Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Water homeostasis in the brain is of central physiologic and clinical importance. Neuronal activity and ion water homeostasis are inextricably coupled. For example, the clearance of K+ from areas of high neuronal activity is associated with a concomitant water flux. Furthermore, cerebral edema, a final common pathway of numerous neurologic diseases, including stroke, may rapidly become life threatening because of the rigid encasement of the brain. A water channel family, the aquaporins, facilitates water flux through the plasma membrane of many cell types. In rodent brain, several recent studies have demonstrated the presence of different types of aquaporins. Aquaporin 1 (AQP1) was detected on epithelial cells in the choroid plexus whereas AQP4, AQP5 and AQP9 were localized on astrocytes and ependymal cells. In rodent brain, AQP4 is present on astrocytic end-feet in contact with brain vessels, and AQP9 is found on astrocytic processes and cell bodies. In basal physiologic conditions, AQP4 and AQP9 appear to be implicated in brain homeostasis and in central plasma osmolarity regulation. Aquaporin 4 may also play a role in pathophysiologic conditions, as shown by the reduced edema formation observed after water intoxication and focal cerebral ischemia in AQP4-knockout mice. Furthermore, pathophysiologic conditions may modulate AQP4 and AQP9 expression. For example, AQP4 and AQP9 were shown to be upregulated after ischemia or after traumatic injuries. Taken together, these recent reports suggest that water homeostasis in the brain is maintained by regulatory processes that, by control of aquaporin expression and distribution, induce and organize water movements. Facilitation of these movements may contribute to the development of edema formation after acute cerebral insults such as ischemia or traumatic injury.
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PMID:Aquaporins in brain: distribution, physiology, and pathophysiology. 1191 8

In this study, we investigated the iron deposition in the cerebral cortex, hippocampus CA1 area and corpus striatum pars dorsolateralis in a rat model of cerebral ischemia. Forebrain ischemia was induced by four-vessel occlusion for 20 min. Using iron histochemistry, regional changes were examined from 1 to 8 weeks of postischemic recirculation. Neuronal death was demonstrated in pyramidal cells of the hippocampal CA1 area and in the dorsolateral part of the corpus striatum, which are known as areas most vulnerable to ischemia. Iron deposition in hippocampal CA1 area was coupled to delayed pyramidal cell death. Perl's reaction with DAB intensification revealed of the 1 week iron deposits in the CA1 area, which gradually increased and formed clusters by 8 weeks. In the corpus striatum, strong iron staining was observed in injured cellular layer pars dorsolateralis 1 week after recirculation. Granular iron was deposited in the cytoplasm of pyramidal cells in layers III and V of the frontal cortex after 2 weeks of recirculation. In contrast to the hippocampus and striatum, the cerebral cortex did not develop severe neuronal cell death and atrophy immediately after the ischemic insult, which suggest that the neuronal cell death in the cerebral cortex occurs extremely late.
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PMID:Iron deposition after transient forebrain ischemia in rat brain. 1195 22

Persephin (Pspn), a recently cloned member of the transforming growth factor-beta superfamily (TGF-beta) and glial cell line-derived neurotrophic factor (GDNF) subfamily, is distributed throughout the nervous system at extremely low levels and is thought to function as a survival factor for midbrain dopaminergic and spinal motor neurons in vivo. Here, we report that mice lacking Pspn by homologous recombination show normal development and behavior, but are hypersensitive to cerebral ischemia. A 300% increase in infarction volume was observed after middle cerebral artery occlusion. We find that glutamate-induced Ca(2+) influx, thought to be a major component of ischemic neuronal cell death, can be regulated directly by the Persephin protein (PSP) and that PSP can reduce hypoxia/reperfusion cell death in vitro. Neuronal cell death can be prevented or markedly attenuated by administration of recombinant human PSP in vivo before ischemia in both mouse and rat models. Taken together, these data indicate that PSP is a potent modulator of excitotoxicity in the central nervous system with pronounced neuroprotective activity. Our findings support the view that PSP signaling can exert an important control function in the context of stroke and glutamate-mediated neurotoxicity, and also suggest that future therapeutic approaches may involve this novel trophic protein.
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PMID:Effects of cerebral ischemia in mice deficient in Persephin. 1209 30

