Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PDZ domains are multifunctional protein-interaction motifs that often bind to the C-terminus of protein targets. Nitric oxide (NO), an endogenous signaling molecule, plays critical roles in nervous, immune, and cardiovascular function. Although there are numerous physiological functions for neuron-derived NO, produced primarily by the neuronal NO synthase (nNOS), excess nNOS activity mediates brain injury in cerebral ischemia and in animal models of Parkinson's disease. Subcellular localization of nNOS activity must therefore be tightly regulated. To determine ligands for the PDZ domain of nNOS, we screened 13 billion distinct peptides and found that the nNOS-PDZ domain binds tightly to peptides ending Asp-X-Val. This differs from the only known (Thr/Ser)-X-Val consensus that interacts with PDZ domains from PSD-95. Preference for Asp at the -2 peptide position is mediated by Tyr-77 of nNOS. A Y77D78 to H77E78 substitution changes the binding specificity from Asp-X-Val to Thr-X-Val. Guided by the Asp-X-Val consensus, candidate nNOS interacting proteins have been identified including glutamate and melatonin receptors. Our results demonstrate that PDZ domains have distinct peptide binding specificity.
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PMID:PDZ domain of neuronal nitric oxide synthase recognizes novel C-terminal peptide sequences. 909 34

The postsynaptic density (PSD) is a cytoskeletal specialization involved in the anchoring of neurotransmitter receptors and in regulating the response of postsynaptic neurons to synaptic stimulation. The postsynaptic protein PSD-95 binds to NMDA receptor subunits NR2A and NR2B and to signaling molecules such as neuronal nitric oxide synthase and p135synGAP. We investigated the effects of transient cerebral ischemia on protein interactions involving PSD-95 and the NMDA receptor in the rat hippocampus. Ischemia followed by reperfusion resulted in a decrease in the solubility of the NMDA receptor and PSD-95 in 1% sodium deoxycholate, the decrease being greater in the vulnerable CA1 hippocampal subfield than in the less sensitive CA3/dentate gyrus regions. Solubilization of the kainic acid receptor GluR6/7 and the PSD-95 binding proteins, neuronal nitric oxide synthase and p135synGAP, also decreased following ischemia. The association between PSD-95 and NR2A and NR2B, as indicated by coimmunoprecipitation, was less in postischemic samples than in sham-operated controls. Ischemia also resulted in a decrease in the size of protein complexes containing PSD-95, but had only a small effect on the size distribution of complexes containing the NMDA receptor. The results indicate that molecular interactions involving PSD-95 and the NMDA receptor are modified by an ischemic challenge.
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PMID:Altered interaction between PSD-95 and the NMDA receptor following transient global ischemia. 1061 18

Cerebral ischemia results in activation of the mitogen-activated protein kinase pathway and increased tyrosine phosphorylation of proteins associated with postsynaptic densities (PSDs). The authors investigated the possible relation between these events by determining the effect of ischemia on tyrosine phosphorylation of the brain-specific, PSD-enriched, Ras-GTPase activating protein, SynGAP. Transient (15 minutes) global ischemia was produced in rats by 4-vessel occlusion and PSDs prepared from forebrains immediately after ischemia or at 20 minutes, 1 hour, or 24 hours of reperfusion. Tyrosine phosphorylation of SynGAP was elevated relative to sham-operated controls by 20 minutes of reperfusion and remained elevated for at least 24 hours. Tyrosine phosphorylation of SynGAP also increased in CA1 and CA3/DG subfields of the hippocampus. Enhanced tyrosine phosphorylation of SynGAP was not accompanied by a change in PSD RasGAP activity. SynGAP bound to the SH2 domains of Src and Fyn in a tyrosine phosphorylation-dependent fashion, and this interaction increased after ischemia. SynGAP binds to the PDZ domains of PSD-95/SAP90 and coimmunoprecipitated with PSD-95. The coimmunoprecipitation of SynGAP with PSD-95 decreased after ischemia. The results indicate that changes in the properties and interactions of SynGAP may be involved in the neuropathology of ischemia.
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PMID:Transient cerebral ischemia increases tyrosine phosphorylation of the synaptic RAS-GTPase activating protein, SynGAP. 1148 31

