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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute excitotoxicity in the chick retina is characterized by cellular swelling and the subsequent selective release of GABA. In order to understand the source of GABA release, embryonic day 15 retina were incubated with 1 mM glutamate for 30 min in the presence or absence of the GABA transport inhibitor SKF 89976A (1-100 microM). SKF 89976A dose-dependently attentuated glutamate-induced GABA release (IC50, 39 microM). Histological examination of retina showed that SKF 89976A greatly reduced cellular swelling caused by glutamate exposure. Interaction of SKF 89976A with glutamate receptors was ruled out as a possible reason for protection vs acute glutamate excitotoxicity, since SKF 89976A had no effect on glutamate receptor-induced 22Na+ influx. In contrast, the NMDA antagonist, MK-801, significantly blocked glutamate-evoked 22NA+ uptake. These studies indicate that reversal of the GABA transporter contributes to the bulk of GABA release during acute excitotoxicity in retina. Further, a net effect of the presence of SKF 89976A during glutamate exposure is reduction in cellular swelling. It is not clear at present if attenuation of swelling is mediated specifically by an interaction with the GABA transporter or by a nonspecific or indirect effect of SKF 89976A.
Mol Chem Neuropathol 1996 Sep
PMID:Attenuation of excitotoxic cell swelling and GABA release by the GABA transport inhibitor SKF 89976A. 888 38

We employed a canine model to test the effects of global cerebral ischemia and reperfusion on binding to alpha-amino-3-hydroxy-5-methyl- 4-isoxazole proprionate (AMPA), kainate (KA), and metabotropic glutamate receptors. Ischemia was induced by 10 min of cardiac arrest, followed by restoration of spontaneous circulation for periods of 0, 0.5, 2, 4, and 24 h. Frozen sections were prepared from parietal and temporal cortex, hippocampus, and striatum, and in vitro autoradiography was performed with one of three radioligands: [3H]AMPA, [3H]KA, or [3H] glutamate (using conditions allowing specific labeling of the metabotropic binding site). In striatum, metabotropic binding was unchanged, whereas AMPA and KA binding decreased by 20-30% at 30 min postischemia, remaining depressed through 24 h. In cortex, AMPA and metabotropic binding were decreased at several time-points after ischemia and recirculation, particularly in parietal cortex, whereas KA binding was unaffected in this tissue. Binding to hippocampal regions was largely unchanged, except for a decrease in KA binding at 2 and 4 h postischemia. These findings contrast with results from parallel studies showing increased striatal binding to NMDA receptors following ischemia. Decreased binding to non-NMDA glutamate receptors in striatum and parietal cortex may serve to protect against damage mediated through these receptors.
Mol Chem Neuropathol 1996 Sep
PMID:Non-NMDA glutamate receptor binding in canine brain after global cerebral ischemia and reperfusion. 888 39

The activation of the glutamatergic NMDA receptor has no effect on arachidonic acid release from cortical synaptoneurosomal lipids prelabeled with [1-14C]arachidonic acid ([14C]AA). However, activation of NMDA receptor leads to the reduction of AA incorporation into rat brain cortex synaptoneurosomal membrane phosphatidylinositol (PI). The competitive NMDA receptor antagonist, 2-amino-5-phosphovaleric acid (APV), completely eliminates the effect of NMDA on this process. More precise analysis of the sequence of events leading to NMDA-induced decrease of AA incorporation indicates that this process is significantly blocked by voltage-gated sodium and calcium channels inhibitors, such as tetrodotoxin (TTX) and omega-conotoxin (CTX), respectively. Then the antagonist of inositol trisphosphate receptor, TMB-8, totally abolishes the effect of NMDA on AA incorporation into PI. The lowering of AA incorporation evoked by NMDA is significantly diminished by nitric oxide (NO) synthase inhibitor, NG-nitro-L- arginine (NNLA). Further studies were carried out with NO donor(s) to explain the mechanism of NO action in the inhibition of AA incorporation into PI. Our results suggest the following sequence of events: opening of voltage-dependent sodium and calcium channels, subsequent activation of PI-4,5-bisphosphate-specific phospholipase C (PLC), elevation of inositol trisphosphate (IP3)-sensitive calcium ions, stimulation of NO production and NO-mediated S-nitrosylation, or free radical effect on enzymes involved in AA incorporation. Our data suggest that NO-mediated events may be responsible for NMDA-evoked inhibition of AA incorporation into PI of synaptoneurosomal membrane.
Mol Chem Neuropathol 1996 Sep
PMID:Nitric oxide responsible for NMDA receptor-evoked inhibition of arachidonic acid incorporation into lipids of brain membrane. 888 42

