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)

Glutamatergic N-methyl-d-aspartate NMDA receptors (NMDAR) are considered to play a key role in ischemia-induced damage. Long-term (hours) changes in their expression upon ischemia have been shown. Here we report short-term changes in the mRNA levels of the major hippocampal NMDAR subunits (NR1, NR2A and NR2B), as well as c-fos, in an ex vivo ischemia model using hippocampal slices. This effect can be observed also in a calcium free incubation solution. Striking early decreases in the NMDAR subunit mRNA levels were observed after 30 min of oxygen and glucose deprivation (OGD) as well as a partial recovery when the tissues were returned to the balanced salt solution (reperfusion-like period) for 3 h. Since OGD-induced damage has been reported to be a consequence of the increase in OGD-related glutamate release, we also analyzed NMDAR mRNA levels following increased glutamate levels in hippocampal sections in which no significant effects on NMDAR subunit mRNA levels were detected. Furthermore, we describe that the presence of MK-801 (a selective NMDAR antagonist), CNQX (a selective AMPA/kainate receptor antagonist) or their combined action in the incubation solution is able to induce a significant decrease in NMDAR expression but in these conditions the OGD does not induce further decreases in mRNA levels. We suggest that the mechanisms triggered during OGD to downregulate mRNA levels of NMDAR subunits could be the same than those induced by glutamate receptor antagonists.
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PMID:Early modifications in N-methyl-D-aspartate receptor subunit mRNA levels in an oxygen and glucose deprivation model using rat hippocampal brain slices. 1976 17

Achyranthes bidentata polypeptides (ABPP), the important constituents separated from the aqueous extract of Achyranthes bidentata, have been shown to attenuate N-methyl-D-aspartate (NMDA)-induced cell apoptosis in cultured hippocampal neurons through differential modulation of NR2A- and NR2B-containing NMDA receptors. The present study sought to investigate the possible mechanism underlying the neuroprotective effect of ABPP on NMDA-induced cell death. Western blot analysis and colorimetric enzymatic assay demonstrated that ABPP pretreatment inhibited NMDA-induced increase of Bax protein expression or caspase-3 activity in cultured hippocampal neurons. Fluorescence measurements after staining with 2,7-dichlorofluorescin diacetate and rhodamine 123 showed that ABPP treatment also reversed NMDA-induced intracellular radical oxygen species (ROS) elevation and mitochondrial membrane potential depression in cultured hippocampal neurons. Furthermore, the in vivo effects of ABPP on cerebral neuronal damage during focal ischemia-reperfusion were also investigated. In rat middle cerebral artery occlusion (MCAO) model, ABPP attenuated the increase in the neurological deficit and cerebral infarction induced by focal ischemia-reperfusion, showing in vivo neuroprotective effects. The results collectively suggest that ABPP might exert neuroprotective actions through inhibiting Bax protein expression, caspase-3 activity, ROS production, and mitochondrial dysfunction that are all caused by overstimulation of NMDA receptors.
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PMID:Achyranthes bidentata polypeptides confer neuroprotection through inhibition of reactive oxygen species production, Bax expression, and mitochondrial dysfunction induced by overstimulation of N-methyl-D-aspartate receptors. 1977 71

The nucleoside adenosine (ADO) is a neuromodulator in brain. ADO and its metabolite inosine (INO) have been shown to increase cell viability in stroke models. During ischemia, extracellular levels of both ADO and INO are increased. In this study, we treated rat cortical neurons with N-methyl-D-aspartate (NMDA) to initiate excitotoxicity and then investigated the mechanisms of ADO and INO release. NMDA induced a significant increase in ADO and INO production. The effect of NMDA receptor antagonists on NMDA-evoked ADO and INO release was examined. MK-801 (1 micromol/L), a potent antagonist that lacks receptor subunit selectivity, completely blocked evoked release of both ADO and INO. Memantine (10 micromol/L), a lower affinity antagonist that also lacks subunit selectivity, blocked INO, but not ADO, release. Ifenprodil (10 micromol/L), an inhibitor selective for NMDA receptors containing the NR2B subunit, completely blocked evoked ADO and INO release. NVP-AAM077 (NVP, 0.4 micromol/L), an inhibitor selective for NMDA receptors containing the NR2A subunit, did not significantly block evoked release of either ADO or INO. Removal of extracellular Ca2+ abolished NMDA-evoked release of both ADO and INO. BAPTA (25 micromol/L), which chelates intracellular Ca2+, had no significant effect on either ADO or INO release unless extracellular Ca2+ was also removed. Inhibitors of Ca2+/calmodulin-dependent protein kinase II (CaMKII) prevented NMDA-evoked ADO and INO release and decreased nucleoside transporter function. These data indicate that NMDA-evoked ADO and INO release is dependent on subunit composition of NMDA receptors. As well, NMDA-evoked ADO and INO release requires nucleoside transporters and extracellular Ca2+ and is enhanced by activation of CaMKII.
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PMID:N-methyl-D-aspartate-evoked adenosine and inosine release from neurons requires extracellular calcium. 2005 11

