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)

After the middle cerebral artery of rats was occluded, changes in the content of 14 free amino acids and the activity of antioxidant enzymes in the ischemic striatum were assessed with respect to the duration of ischemia. Glu and Asp levels were significantly reduced by 60 min of ischemia, GABA was increased by 30 and 60 min and Ala was increased by 5, 15, and 30 min. During ischemia, the levels of striatal Gln, Asn, Ser, Tau, Gly and Pro were found to be normal. In comparison with the sham-operated rats, the changes in the content of Thr, His, Arg and Tyr were inconclusive, since the effect of operative stress could not be ruled out on such occasion. Concomitantly, the Zn-Cu superoxide dismutase and glutathione peroxidase activity were significantly reduced by 30 min of ischemia. It revealed that the reduced capacity to scavenge the oxygen free radicals occurred during the early stage of cerebral ischemia. The above changes of Glu, Gln, GABA and Pro level might be considered as the final outcome of the decrease of glutamate synthesis, the acceleration of its conversion to GABA, and the extracellular leakage of glutamate. According to our data, the oxygen free radicals might be involved in the evolution of primary neuronal damage at the ischemic striatum.
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PMID:[Mechanism of neuronal damage caused by cerebral ischemia]. 133 25

The concentrations of amino acids (AA), stroke index and infarct area were determined in 26 gerbils which were divided into 3 groups: RSM-treated (n = 8), Saline-treated (n = 10) and sham-operated (n = 8). The levels of AA were measured with microdialysis technique in cerebral cortex. The concentrations of neurotransmitter AA, as Glu and GABA and Asp, were significantly increased during the first 60 min after CCA ligation, while the concentrations of non-neurotransmitter AA, as Thr and Ser, had no significant changes. In RSM-treated gerbils, the level of Glu was significantly lower than that of the saline-treated, but the GABA in RSM-treated was significantly higher than that of the saline-treated. The ratio of Glu/GABA was significantly decreased after ischemia. The RSM could improve the reduction of ratio of Glu/GABA during 0-30 min and 91-120 min after cerebral ischemia. There were statistically significant decrease in terms of stroke index in RSM-treated group when compared with saline-treated group at 24 h and 16 h after CCA ligation respectively. The RSM has a tendency to decrease the size of infarct area, but no statistical difference. The results suggest that the neurotransmitter AA involve in the pathophysiological procedures of cerebral ischemia and the RSM can attenuate dysfunctions of EAA and IAA. Furthermore, the results also imply that there may be an alternate way to treat cerebral ischemia by inhibiting the presynaptic releasing of Glu and stimulating the releasing of GABA.
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PMID:Effect of radix salviae miltiorrhizae on EAA and IAA during cerebral ischemia in gerbils: a microdialysis study. 819 18

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 regional selectivity and mechanisms underlying the toxicity of the serine/threonine protein phosphatase inhibitor okadaic acid (OA) were investigated in hippocampal slice cultures. Image analysis of propidium iodide-labeled cultures revealed that okadaic acid caused a dose- and time-dependent injury to hippocampal neurons. Pyramidal cells in the CA3 region and granule cells in the dentate gyrus were much more sensitive to okadaic acid than the pyramidal cells in the CA1 region. Electron microscopy revealed ultrastructural changes in the pyramidal cells that were not consistent with an apoptotic process. Treatment with okadaic acid led to a rapid and sustained tyrosine phosphorylation of the mitogen-activated protein kinases ERK1 and ERK2 (p44/42(mapk)). The phosphorylation was markedly reduced after treatment of the cultures with the microbial alkaloid K-252a (a nonselective protein kinase inhibitor) or the MAP kinase kinase (MEK1/2) inhibitor PD98059. K-252a and PD98059 also ameliorated the okadaic acid-induced cell death. Inhibitors of protein kinase C, Ca2+/calmodulin-dependent protein kinase II, or tyrosine kinase were ineffective. These results indicate that sustained activation of the MAP kinase pathway, as seen after e.g., ischemia, may selectively harm specific subsets of neurons. The susceptibility to MAP kinase activation of the CA3 pyramidal cells and dentate granule cells may provide insight into the observed relationship between cerebral ischemia and dementia in Alzheimer's disease.
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PMID:Regional selective neuronal degeneration after protein phosphatase inhibition in hippocampal slice cultures: evidence for a MAP kinase-dependent mechanism. 973 50