The chemoattractant stromal cell-derived factor-1 (SDF-1) and its receptor CXC chemokine receptor 4 (CXCR4) are key modulators of immune function. In the developing brain, SDF-1 is crucial for neuronal guidance; however, cerebral functions of SDF-1/CXCR4 in adulthood are unclear. Here, we examine the cellular expression of SDF-1 isoforms and CXCR4 in the brain of mice receiving systemic lipopolysaccharide (LPS) or permanent focal cerebral ischemia. CXCR4 mRNA was constitutively expressed in cortical and hippocampal neurons and ependymal cells. Hippocampal neurons targeted the CXCR4 receptor to their somatodendritic and axonal compartments. In cortex and hippocampus, CXCR4-expressing neurons exhibited an overlapping distribution with neurons expressing SDF-1 transcripts. Although neurons synthesized SDF-1alpha mRNA, the SDF-1beta isoform was selectively expressed by endothelial cells of cerebral microvessels. LPS stimulation dramatically decreased endothelial SDF-1beta mRNA expression throughout the forebrain but did not affect neuronal SDF-1alpha. After focal cerebral ischemia, SDF-1beta expression was selectively increased in endothelial cells of penumbral blood vessels and decreased in endothelial cells of nonlesioned brain areas. In the penumbra, SDF-1beta upregulation was associated with a concomitant infiltration of CXCR4-expressing peripheral blood cells, including macrophages. Neuronal SDF-1alpha was transiently downregulated and neuronal CXCR4 was transiently upregulated in the nonlesioned cerebral cortex in response to ischemia. Although endothelial SDF-1beta may control cerebral infiltration of CXCR4-carrying leukocytes during cerebral ischemia, the neuronal SDF-1alpha/CXCR4 system may contribute to ischemia-induced neuronal plasticity. Thus, the isoform-specific regulation of SDF-1 expression modulates neurotransmission and cerebral infiltration via distinct CXCR4-dependent pathways.
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PMID:A dual role for the SDF-1/CXCR4 chemokine receptor system in adult brain: isoform-selective regulation of SDF-1 expression modulates CXCR4-dependent neuronal plasticity and cerebral leukocyte recruitment after focal ischemia. 1212 49

Expression levels of mRNA are commonly measured as a ratio of test to reference gene. The assumption is that reference genes such as beta-actin or cyclophilin are unaffected by treatment and act as steady-state controls. TaqMan real-time RT-PCR was used to test these assumptions in a rat model of cerebral ischaemia (tMCAO). Following measurement of 24 genes, we show that reference genes in this animal model fail the criteria for steady-state controls. Neuronal loss, glial proliferation and an influx of leukocytes into the lesioned brain result in major disturbance to cell populations. The mRNA for reference genes, as for test genes, reflects these changes. Specific mRNA levels vary according to the choice of reference gene to which they are normalised. In the process of resolving reference gene issues, mRNA increases were discovered for leukaemia inhibitory factor, nestin and galanin in rat brain hemispheres affected by ischaemia. Results are reported for a further 21 genes and mathematical and statistical methods are described that allow in this study fraction-fold changes in mRNA to be detected.
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PMID:The quantification of gene expression in an animal model of brain ischaemia using TaqMan real-time RT-PCR. 1239 70

Prostaglandins and leukotrienes (eicosanoids), metabolites of the arachidonic acid pathway, are subjected to altered synthesis or relocation after an ischemic insult. Although cyclooxygenase (COX) expression has been reported in human cerebral ischemia, no information is available on the expression of 5-lipoxygenase (5-LO) and its topographical correlation to COX induction. The objective of this study was to elucidate the comparative distribution of eicosanoids in ischemic tissues. COX and 5- LO, key enzymes for the synthesis of prostaglandins and leukotrienes, respectively, were examined in autopsied brains. COX1 was expressed intensely in the microglia but weakly in the neurons in control brains. These COX1-immunoreactive microglia showed a more activated form following ischemic damage and hypoxemia. In contrast, COX2 was absent in the control brains, and was induced robustly in the neuronal cell bodies and dendrites during the acute stages of focal ischemic damage, and then subsided at the subacute stages. These COX2-immunoreactive neurons accumulated in the peri-infarct regions, but were absent from the distant regions. In focal ischemic damage and Binswanger's disease, COX2 was up-regulated in the microglia. Neuronal immunostaining for 5-LO was up-regulated occasionally during hypoxemia and focal ischemic damage. Glial cells immunoreactive for 5-LO appeared in the foci of the ischemic damage, with small blood vessels being infiltrated by 5-LO-immunoreactive mononuclear leukocytes. These findings indicate that the isozymes of COX are differentially regulated depending on the cellular source and the types of ischemic damage, and that vascular 5-LO may accelerate the migration of leukocytes and augment the blood-brain barrier permeability. The possibility of increased substrate availability for the other should be noticed in specific inhibition of either COX or 5-LO since these two enzymes are accumulated in parallel in ischemic tissues.
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PMID:A comparative study on the expression of cyclooxygenase and 5-lipoxygenase during cerebral ischemia in humans. 1241 Mar 81