It has been reported that N-methyl-D-aspartate receptor (NMDAR)-triggered neurotoxicity is related to excessive Ca(2+) loading and an increase in nitric oxide (NO) concentration. However, the molecular mechanisms that underlie these events are not completely understood. NMDARs and neuronal NO synthase each binds to the scaffolding protein postsynaptic density (PSD)-93 through its PDZ domains. In this study, we determined whether PSD-93 plays a critical role in NMDAR/Ca(2+)/NO-mediated neurotoxicity. We found that the targeted disruption of the PSD-93 gene attenuated the neurotoxicity triggered by NMDAR activation, but not by non-NMDAR activation, in cultured mouse cortical neurons. PSD-93 deficiency reduced the amount of NMDAR subunits NR2A and NR2B in synaptosomal fractions from the cortical neurons and significantly prevented NMDA-stimulated increases in cyclic guanosine 3',5'-monophosphate and Ca(2+) loading in the cortical neurons. These findings indicate that PSD-93 deficiency could block NMDAR-triggered neurotoxicity by disrupting the NMDAR-Ca(2+)-NO signaling pathway and reducing expression of synaptic NR2A and NR2B. Since NMDARs, Ca(2+), and NO play a critical role during the development of brain trauma, seizures, and ischemia, the present work suggests that PSD-93 might contribute to molecular mechanisms of neuronal damage in these brain disorders.
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PMID:Postsynaptic density-93 deficiency protects cultured cortical neurons from N-methyl-D-aspartate receptor-triggered neurotoxicity. 2009 70

This study describes the effect of global brain ischemia followed by 48 h reperfusion, when delayed neuronal death can be already observed. We quantified the mRNA levels of the N-methyl-D-aspartate receptor (NMDAR) subunits and those of the astroglia (glial fibrilar acidic protein, GFAP) and microglia (CD11b) markers using real time PCR on the cerebral cortex and hippocampus of 3- and 18-month-old Sprague-Dawley rats. Data show an ischemia/reperfusion-induced decrease in the mRNA levels of the NMDAR NR1, NR2A and NR2B subunits genes, which contrasts with the increase in the CD11b and GFAP mRNA levels. These effects are attenuated in all the genes studied in 18-month-old animals, suggesting that this mechanism of response is less efficient in aged animals. Western blot assays of NR1, NR2A and NR2B show parallels with the real time PCR data, indicating that the down-regulation of these genes is controlled at the transcriptional level. We suggest that a decrease in the efficiency in the control of the NMDAR transcription could account for the higher vulnerability in aged animals, but it cannot explain by itself differences in the vulnerability to ischemia in different areas of the brain. In the assays of ischemia/reperfusion followed by a treatment with the anti-inflammatory agent meloxicam, we observed that ischemic insult was unable to elicit changes in the NMDAR transcription, thus suggesting that inflammation plays a crucial role in the transcriptional control of these genes.
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PMID:Age and meloxicam attenuate the ischemia/reperfusion-induced down-regulation in the NMDA receptor genes. 2035 May 75

Imaging the N-methyl-D-aspartate receptors (NMDARs) in the living human brain by positron emission tomography (PET) or single photon emission computed tomography (SPECT) would provide useful information on the role of these receptors in ischemia and in various neurological disorders such as degenerative diseases, epilepsy or schizophrenia. To assess NMDAR radiotracer development and to propose perspectives, we overviewed the PET and SPECT candidate radioligands developed until now. Labelled molecules of interest were classified in three groups according to their binding site: intrachannel pore site blockers, glycine site inhibitors and NR2B selective subunit antagonists.
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PMID:PET and SPECT imaging of the NMDA receptor system: an overview of radiotracer development. 2050 76

Lipid rafts are dynamic membrane microdomains enriched in cholesterol and sphingolipids involved in the compartmentalization of signaling pathways, trafficking and sorting of proteins. At synapses, the glutamatergic NMDA receptor and its cytoplasmic scaffold protein PSD-95 move between postsynaptic density (PSD) and rafts following learning or ischemia. However it is not known whether the signaling complexes formed by these proteins are different in rafts nor the molecular mechanisms that govern their localization. To examine these issues in vivo we used mice carrying genetically encoded tags for purification of protein complexes and specific mutations in NMDA receptors, PSD-95 and other postsynaptic scaffold proteins. Isolation of PSD-95 complexes from mice carrying tandem affinity purification tags showed differential composition in lipid rafts, postsynaptic density and detergent-soluble fractions. Raft PSD-95 complexes showed less CaMKIIalpha and SynGAP and enrichment in Src and Arc/Arg3.1 compared with PSD complexes. Mice carrying knock-outs of PSD-95 or PSD-93 show a key role for PSD-95 in localizing NR2A-containing NMDA receptor complexes to rafts. Deletion of the NR2A C terminus or the C-terminal valine residue of NR2B, which prevents all PDZ interactions, reduced the NR1 association with rafts. Interestingly, the deletion of the NR2B valine residue increased the total amount of lipid rafts. These data show critical roles for scaffold proteins and their interactions with NMDA receptor subunits in organizing the differential expression in rafts and postsynaptic densities of synaptic signaling complexes.
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PMID:In vivo composition of NMDA receptor signaling complexes differs between membrane subdomains and is modulated by PSD-95 and PSD-93. 2055 66

