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)

Several lines of evidence indicate that a rapid loss of neuronal protein kinase C (PKC) activity is a characteristic feature of cerebral ischemia and is a necessary step in the NMDA-induced death of cultured neurons. Exposing embryonic day 18 primary rat cortical neurons to 50 microM NMDA or 50 microM glutamate for 10 min caused approximately 80% cell death over the next 24 h, but excitotoxic death was largely averted, i.e., by 70-80%, in cells pretreated with brain-derived neurotrophic factor (BDNF). An 8-h preexposure to BDNF (50-100 ng/ml) maximally protected cortical cells from the effects of NMDA and glutamate, although the transient application of BDNF between 8 and 4 h before NMDA was equally protective. These effects of BDNF were abolished at supralethal, i.e., >100 microM, NMDA concentrations. It is significant that BDNF pretreatment prevented the inactivation of PKC in cortical cells normally seen 30 min to 2 h following lethal NMDA or glutamate exposure. This BDNF effect did not arise from changes in NMDA channel activity because neither whole-cell NMDA current amplitudes nor increases in intracellular free Ca2+ concentration were altered by the 8-h BDNF pretreatment. Furthermore, BDNF offered no neuroprotection to cells treated with the PKC inhibitors staurosporine (10-20 nM), calphostin C (1-2.5 microM), or GF-109203X (100 nM) at the time of NMDA addition. These results underscore the importance of PKC inactivation in glutamate-induced neuronal death. They also suggest that BDNF neuroprotection arises, at least in part, via its ability to block the mechanism by which pathophysiological Ca2+ influx through the NMDA receptor causes membrane PKC inactivation.
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PMID:Evidence that brain-derived neurotrophic factor neuroprotection is linked to its ability to reverse the NMDA-induced inactivation of protein kinase C in cortical neurons. 988 60

Progenitor cells in the subventricular zone of the lateral ventricle and in the dentate gyrus of the hippocampus can proliferate throughout the life of the animal. To examine the proliferation and fate of progenitor cells in the subventricular zone and dentate gyrus after focal cerebral ischemia, we measured the temporal and spatial profiles of proliferation of cells and the phenotypic fate of proliferating cells in ischemic brain in a model of embolic middle cerebral artery occlusion in the adult rat. Proliferating cells were labeled by injection of bromodeoxyuridine (BrdU) in a pulse or a cumulative protocol. To determine the temporal profile of proliferating cells, ischemic rats were injected with BrdU every 4 h for 12 h on the day preceding death. Rats were killed 2-14 days after ischemia. We observed significant increases in numbers of proliferating cells in the ipsilateral cortex and subventricular zone 2-14 days with a peak at 7 days after ischemia compared with the control group. To maximize labeling of proliferating cells, a single daily injection of BrdU was administered over a 14-day period starting the day after ischemia. Rats were killed either 2 h or 28 days after the last injection of BrdU. A significant increase in numbers of BrdU immunoreactive cells in the subventricular zone was coincident with a significant increase in numbers of BrdU immunoreactive cells in the olfactory bulb 14 days after ischemia and numbers of BrdU immunoreactive cells did not significantly increase in the dentate gyrus. However, 28 days after the last labeling, the number of BrdU labeled cells decreased by 90% compared with number at 14 days. Clusters of BrdU labeled cells were present in the cortex distal to the infarction. Numerous cells immunostained for the polysialylated form of the neuronal cell adhesion molecule were detected in the ipsilateral subventricular zone. Only 6% of BrdU labeled cells exhibited glial fibrillary acidic protein immunoreactivity in the cortex and subcortex and no BrdU labeled cells expressed neuronal protein markers (neural nuclear protein and microtubule associated protein-2). From these data we suggest that focal cerebral ischemia induces transient and regional specific increases in cell proliferation in the ipsilateral hemisphere and that proliferating progenitor cells may exist in the adult cortex.
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PMID:Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebral ischemia. 1148 98