NMDA receptors are composed of proteins from two families: NMDAR1, which are required for channel activity, and NMDAR2, which modulate properties of the channels. The mRNA encoding the NMDAR2D subunit has a highly restricted pattern of expression: in the forebrain, it is found in only a small subset of cortical, neostriatal and hippocampal neurons. We have used a quantitative double-label in situ hybridization method to examine the expression of NMDAR2D mRNA in neurochemically defined populations of neurons. In the neostriatum, NMDAR2D was expressed by the interneuron populations marked by preprosomatostatin (SOM), the 67-kDa form of glutamic acid decarboxylase (GAD67), parvalbumin (PARV), and choline acetyltransferase (ChAT) mRNAs but not by the projection neurons expressing beta-preprotachykinin (SP) or preproenkephalin (ENK) mRNAs. In the neocortex, NMDAR2D expression was observed in only a small number of neurons, but these included almost all of the SOM-, GAD67-, and PARV-expressing interneurons. In the hippocampus, NMDAR2D was not present in pyramidal or granule cells, but was abundant in SOM-, GAD67-, and PARV-positive interneurons. NMDAR2D expression appears to be a property shared by interneurons in several regions of the brain. The unique electrophysiological characteristics conveyed by this subunit, which include resistance to blockade by magnesium ion and long channel offset latencies, may be important for the integrative functions of these neurons. NMDAR2D-containing receptor complexes may prove to be important therapeutic targets in human disorders of movement. In addition, the presence of NMDAR2D subunits may contribute to the differential vulnerability of interneurons to excitotoxic injury.
Brain Res Mol Brain Res 1996 Nov
PMID:Expression of NMDAR2D glutamate receptor subunit mRNA in neurochemically identified interneurons in the rat neostriatum, neocortex and hippocampus. 891 84

Our previous work has shown that chronic ethanol treatment upregulated NMDA receptor function and binding in mammalian cortical neurons. However, the potential molecular mechanisms involved in these phenomenon have yet to be elucidated. In the present study, using RNase protection assay, we investigated the effect of chronic ethanol treatment on the NMDA receptor subunits R1, R2A, and R2B mRNA levels in cultured cortical neurons. We found that chronic ethanol (50 mM, 5 days) exposure did not change the NMDA receptor R1 and R2A subunits mRNA levels. In contrast, the NMDA receptor R2B subunit mRNA level was increased by approximately 40% with respect to the control values. The levels of the R2B subunit mRNA returned to the control values following the removal of ethanol for 72 h. In order to determine the involvement of the NMDA receptors in the action of chronic ethanol exposure, we further investigated the effect of the NMDA receptor antagonists on the upregulation induced by chronic ethanol exposure. The results indicate that the increased R2B subunit level was reversed by concomitant chronic exposure of the cortical neurons to the NMDA receptor competitive (10 microM; CPP), and non-competitive (1 microM; MK-801) antagonists, but not by the non-NMDA receptor antagonist, CNQX (10 microM), or the L-type calcium channel blocker, nitrendipine (10 microM). Taken together, these results suggested that chronic ethanol exposure selectively upregulated the NMDA receptor subunit R2B mRNA level in cortical neurons, and this increased NMDA receptor gene expression appears to be a NMDA receptor mediated process. The altered NMDA receptor gene expression may be responsible for the observed upregulation of the NMDA receptor binding and function in the cortical neurons following chronic ethanol exposure.
Brain Res Mol Brain Res 1996 Mar
PMID:Chronic ethanol treatment produces a selective upregulation of the NMDA receptor subunit gene expression in mammalian cultured cortical neurons. 896 41