Cyclin G1 is a recently cloned transcriptional target of p53, it is located in neurons and ventricular ependymal cells and is elevated in neurons after axotomy and cerebral ischemia. The biological function for cyclin G1 in differentiated neurons has thus far not been elucidated. Recently, cyclin G1 has been shown to interact with the B' subunits of serine/threonine protein phosphatase 2A (PP2A) in a rat fibroblast cell line [K. Okamoto, C., Kamibayashi, M. Serrano, C. Prives, M.C. Mumby, D. Beach, p53-dependent association between cyclin G and the B' subunit of protein phosphatase 2A, Mol. Cell. Biol. 16 (1996) 6593-6602]. To further explore whether a similar interaction between cyclin G1 and PP2A B' subunits exists in the central nervous system, the present study compared the regional and developmental expression pattern, subcellular distribution and complex formation between cyclin G1 and the PP2A B' regulatory subunits in the rat brain. In situ hybridization of cyclin G1 and the B'alpha and B'beta subunits of PP2A showed an overlapping distribution in neurons of the cerebral cortex, hippocampus and thalamus at embryonic and early postnatal ages, but their developmental regulation differed. Whereas mRNA and protein levels of PP2A B' subunits were high in the cortical plate, subiculum, hippocampal areas and thalamus at E20 and decreased with age, those of cyclin G1 increased with age and were maximal in the adult cortex and hippocampus. In rat 14-day-old embryonic cortical cultures, cyclin G1 and PP2A B'alpha protein co-localized in nuclear and perinuclear areas of neurons, and both proteins were highly expressed in nuclei of cortical and hippocampal pyramidal cells and the mitral cell layer of the neonatal olfactory bulb. Both cyclin G1 and the PP2A regulatory B'alpha subunits were specifically expressed in neurons and not in glial cells. Antibodies raised against the B'alpha subunits of PP2A immunoprecipitated cyclin G1 in adult cortical lysates, indicating the presence of a complex involving cyclin G1 and the B'alpha subunits of PP2A. This study shows that the regional and subcellular localization of PP2A B' regulatory subunits and cyclin G1 are very similar at early postnatal stages. We discuss the possible functions of a cyclin G1-PP2A B'alpha complex in neurons.
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PMID:Developmental expression and co-localization of cyclin G1 and the B' subunits of protein phosphatase 2a in neurons. 988 95

Although interleukin-1beta (IL-1beta) has recently been implicated in neuronal cell death in vitro and in vivo after global forebrain ischemia, the role of IL-1beta in the functional injuries, i.e. impairment of synaptic transmission, after cerebral ischemia that does not cause neuronal death in the nervous system remains unknown. To address this question, we investigated the effect of short-term incomplete ischemia without apparent neural death on hippocampal long-term potentiation (LTP) in anesthetized rats, and examined the possible role of IL-1beta as an intermediary in this effect. Short-term incomplete cerebral ischemia (10 min) was induced in halothane-anesthetized rats by bilaterally clamping the common carotid arteries. Four days after ischemia, functional injuries in neuronal transmission in the hippocampal formation were observed without significant changes in pathological studies such as neuronal cell death. The LTP elicited in both Shaffer-CA1 synapses and perforant path-dentate gyrus synapses was significantly inhibited by the short-term incomplete ischemia. This inhibition of LTP was blocked by IL-1beta tripeptide antagonist (Lys-D-Pro-Thr), suggesting that the inhibitory effect of mild ischemia on synaptic potentials and LTP may be mediated by the generation of IL-1beta. These findings have important implications for the role of IL-1beta in not only neuronal cell death but also functional injuries without cell loss, perhaps elicited by transient cerebral ischemia.
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PMID:Effects of an interleukin-1beta analogue [Lys-D-Pro-Thr], on incomplete cerebral ischemia-induced inhibition of long-term potentiation in rat hippocampal neurons in vivo. 1008 76

The effects of cerebral ischemia/reperfusion on phosphorylation of microtubule-associated tau proteins were assessed in a canine model of cardiac arrest. As tau proteins are phosphorylated by kinases involved in different transduction signal pathways, their phosphorylation state is an excellent marker of neuronal homeostasis and microtubule dynamics. Canine brain tau proteins were characterized by immunoblotting using phosphorylation-dependent antibodies and antisera raised against different amino- and carboxy-terminal tau sequences. The present study reports a complete dephosphorylation of tau proteins during ischemia, which is shown by a higher electrophoretic mobility and the almost (if not total) disappearance of phosphorylation-dependent monoclonal antibody labeling. After 2-hour restoration of spontaneous circulation, a decrease in the electrophoretic mobility was observed, and after 24 hours of reperfusion, a full restoration of the phosphorylation was visualized using phosphorylation-dependent monoclonal antibodies directed against Ser/Thr-Pro sites. However, one particular phosphorylation site involved in tau binding to microtubules, located on Ser262/356, was never fully significantly rephosphorylated, suggesting that microtubule metabolism was still affected after 24 hours of reperfusion. Thus, the sequential and differential recovery of tau phosphorylation after ischemia followed by reperfusion is a useful marker with which to monitor neuronal integrity after brain ischemia.
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PMID:Rapid tau protein dephosphorylation and differential rephosphorylation during cardiac arrest-induced cerebral ischemia and reperfusion. 1072 19