Physical exercise has been demonstrated to be neuroprotective in both clinical and laboratory settings. However, the exact mechanism underlying this effect is unclear. Our study aimed to investigate whether pre-ischemic treadmill training could serve as a form of ischemic preconditioning in a rat model undergoing middle cerebral artery occlusion (MCAO). Thirty-six rats were divided into three groups: a sham control group, a non-exercise with operation group and an exercise with operation group. After treadmill training, ischemia was induced by occluding the MCA for 2 h, followed by reperfusion. Half of the rats in each group were sacrificed for mRNA detection of mGluR5 and NR2B 80 min after occlusion. The remaining animals were evaluated for neurological deficits by behavioral scoring and then decapitated to assess the infarct volume. The mRNA expression of mGluR5 and NR2B was detected by real-time PCR. The results suggest that pre-ischemic treadmill training may induce brain ischemic tolerance by reducing the mRNA levels of mGluR5 and NR2B, and thus, the results indicate that physical exercise might be an effective method to establish ischemic preconditioning.
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PMID:The effect of treadmill training pre-exercise on glutamate receptor expression in rats after cerebral ischemia. 2071 28

Glutamate excitotoxicity mediated by NMDA receptor activation plays a key role in many aspects of ischemic brain injury, but the expression of NMDA receptor subunits NR1, NR2A and NR2B mRNA and their relationship to apoptosis is still unclear. In this study, we applied in situ hybridization and TUNEL staining to investigate the expression of NMDA receptor subunit mRNA and apoptosis in hippocampus of rats after transient forebrain ischemia. The results showed that in the CA1 region, NR1 mRNA expression was significantly increased following ischemia-reperfusion (IR), reaching peak levels at IR 24h, and then gradually decreasing until IR 7 days. NR2A and NR2B mRNA expression dropped to lowest levels at IR 6h and IR 12h, respectively, and then started to recover. The mRNA expression of both NR2A and NR2B then increased to peak levels at IR 48h, followed by a sustained decline until IR 7 days. In the CA3 region and dentate gyrus the range of variation in mRNA expression was significantly reduced gradually. At IR 24h, apoptosis-positive cells were observed mainly in the CA1 region. The number of apoptosis-positive cells continuously grew and showed a dramatic increase at IR 48h and peaked at IR 72h. Then, the number of apoptosis-positive cells started to decrease, but at IR 7 days the apoptosis-positive cells still remained. These results indicate that the alterations of NMDA receptor subunit mRNA expression may contribute to the ischemic apoptosis of hippocampus after transient forebrain ischemia.
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PMID:Alterations of NMDA receptor subunits NR1, NR2A and NR2B mRNA expression and their relationship to apoptosis following transient forebrain ischemia. 2085 Apr 19

The vulnerability of brain neuronal cell subpopulations to neurologic insults varies greatly. Among cells that survive a pathological insult, for example ischemia or brain trauma, some may undergo morphological and/or biochemical changes that may compromise brain function. The present study is a follow-up of our previous studies that investigated the effect of glutamate-induced excitotoxicity on the GABA synthesizing enzyme glutamic acid decarboxylase (GAD65/67)'s expression in surviving DIV 11 cortical GABAergic neurons in vitro [Monnerie and Le Roux, (2007) Exp Neurol 205:367-382, (2008) Exp Neurol 213:145-153]. An N-methyl-D-aspartate receptor (NMDAR)-mediated decrease in GAD expression was found following glutamate exposure. Here we examined which NMDAR subtype(s) mediated the glutamate-induced change in GAD protein levels. Western blotting techniques on cortical neuron cultures showed that glutamate's effect on GAD proteins was not altered by NR2B-containing diheteromeric (NR1/NR2B) receptor blockade. By contrast, blockade of triheteromeric (NR1/NR2A/NR2B) receptors fully protected against a decrease in GAD protein levels following glutamate exposure. When receptor location on the postsynaptic membrane was examined, extrasynaptic NMDAR stimulation was observed to be sufficient to decrease GAD protein levels similar to that observed after glutamate bath application. Blocking diheteromeric receptors prevented glutamate's effect on GAD proteins after extrasynaptic NMDAR stimulation. Finally, NR2B subunit examination with site-specific antibodies demonstrated a glutamate-induced, calpain-mediated alteration in NR2B expression. These results suggest that glutamate-induced excitotoxic NMDAR stimulation in cultured GABAergic cortical neurons depends upon subunit composition and receptor location (synaptic vs. extrasynaptic) on the neuronal membrane. Biochemical alterations in surviving cortical GABAergic neurons in various disease states may contribute to the altered balance between excitation and inhibition that is often observed after injury.
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PMID:Role of the NR2A/2B subunits of the N-methyl-D-aspartate receptor in glutamate-induced glutamic acid decarboxylase alteration in cortical GABAergic neurons in vitro. 2092 97


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