To investigate whether the kainate (KA) receptors subunit GluR6 is involved in the neuronal cell death induced by cerebral ischemia followed by reperfusion, the antisense oligodeoxynucleotides (ODNs) of GluR6 were used to suppress the expression of GluR6 by intracerebroventricular infusion once per day for 3 days before ischemia. Transient brain ischemia was induced by four-vessel occlusion in Sprague-Dawley rats. The effects of GluR6 antisense ODNs on the phosphorylation of MLK3 and JNK and the interactions of MLK3 and PSD-95 with GluR6 were examined by immunoprecipitation and immunoblotting. Our results show that GluR6 antisense ODNs can knock down the expression of GluR6 and suppress the assembly of the GluR6.PSD-95.MLK3 signaling module and, therefore, inhibit JNK activation and phosphoralation of c-jun. On the other hand, the GluR6 antisense ODNs also show a protective role against neuronal cell death induced by cerebral ischemia/reperfusion. Administration of GluR6 antisense ODNs once per day for 3 days before cerebral ischemia significantly decreased neuronal degeneration. In conclusion, our results demonstrate that kainate receptor subunit GluR6 plays an important role in neuronal death induced by cerebral ischemia followed by reperfusion.
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PMID:Neuroprotective effects of GluR6 antisense oligodeoxynucleotides on transient brain ischemia/reperfusion-induced neuronal death in rat hippocampal CA1 region. 1626 25

We investigated the possible relationships between KA2 subunit and GluR6 subunit, as well as the role of KA2 subunit in neuronal death induced by cerebral ischemia/reperfusion. Our results indicated that intracerebroventricular infusion of KA2 antisense oligodeoxynucleotides (AS) not only knocked down the expressions of KA2 and GluR6, but also suppressed the assembly of the GluR6/KA2-PSD95-MLK3 signaling module, and inhibited JNK activation and phosphorylation of c-jun. In addition, infusion of KA2 AS increased neuronal survival in CA1 region after 5 days of reperfusion. More interestingly, we found that the combination of KA2 and GluR6 AS exerted more significant effects than when pretreated with KA2 AS or GluR6 AS alone. Our results suggest that the KA2 subunit is involved in delayed neuronal death induced by cerebral ischemia, at the same time, it is noteworthy that the functional cooperation between KA2 and GluR6 subunits plays a critical role in the ischemic brain injury by PSD95-MLK3-MKK4/7-JNK3 signal pathway.
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PMID:Functional cooperation between KA2 and GluR6 subunits is involved in the ischemic brain injury. 1763 97

Kainate receptor containing GluR6 subunit (KAR) is involved in the neuronal cell death induced by cerebral ischemia/reperfusion (I/R). Hypothermia is an effective neuroprotectant in brain ischemia, whereas the neuroprotective mechanisms have not been clearly established. The present study was set out to examine whether hypothermia would cause the alternation of the assembly of the GluR6-PSD95-MLK3 signaling module and the activation of c-Jun N-terminal kinase (JNK) pathway through KAR. Hypothermia (32 degrees C) was induced 10 min before ischemia and was maintained for 3 h after ischemia. Our results indicated that hypothermia could inhibit the assembly of GluR6-PSD95-MLK3 signaling module and suppressed the activation of MLK3, MKK4/7, and JNK3. The inhibition of JNK3 activation by hypothermia diminished the phosphorylation of the transcription factor c-Jun and downregulated FasL expression in hippocampal CA1. Meanwhile, the inhibition of JNK3 activation by hypothermia attenuated bax translocation, the release of cytochrome c, and the activation of caspase-3 in CA1 subfields. Both GluR6 antagonist NS102 and GluR6 antisense oligodeoxynucleotides partly blocked the aforementioned effects of hypothermia, which was further confirmed by histology. Taken together, our results strongly suggest that hypothermia decreased the increased assembly of the GluR6-PSD95-MLK3 signaling module and the activation of JNK pathway induced by I/R through KAR, which gave a new insight into the ischemic therapy.
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PMID:Neuroprotection of hypothermia against neuronal death in rat hippocampus through inhibiting the increased assembly of GluR6-PSD95-MLK3 signaling module induced by cerebral ischemia/reperfusion. 1817 94

In this study, we investigated whether the increase of inhibitory gamma-amino butyric acid (GABA) signal suppresses the excitatory glutamate signal induced by cerebral ischemia and the underlying mechanisms. In global cerebral ischemia, focal cerebral ischemia and oxygen-glucose deprivation, application of muscimol and baclofen, agonists of GABA(A) receptor and GABA(B) receptor, exerted neuroprotection. The agonists inhibited the increased assembly of the GluR6-PSD-95-MLK3 module induced by cerebral ischemia and the activation of the MLK3-MKK4/7-JNK3 cascade. Our results suggest that stimulation of the inhibitory GABA receptors can attenuate the excitatory JNK3 apoptotic signaling pathway via inhibiting the increased assembly of the GluR6-PSD-95-MLK3 signaling module in cerebral ischemia.
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PMID:Co-activation of GABA receptors inhibits the JNK3 apoptotic pathway via the disassembly of the GluR6-PSD95-MLK3 signaling module in cerebral ischemic-reperfusion. 1830 89