The purpose of this study was to develop a primate model for assessing EEG, behavior and histology, and to test the effect of NMDA receptor blockade in transient focal ischemia. Squirrel monkeys (Saimiri sciureus) under halothane anesthesia were subjected to 110 min of transient focal ischemia (n = 15) by temporary clip occlusion of the MCA. An eight-lead EEG was recorded. Neurobehavioral testing was done in a subgroup of animals (n = 6). Brain temperature (37.5 degrees C) was monitored and controlled to avoid hypothermia or intergroup temperature differences, and blood pressure was regulated to 60 mmHg. The entire brain was subserially sectioned, and 52 standardized coronal sections encompassing the infarct were examined histologically 2 wk after the ischemia. Animals were randomized to receive either (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) 1 mg/kg of maleate salt or carrier solution, 20 min and again at 12 h after the onset of ischemia. Cingulate and retrosplenial cortex were examined for NMDA-antagonist-induced neuronal necrosis. No reduction, or trend toward reduction of neurobehavioral deficit was seen with MK-801. MCA occulsion reduced EEG power over the ischemic hemisphere. MK-801 appeared to cause brain activation, and globally increased power at several frequencies. MK-801 did not reduce infarction in either neocortex (p > 0.05) or striatum (p > 0.05). No selective neuronal necrosis was seen in the cingulate or retrosplenial cortex. We conclude that MK-801 given 20 min after the onset of transient ischemia offers no significant neuroprotective effect against either neurobehavioral deficit or ischemic infarction in this model of transient focal ischemia. Further experiments in unanesthetized animals are necessary to determine if MK-801-induced necrosis exists in the gyrencephalic brain, but the enhancement of primate brain electrical activity by MK-801 suggests that brain activation occurs in primates as it does in rodents.
Mol Chem Neuropathol
PMID:Postischemic therapy with MK-801 (dizocilpine) in a primate model of transient focal brain ischemia. 897 96

Nitric oxide (NO) exerts its vasodilatator effect in smooth muscle by activation of guanylyl cyclase. This in turn leads to decreases in intracellular calcium and dephosphorylation of myosin light chains and relaxation. NO is synthesised from L-arginine by a family of enzymes called Nitric oxide synthase (NOS). In the vascular system two isoenzymes of NOS are largely expressed: the constitutive NOS and the inducible NOS. The constitutive NOS identified in the endothelium generates NO continuously providing the vasodilatator tone and modulating platelet function. NOS type 1 is expressed in preoptic and infundibular nucleus of hypothalamus. NO acts as presynaptic agonist of glutamatergic NMDA-receptor mediation in the motor nucleus of nervus vagus. NO decreases the frequency of the spontaneous discharges in the carotid bodies. NO is involved in the processes of synaptic plasticity in the hippocampus.
Mol Med (Sofia) 1996
PMID:[The participation of nitric oxide in the functions of the central nervous system and the cardiovascular system]. 898 11

