considered neurotoxic substances and there are many indirect evidences to support this statement. Pathogenesis of neuronal damage elicited by EAA involves the events shown in Fig. 3. Prevention of the cascade of events that provokes neurotoxicity may be achieved by NMDA antagonists, but once it has begun it may be only aborted subtracting the Ca2+ from the medium, using nifedipine or blocking AMPA receptor with an antagonist (CNQX). EAA have been shown to play a toxic role in neuronal damage induced by ischemia. Research using various experimental models demonstrated that NMDA receptor antagonists (i.e. MK 801) blocks postischemic damage. Interventions at various levels of the pathogenic cascade shown in Fig. 4 provoke the same results. There is enough evidence to suspect that NMDA and AMPA receptors are altered in epilepsy. NMDA antagonists (i.e. MK801 or AP5) prevent the development of epileptic seizures induced by kindling; CNQX, an AMPA antagonist, blocks the increase in electrical activity induced by K+ in slices of hypocampus; felbamate, an antiepileptic drug, blocks the glycine site (not strychnine sensitive) decreasing NMDA receptor activity. Several neurodegenerative disorders have been associated with exogenous administration or accidental intake of EAA. (i.e. neurolatirism, Guam disease). Similarities between these diseases and lateral aminotrophic sclerosis indicate that in the latter EAA may play a pathogenic role. Finally, the psychotomimetic effect of phencyclidine (an antagonist of NMDA receptor) suggests that in schizophrenia, together with dopaminergic neurotransmission impairment, some dysfunction of glutamate pathways may be present.
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PMID:[Role of excitatory amino acids in neuropathology]. 872 78

The glutamate excitotoxicity hypothesis of ischemic cell damage holds that cell damage caused by transient cerebral ischemia is triggered by glutamate, released during ischemia from the intracellular compartment into the synaptic cleft: high extracellular glutamate levels activate ionotropic glutamate receptors, thus inducing an overflow of calcium ions into the neurones and a calcium-induced activation of catabolic processes. However, several arguments (and much of the evidence) in favour of this hypothesis do not bear closer examination. On the other hand, evidence is accumulating that, after transient ischemia, calcium fluxes through ionotropic glutamate receptors of the non-NMDA type may play a major role in the manifestation of ischemic cell damage. Calcium fluxes through non-NMDA receptors are determined by mRNA editing of non-NMDA receptor subunits: calcium fluxes are blocked in the presence of an edited subunit. A possible role of mRNA editing in the development of ischemic cell damage is discussed.
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PMID:Glutamate excitotoxicity in transient global cerebral ischemia. 878 92

Effects of intrauterine hypoxia-ischemia (HI) on receptor-stimulated phosphoinositide (PPI) hydrolysis were studied in rat cerebellar granule cell cultures prepared from an in utero HI model. On gestation day 17, HI conditions were achieved by complete clamping of the uterine vasculature for 30 min followed by removal of the clamps to permit reperfusion. Sham operation (SH, surgery without vasculature ligation) was performed as the control. Intrauterine HI did not affect the basal level of PPI hydrolysis (in the absence of stimulants) in cells prepared from either the SH or the HI group. PPI hydrolysis stimulated by quisqualate (QA) or trans-(1S,3R)-1-amino-1,3-cyclo-pentanedicarboxylic acid (trans-ACPD) was significantly reduced in cells prepared from the HI group, whereas intrauterine HI did not affect the PPI hydrolysis induced by ionotropic glutamate receptor agonists or by norepinephrine or serotonin. At a dose range of 100-300 microM, QA-stimulated PPI hydrolysis in cells prepared from the SH group increased by 3-to 4.5-fold, while this increase was only 2- to 2.5-fold in cells prepared from the HI group. Presence of L-NG-monomethyl-arginine (L-NMMA), a nitric oxide (NO) synthase inhibitor, did not increase QA-stimulated PPI hydrolysis in cells prepared from either the SH or the HI group, indicating that stimulation of NO formation is unlikely involved in the suppressive effects of intrauterine HI on QA-induced PPI hydrolysis. The QA-stimulated PPI hydrolysis in cells prepared from the HI group, but not from the SH group, was further inhibited by L-(+)-2-amino-3-phosphono-propionic acid (L-AP3). The overall results suggest that intrauterine HI has long-lasting suppressive effects on metabotropic glutamate receptor agonist-stimulated PPI hydrolysis and these effects might be associated with alterations in expression of metabotropic glutamate receptor subtypes.
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PMID:Intrauterine hypoxia-ischemia reduces phosphoinositide hydrolysis stimulated by metabotropic glutamate receptor agonists in cultured rat cerebellar granule cells. 880 99

1. Brain ischemia causes excess release and accumulation of glutamate that binds to postsynaptic receptors. This opens ionotropic channels that mediate neuronal depolarization and ionic fluxes that can lead to neuronal death. 2. The CA1 pyramidal cell region of the hippocampus is particularly susceptible to this neurotoxic process. Brain cell swelling is considered an early excitotoxic event, but remains poorly under stood and documented. As cells swell, light transmittance (LT) increases through brain tissue, so we hypothesized that brief exposure to glutamate agonists would elicit cell swelling that could be imaged in real time in the hippocampal slice. 3. A 1-min bath application of 100 microM N-methyl-D-aspartate (NMDA) or 100 microM kainate at 22 degrees C greatly increased LT, particularly in the dendritic regions of CA1. The response peaked by 2-3 min and slowly reversed over the subsequent 20 min following exposure. Peak LT increases were > 50% in CA1 stratum radiatum and > 20% in both CA1 stratum oriens and the dendritic region of the dentate gyrus, all areas with a high concentration of NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors. The CA3 stratum radiatum, which contains fewer of these receptors, showed a comparatively small LT increase. 4. The NMDA receptor antagonist 2-amino-5-phosphonovalerate (AP-5) [but not 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)] blocked the CA1 response to NMDA, whereas the non-NMDA receptor antagonist CNQX (but not AP-5) blocked the response to kainate. The relative tissue resistance measured across CA1 stratum radiatum increased after NMDA or kainate exposure with a time course similar to the LT change described above. The increase in relative tissue resistance was blocked by kynurenate, a nonspecific glutamate antagonist. Increases in both LT and tissue resistance provide two independent lines of evidence that cell swelling rapidly developed in CA1 dendritic areas after activation of NMDA or AMPA receptors. 5. This swelling at 22 degrees C was accompanied by a temporary loss of the evoked CA1 field potential. However, at 37 degrees C the dendritic swelling rapidly progressed to an irreversible LT increase (swelling) of the CA1 cell bodies accompanied by a permanent loss of the evoked field. 6. We propose that dendritic swelling mediated by NMDA and AMPA receptors is an early excitotoxic event that can herald permanent damage to CA1 neurons, those cells most vulnerable to ischemic insult.
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PMID:Imaging NMDA- and kainate-induced intrinsic optical signals from the hippocampal slice. 889 40


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