A brief period of sublethal ischemia induces resistance to a subsequent, otherwise lethal, ischemic insult, a process named ischemic tolerance or preconditioning. A persistently disturbed cell signaling during reperfusion after cerebral ischemia has been proposed to contribute to ischemic cell death. Here, we report on the effect of ischemic preconditioning on the levels of the regulatory alpha-subunit of calcium/calmodulin protein kinase II and its phosphorylation in the hippocampal CA1 region. We found that during and following lethal cerebral ischemia, calcium/calmodulin protein kinase II-alpha is persistently translocated to cell membranes, where it becomes phosphorylated at threonine 286. In contrast, in the preconditioned brains the translocation and phosphorylation are transient and return to preischemic values after one day of reperfusion. At this time of reperfusion, the total level of calcium/calmodulin protein kinase II-alpha is significantly lower in preconditioned animals compared to the sham and non-conditioned animals. After one day of reperfusion, the level of calcium/calmodulin protein kinase II-alpha messenger RNA decreases in the non-conditioned brains, whereas it is unchanged in preconditioned brains. We conclude that, during and after ischemia, calcium/calmodulin protein kinase II-alpha is translocated to cell membranes and becomes phosphorylated at threonine 286. This could detrimentally influence cell survival by changing receptor function and ion channel conductance. Ischemic preconditioning prevents the persistent presence of calcium/calmodulin protein kinase II-alpha at cell membranes, presumably by enhancing its degradation, which could be part of a neuroprotective mechanism of ischemic tolerance.
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PMID:Subcellular distribution and autophosphorylation of calcium/calmodulin-dependent protein kinase II-alpha in rat hippocampus in a model of ischemic tolerance. 1072 85

c-Jun N-terminal protein kinase (JNK) activation and subsequent c-Jun phosphorylation which stimulates its transcriptional activity have been well studied in cerebral ischemia. To determine whether mitogen-activated protein kinase kinase 7 (MKK7) play a role in JNK activation in response to the stress of global cerebral ischemia, we tested the activation of such a kinase by using phospho-Ser and phospho-Thr antibodies. Immunoprecipitation and Western blot analysis revealed that MKK7 was expressed at similar levels in all conditions, whereas phospho-MKK7 was highly augmented from 1 to 5 days and reached its peak at 3 days after 15 min of ischemia. Consistent with the active phase, the interaction of MLK3, ASK1 and phospho-JNK with MKK7 was increased compared with sham control, as shown by coimmunoprecipitation experiments. Moreover, MKK7 activation was markedly reduced by pretreatment of the free radical scavenging thiol antioxidant N-acetylcysteine (NAC). Together with previous studies, the late activation of MKK7 in hippocampal CA1 region may contribute to delayed cell death, and the protective effects of antioxidant against ischemia-induced injury may be partially mediated by the down-regulation of JNK signal pathway.
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PMID:Delayed activation and regulation of MKK7 in hippocampal CA1 region following global cerebral ischemia in rats. 1457 11

Cerebral ischaemia induces transcriptional changes in a number of pathophysiologically important genes. Here we have systematically studied gene expression changes after 90 min and 24 h of permanent focal ischaemia in the mouse by an advanced fragment display technique (restriction-mediated differential display). We identified 56 transcriptionally altered genes, many of which provide novel hints to ischaemic pathophysiology. Particularly interesting were two pro-apoptotic genes (Grim19 and Tdag51), whose role in cerebral ischaemia and neuronal cell death has not been recognized so far. Among the unknown sequences, we identified a gene that was rapidly and transiently up-regulated. The encoded protein displayed high homology to the MARK family of serine-threonine protein kinases and has recently been described as MARKL1/MARK4. Here we demonstrate that this protein is a functional protein kinase with the ability to specifically phosphorylate a cognate peptide substrate for the AMP-kinase family. Upon overexpression in heterologous cells, the functional wild-type protein, but not its kinase-dead mutant, led to decreased cell viability. We conclude that the up-regulation of this kinase during focal ischaemia may represent an interesting new target for pharmacological intervention.
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PMID:Identification of regulated genes during permanent focal cerebral ischaemia: characterization of the protein kinase 9b5/MARKL1/MARK4. 1500 67


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