Synthesis of the neurotrophic factor brain-derived neurotrophic factor (BDNF) and its receptor TrkB in the hippocampus have been proposed to be influenced by endogenous glutamate. To test this hypothesis we have investigated if increases in BDNF and trkB mRNAs are associated with changes in the synaptic release of glutamate in the dorsal hippocampus in the conscious rat by combining the technique of in vivo microdialysis with in situ hybridization histochemistry. A 35% and 66% increase in extracellular levels of glutamate in the dorsal CA1 region was detected following injection into the lateral entorhinal cortex of 2.4 and 9.6 microg of the non-NMDA glutamate receptor agonist quisqualate, respectively. The increase in glutamate was attenuated by local administration of tetrodotoxin (TTX) indicating neuronal origin. Levels of BDNF and trkB mRNAs were increased in the hippocampus in a dose-dependent fashion following the stimulations. The extracellular levels of glutamate in individual animals correlated to the levels of BDNF and trkB mRNAs in the dorsal CA1 region of the hippocampus. This study provides for the first time evidence of an entorhinal cortex influenced concentration-dependent relationship between the release of endogenous glutamate in vivo and neuronal expression of mRNAs for BDNF and its receptor trkB in the hippocampus.
Brain Res Mol Brain Res 1996 Dec
PMID:Glutamate release correlates with brain-derived neurotrophic factor and trkB mRNA expression in the CA1 region of rat hippocampus. 901 89

Brain synaptic junctions are marked by a prominent dense-staining structure, the postsynaptic density (PSD), embedded in the postsynaptic membrane. Isolated PSDs contain a complex mixture of proteins among which the most abundant are the alpha subunit of calcium/calmodulin-dependent kinase II (CaMK II alpha) the membrane cytoskeletal proteins actin and spectrin and receptors for both excitatory and inhibitory neurotransmitters. We have investigated the relationship of these proteins to the junctional structure by extracting isolated PSDs with lithium diiodosalicylate (LIS). This selectively solubilized actin and spectrin while other prominent PSD proteins, such as CaMK II alpha, the AMPA- and NMDA-type glutamate receptors and GABA receptors, were not extracted at all. Electron microscopy revealed that LIS treatment caused some fragmentation of PSDs but that their basic lattice-like structure remained intact. These observations suggest that PSD structure is organised at two levels; a core component containing CaMK II alpha and neurotransmitter receptors which we have previously described as the postsynaptic junctional lattice and a peripheral actin-associated component that draws the lattice components together into the complete PSD structure.
Brain Res Mol Brain Res 1996 Dec 31
PMID:Role of actin in the organisation of brain postsynaptic densities. 903 39

Subtypes I, II and III of sodium channel alpha-subunit mRNAs were analyzed in adult rat brain areas after kainate-induced seizures. Tissue samples were microdissected from occipital neocortex, CA1 and CA3 hippocampus areas and dentate gyrus. Three reverse transcriptase-polymerase chain reaction (RT-PCR) protocols were undertaken to amplify these mRNAs. Amplification products were then distinguished after digestion by restriction enzymes, electrophoresis separation and densitometric analysis of gel profiles. PCR 1 evidenced the relative percentage of mRNAs I, II and III as well as neonatal II and III subtype isoforms, which resulted from an alternative splicing. PCR 2 and 3 were performed to focus on the neonatal vs. adult ratio in II and III subtypes, respectively. Seizures were shown to induce an increase in both neonatal subtypes, which suggested an alteration at the splicing level. These changes exhibited a peculiar brain regional distribution, the maximal effect being observed in dentate gyrus and hippocampus CA1 area. In situ hybridization experiments, using a digoxigenin-labeled oligonucleotide probe-specific for neonatal II and III mRNAs, confirmed this increase in neonatal mRNA subtypes. These changes were transient, reaching a maximum 6 h after drug injection, then disappearing between 12 and 48 h. They were prevented by a pre-treatment of animals by MK-801, a non-competitive antagonist of NMDA receptors. This work, thus, suggested that KA-induced seizures can be accompanied by transient alteration in the splicing pattern of sodium channel alpha-subunit mRNAs which resulted in an increase in expression of their neonatal isoforms within localized areas of adult rat brain.
Brain Res Mol Brain Res 1997 Mar
PMID:Increase in mRNAs encoding neonatal II and III sodium channel alpha-isoforms during kainate-induced seizures in adult rat hippocampus. 907 59


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