The release of the neuronal protein S-100B into the circulation has been suggested as an early indication of cellular brain damage. The objective of this prospective pilot study was to determine S-100B serum levels in patients undergoing cross-clamping during carotid endarterectomy (CEA) and to correlate the results with the monitoring of somatosensory evoked potentials (SSEP) and the neurological short-term outcome. Arterial blood samples of 21 patients were drawn before oral intubation, cross-clamping, and unclamping, as well as before extubation and 6 hours later. Recording of SSEP was obtained during carotid occlusion and reperfusion. If loss of SSEP appeared, cerebral ischemia was assumed and an intraluminal shunt was placed. During cross-clamping, S-100B serum levels of 14 patients increased significantly from 0.05 ng/ml to 0.21 ng/ml, but returned to baseline levels after unclamping. In 5 cases, loss of SSEP amplitudes occurred but was reversed by the shunt insertion. No significant differences of S-100B serum values, neurological examination, and carotid duplex surveillance became obvious in this group when compared to the patients with undisturbed SSEP. However, 2 patients with complete disappearance of postcentral SSEP components suffered from neurological deficits in the postoperative period. S-100B serum levels remained highly elevated 6 hours after extubation (0.78 ng/ml and 0.41 ng/ml) compared to the baseline values (0.15 ng/ml and 0.07 ng/ml). During CEA a transitory increase of the S-100B serum levels appears to present an impairment of the blood-brain barrier integrity without any neurological deficits. In contrast, persistently elevated S-100B serum levels seem to be associated with transient loss of SSEP and development of neurological deficits.
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PMID:Assessment of early brain damage in carotid endarterectomy: evaluation of S-100B serum levels and somatosensory evoked potentials in a pilot study. 1220 50

Upon brain reperfusion following ischemia, there is widespread inhibition of neuronal protein synthesis that is due to phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha), which persists in selectively vulnerable neurons (SVNs) destined to die. Other investigators have shown that expression of mutant eIF2alpha (S51D) mimicking phosphorylated eIF2alpha induces apoptosis, and expression of non-phosphorylatable eIF2alpha (S51A) blocks induction of apoptosis. An early event in initiating apoptosis is the release of cytochrome c from mitochondria, and cytochrome c release corresponds to the selective vulnerability of hippocampal CA1 neurons in rats after transient global cerebral ischemia. At present the signaling pathways leading to this are not well defined. We hypothesized that persistent eIF2alpha(P) reflects injury mechanisms that are causally upstream of release of cytochrome c and induction of apoptosis. At 4 h of reperfusion following 10-min cardiac arrest, vulnerable neurons in the striatum, hippocampal hilus and CA1 showed colocalized intense immunostaining for both persistent eIF2alpha(P) and cytoplasmic cytochrome c, while resistant neurons in the dentate gyrus and elsewhere did not immunostain for either. A lower intensity of persistent eIF2alpha(P) immunostaining was present in cortical layer V pyramidal neurons without cytoplasmic cytochrome c, possibly reflecting the lesser vulnerability of this area to ischemia. We did not observe cytoplasmic cytochrome c in any neurons that did not also display persistent eIF2alpha(P) immunostaining. Because phosphorylation of eIF2alpha during early brain reperfusion is carried out by PERK, these findings suggest that there is prolonged activation of the unfolded protein response in the reperfused brain.
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PMID:Persistent eIF2alpha(P) is colocalized with cytoplasmic cytochrome c in vulnerable hippocampal neurons after 4 hours of reperfusion following 10-minute complete brain ischemia. 1268 90

Transient cerebral ischemia leads to protein aggregation mainly in neurons destined to undergo delayed neuronal death after ischemia. This study utilized a rat transient cerebral ischemia model to investigate whether ischemic preconditioning is able to alleviate neuronal protein aggregation, thereby protecting neurons from ischemic neuronal damage. Ischemic preconditioning was introduced by a sublethal 3 min period of ischemia followed by 48 h of recovery. Brains from rats with either ischemic preconditioning or sham-surgery were then subjected to a subsequent 7 min period of ischemia followed by 30 min, 4, 24, 48 and 72 h of reperfusion. Protein aggregation and neuronal death were studied by electron and confocal microscopy, as well as by biochemical analyses. Seven minutes of cerebral ischemia alone induced severe protein aggregation after 4 h of reperfusion mainly in CA1 neurons destined to undergo delayed neuronal death (which took place after 72 h of reperfusion). Ischemic preconditioning reduced significantly protein aggregation and virtually eliminated neuronal death in CA1 neurons. Biochemical analyses revealed that ischemic preconditioning decreased accumulation of ubiquitin-conjugated proteins (ubi-proteins) and reduced free ubiquitin depletion after brain ischemia. Furthermore, ischemic preconditioning also reduced redistribution of heat shock cognate protein 70 and Hdj1 from cytosolic fraction to protein aggregate-containing fraction after brain ischemia. These results suggest that ischemic preconditioning decreases protein aggregation after brain ischemia.
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PMID:Ischemic preconditioning prevents protein aggregation after transient cerebral ischemia. 1593 39