Calpains, cathepsins and caspases play crucial role in mediating cell death. In the present study we observed a cascade of events involving the three proteases during middle cerebral artery occlusion (MCAo) in Wistar rats. The rats were MCA occluded and reperfused at various time points. We observed a maximal increase in the levels of calpains during 1h and 12 h after reperfusion than permanently occluded rats. Further, these levels were reduced by 1st and 3rd day of reperfusion. Similarly the cathepsin-b levels were significantly increased during 1h and 12 h, of reperfusion, followed by activation of caspase-3 which reached maximal levels by 1st and 3rd day of reperfusion. The sequential activation of calpains, cathepsin-b and cleaved caspase-3 is evident by the Western blot analysis which was further confirmed by the cleavage of substrates like PSD-95 and spectrin. The differences in the regional distribution and elevation of these proteases at different reperfusion time periods indicates that differential mode of cell death occur in the brain during cerebral ischemia in rat model.
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PMID:Activation of calpain, cathepsin-b and caspase-3 during transient focal cerebral ischemia in rat model. 1833 60

Sema4C is a transmembrane protein that belongs to axon guidance molecules of semaphorin family. Previous reports have shown that Sema4C could interact with postsynaptic protein PSD95, etc, but the expression and the role of Sema4C in neurogenesis remains unknown. In this study, whole-mount in situ hybridization result showed that Sema4C was expressed abundantly in the areas of lateral ventricle, the striatum, the wall of midbrain, and the pons/midbrain junction of E11.5 embryos brain. Neural stem/progenitor cells (NSPs) obtained from E13.5 embryonic rat midbrain are also positive for Sema4C immunoreactivity. Sema4C expression was dramatically downregulated during induction of NSP differentiation. In order to confirm the involvement of Sema4C in neurogenesis, we used the rat global cerebral ischemia model to make adult neurogenesis in vivo. The robust proliferative NSPs were monitored by labeling with bromodeoxyuridine (BrdU) within the subventricular zone and dentate gyrus that continues for at least 2 weeks. Immunohistochemistry and Western blot analysis showed that Sema4C expression was dramatically upregulated during neurogenesis after cerebral ischemia-perfusion injury. Double immunostaining and stereologic counting analysis indicated that a high proportion of BrdU-positive proliferative cells were Nestin-positive NSPs, and also, Sema4C was highly expressed in these proliferative populations at specific stages after ischemic injury. These observations provide the evidence to support a putative role of Sema4C during neurogenesis both in vivo and in vitro.
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PMID:Sema4C expression in neural stem/progenitor cells and in adult neurogenesis induced by cerebral ischemia. 1918 44

Environmental enrichment (EE), where animals are exposed to a complex novel environment, has been shown to induce synaptic plasticity in both intact and injured animals. The purpose of this study was to investigate the effects of EE on spatial memory and structural modifications of synaptic junctions in rats following transient focal cerebral ischemia. Adult male Sprague-Dawley rats underwent right middle cerebral artery occlusion (MCAO) for 40 min and reperfusion. On day 3 after MCAO or sham surgery, rats were randomly assigned for 14 days to enriched or standard environmental housing. Spatial memory was then tested by the Morris water maze. Parietal cortex and the CA1 region of hippocampus were processed for electron microscopy and stereological techniques were used to evaluate plasticity of synaptic junctions. EE after MCAO improved spatial memory, with shortened escape length, increased frequency of crossings at the location of the platform, and increased percentage of time spent in the quadrant where the platform was previously located. Synaptic ultrastructural analysis showed that EE after MCAO increased numeric synaptic density in parietal cortex, and induced structural changes in synaptic junctions, with a decreased width of synaptic clefts and increased thickness of postsynaptic densities (PSD) in parietal cortex and hippocampus, accompanying improved performance on the spatial memory task. Using Western blot analysis, we determined the expression of glutamate receptor NMDAR1, and PSD-95, the best characterized protein member of the PSD-95 family, that was abundantly expressed in the PSD of excitatory synapses. The results showed that the content of NMDAR1 was not altered in MCAO rats of EE; however, the phosphorylated NMDAR1 increased significantly when compared with the standard environment housing MCAO rats. In addition, EE inhibited the impaired expression of PSD-95 induced by MCAO in parietal cortex and hippocampus. These data suggest that improved spatial memory of cerebral ischemic rats by EE is associated with structural modifications of synaptic junctions in several brain regions.
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PMID:Environmental enrichment induces synaptic structural modification after transient focal cerebral ischemia in rats. 1924 5


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