Neuronal cells are susceptible to cerebral ischaemia. As gamma-aminobutyric acid(A) (GABA(A)) receptors are specific for neurones, functional receptor imaging using I-iomazenil (IMZ), a ligand to the GABA benzodiazepine receptor, has been proposed as an imaging modality for the assessment of neuronal integrity. However, there is only limited experience with IMZ in patients with acute cerebral infarction. Therefore, the aim of this study was to evaluate IMZ single photon emission computed tomography (SPECT) in patients with acute cerebral ischaemia. IMZ SPECT was performed in 21 patients with acute cerebral infarction 7-10 days after stroke onset. Eleven patients underwent systemic thrombolysis within 6 h after symptom onset (group 1), whereas 10 patients were treated conservatively (group 2). IMZ (150-200 MBq) was injected intravenously and imaging was performed using a dedicated four-head SPECT camera at 5 min (perfusion) and 90 min (receptor distribution) post-injection, with an acquisition time of 50 min each. Images were analysed by visual inspection. Four patients showed normal IMZ distribution, and 17 patients showed abnormalities of IMZ uptake on both early and late images. In six patients with regional uptake deficits, a crossed cerebellar diaschisis was observed on early images. Cerebellar inhomogeneity of tracer uptake was absent at the time of late images in all six patients. In eight patients, areas of hypoperfusion corresponded exactly to the regions of receptor deficiency (match). In five patients, preserved neuronal integrity was present in hypoperfused areas (mismatch). In four patients, normally or even hyperperfused areas exhibited regional receptor deficiency (inverse mismatch). In conclusion, IMZ SPECT demonstrated differences between regional perfusion and receptor distribution in about one-half of patients 7-10 days after acute cerebral ischaemia. Interesting patterns between the early phase (perfusion) and the late phase (receptor distribution) were found. These patterns are indicative of the heterogeneous development of cerebral ischaemia where, even days after stroke onset, areas of hypoperfusion but preserved neuronal integrity may be present. However, the evaluation of the potential clinical and therapeutic impact of individual IMZ distribution patterns requires further investigation.
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PMID:Experience with 123I-iomazenil SPECT in acute cerebral infarction. 1246 84

Fructose-1,6-bisphosphate (FBP), an endogenous intermediate of glycolysis, protects the brain against ischemia-reperfusion injury. The mechanisms of FBP protection after cerebral ischemia are not well understood. The current study was undertaken to determine whether FBP protects primary neurons against hypoxia and oxidative stress by preserving reduced glutathione (GSH). Cultures of pure cortical neurons were subjected to oxygen deprivation, a donor of nitric oxide and superoxide radicals (3-morpholinosydnonimine), an inhibitor of glutathione synthesis (L-buthionine-sulfoximine) or glutathione reductase (1,3-bis(2-chloroethyl)-1-nitrosourea) in the presence or absence of FBP (3.5 mM). Neuronal viability was determined using an 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. FBP protected neurons against hypoxia-reoxygenation and oxidative stress under conditions of compromised GSH metabolism. The efficacy of FBP depended on duration of hypoxia and was associated with higher intracellular GSH concentration, an effect partly mediated via increased glutathione reductase activity.
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PMID:Fructose-1,6-bisphosphate preserves intracellular glutathione and protects cortical neurons against oxidative stress. 1250 61

Oxidative stress is believed to play an important role in neuronal cell death associated with several neurodegenerative diseases (e.g., Alzheimer disease, Parkinson disease, and cerebral ischemia). Neuronal cell death might be one of the crucial mediators of these diseases. The transcription factor NF-kappaB is well-known for its roles in preventing apoptotic cell death. Data indicated that NF-kappaB activation by pre-conditioning is part of a general brain tolerance program. Here we show that pre-conditioning leading to NF-kappaB activation also protects against oxidative insults generated by Fe2+ ions. Protection was accompanied by a long-lasting (more than 24 h) NF-kappaB activation. Using this paradigm of oxidative insult, we analyzed the effect of hypericin, one of the active principles of St. John's Wort. Hypericin alone was able to induce short-time activation of NF-kappaB, which declined to basal levels after 24 h. Cell death was induced by hypericin at a concentration of 10 microM. A profound synergistic action in inducing apoptosis was detected in co-treatment of hypericin together with FeSO4. In contrast, hypericin in low concentrations was able to partly prevent cell death induced by amyloid-beta-peptide (Abeta). Hypericin (10 microM) synergistically enhanced Abeta neurotoxicity. Since hypericin is a described inhibitor of protein kinase C, we compared its action to staurosporine, another natural neuronal death-promoting PKC inhibitor. Staurosporine induced cell death and activates NF-kappaB. Molecular inhibition of NF-kappaB activation with a transdominant negative IkappaB-alpha protected against staurosporine-induced cell death. In summary, the data describe NF-kappaB in the same primary neuronal culture as stimulus-dependent, anti-apoptotic, or pro-apoptotic factor.
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PMID:Stimulus-dependent activation of NF-kappaB specifies apoptosis or neuroprotection in cerebellar granule cells. 1262 8

Neuronal death in cerebral ischemia is largely due to excitotoxic mechanisms, which are known to activate the c-Jun N-terminal kinase (JNK) pathway. We have evaluated the neuroprotective power of a cell-penetrating, protease-resistant peptide that blocks the access of JNK to many of its targets. We obtained strong protection in two models of middle cerebral artery occlusion (MCAO): transient occlusion in adult mice and permanent occlusion in 14-d-old rat pups. In the first model, intraventricular administration as late as 6 h after occlusion reduced the lesion volume by more than 90% for at least 14 d and prevented behavioral consequences. In the second model, systemic delivery reduced the lesion by 78% and 49% at 6 and 12 h after ischemia, respectively. Protection correlated with prevention of an increase in c-Jun activation and c-Fos transcription. In view of its potency and long therapeutic window, this protease-resistant peptide is a promising neuroprotective agent for stroke.
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PMID:A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia. 1293 12


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