Cerebral ischaemia is associated with brain damage and inhibition of neuronal protein synthesis. A deficit in neuronal metabolism and altered excitatory amino acid release may both contribute to those phenomena. In the present study, we demonstrate that both NMDA and metabolic impairment by 2-deoxyglucose or inhibitors of mitochondrial respiration inhibit protein synthesis in cortical neurons through the phosphorylation of eukaryotic elongation factor (eEF-2), without any change in phosphorylation of initiation factor eIF-2alpha. eEF-2 kinase may be activated both by Ca(2+)-independent AMP kinase or by an increase in cytosolic Ca2+. Although NMDA decreases ATP levels in neurons, only the effects of 2-deoxyglucose on protein synthesis and phosphorylation of elongation factor eEF-2 were reversed by Na(+) pyruvate. Protein synthesis inhibition by 2-deoxyglucose was not as a result of a secondary release of glutamate from cortical neurons as it was not prevented by the NMDA receptor antagonist 5-methyl-10,11-dihydro-5H-dibenzo-(a,d)-cyclohepten-5,10-imine hydrogen maleate (MK 801), nor to an increase in cytosolic-free Ca2+. Conversely, 2-deoxyglucose likely activates eEF-2 kinase through a process involving phosphorylation by AMP kinase. In conclusion, we provide evidence that protein synthesis can be inhibited by NMDA and metabolic deprivation by two distinct mechanisms involving, respectively, Ca(2+)-dependent and Ca(2+)-independent eEF-2 phosphorylation.
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PMID:2-Deoxyglucose and NMDA inhibit protein synthesis in neurons and regulate phosphorylation of elongation factor-2 by distinct mechanisms. 1640 6

The neuronal protein S-100B has been found to be an indicator of cellular brain damage. The aim of the study was to evaluate whether cross-clamping of the carotid artery for carotid endarterectomy (CEA) under local anesthesia is associated with the same S-100B release pattern as during general anesthesia, where an increase in S-100B concentration in the jugular vein blood of 120% has been reported. In 45 consecutive patients undergoing CEA under local anesthesia, serum S-100B samples were drawn before surgery (T1), before carotid cross-clamping (T2), before cerebral reperfusion (T3), after reperfusion but before the end of surgery (T4), and 6 hr postoperatively (T5). At T1 and T5, blood samples were drawn only from the radial artery. Intraoperatively (T2-T4), samples were collected from the internal jugular vein additionally. S-100B levels were determined using an immunoluminometric assay (LIAISON) Sangtec 100; Sangtec, Bromma, Sweden). In eight patients, it was necessary to insert an intraluminal shunt because of signs of cerebral ischemia. In the remaining 37 patients, median carotid clamping time was 40 min. There were no neurological complications. There were no differences in baseline S-100B levels regarding gender and symptomatology. Median baseline (T1) and postoperative (T5) S-100B levels were identical (0.077 microg/L). All blood samples from the jugular vein showed significantly higher median S-100B levels than the corresponding arterial blood samples. Only slight increases of 13% and 18% were found during cross-clamping (T3) compared to the first intraoperative measurement (T2) in the venous and arterial samples, respectively, which was followed by decreases of 5% and 18%, respectively (T3-T4). S-100B release did not differ at any time point between patients who needed and patients who did not need a shunt, in either the arterial or the venous blood samples. During uncomplicated CEA under local anesthesia, there is no relevant increase of S-100B. These results are different from those reported when CEA is done under general anesthesia.
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PMID:S-100B release during carotid endarterectomy under local anesthesia. 1752 74

Post-stroke induction of alpha-synuclein (AS), a neuronal protein implicated in the pathogenesis of Parkinson's disease (PD), has been demonstrated to induce secondary brain damage after cerebral ischemia. Therefore, understanding the expression and pathogenic modifications of AS is clinically meaningful for evaluating the prognosis of stroke. Here, 54 patients with acute ischemic stroke (AIS) and 55 controls were enrolled. Different forms of AS in red blood cells (RBCs), including hemoglobin-bound AS (Hb-AS), oligomeric AS (O-AS), and serine 129-phosphorylated AS (pS-AS), were measured using ELISA methods. Compared with controls, significantly increased levels of Hb-AS, O-AS, and pS-AS were observed in AIS patients. The levels of O-AS and pS-AS were both positively correlated with that of Hb-AS. However, no correlation was observed between O-AS and pS-AS. The levels of all three forms of AS were associated with increased risk of AIS diagnosis. Receiver operating characteristic (ROC) curves revealed that the three forms of AS yielded a moderate discriminative power (AUC ranging from 0.67 to 0.71 in discriminating AIS patients from controls, with varying sensitivity (0.41~0.61), specificity (0.78~0.90), PPV (0.73~0.81), and NPV (0.61~0.68)). These findings suggest that RBC AS can be a potential biomarker for evaluating AS changes in the brain of AIS patients.
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PMID:Alpha-synuclein alterations in red blood cells of peripheral blood after acute ischemic stroke. 3193 94