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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have used a rat model of focal cerebral ischemia to investigate changes in gene expression that occur during stroke. To monitor these changes, we employed representational difference analysis-polymerase chain reaction (PCR). A total of 128 unique gene fragments were isolated, and we selected 13 of these for quantitative reverse transcriptase-PCR analysis. Of these 13 genes, we found seven that were differentially expressed. Four of these genes have not previously been implicated in stroke, and include neuronal activity regulated pentraxin (Narp), cysteine rich protein 61 (Cyr61), Bcl-2 binding protein BIS (Bcl-2-interacting death suppressor), and lectin-like ox-LDL receptor (LOX-1). We demonstrated differential expression of each gene by quantitative PCR analysis, and in the case of LOX-1, we further confirmed differential expression by in situ hybridization. LOX-1 expression is induced greater than ten fold at the core lesion site, and is essentially localized to the ipsilateral half of the brain. LOX-1 appears to be expressed in a non-neuronal cell type, and it does not appear to be expressed in vascular endothelial cells within the brain. This suggests that LOX-1 may serve a novel function in the brain.
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PMID:Identification of differentially expressed genes induced by transient ischemic stroke. 1200 27

Matrix metalloproteinases (MMPs) are hypothesized to play an important role in the pathogenesis of several central nervous system disorders. Increased levels of expression of MMP-9 (gelatinase B) and MMP-2 (gelatinase A) have been observed in Alzheimer's disease, stroke, multiple sclerosis, and amyotrophic lateral sclerosis. This suggests an aberrant regulation of MMPs that could lead to inappropriate expression of MMP activity. To allow us to evaluate the effect of increased levels of active MMP-9 in the central nervous system, mutant forms of the enzyme were designed to autocatalytically remove the pro domain, yielding active enzyme. This was accomplished by modifying residues in the cysteine switch autoinhibitor region of the propeptide. Stable cell lines and transgenic mice that express G100L and D103N autoactive forms of human MMP-9 were developed to study the role of dysregulation of MMP-9 in disease.
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PMID:Engineering autoactivating forms of matrix metalloproteinase-9 and expression of the active enzyme in cultured cells and transgenic mouse brain. 1208 77

Understanding the mechanisms of free energy transfer in metabolism is fundamental to understanding how the chemical forces that sustain the molecular organization of the cell are distributed. Recent studies of molecular motors (1-3) and ATP-driven proton transport (4-6) describe how chemical potential is transferred at the molecular level. These systems catalyze energy transfer through structural change and appear to be dedicated exclusively to their coupling tasks (7, 8). Here we report the discovery of a new class of energy-transfer system. It is a biosynthetic pump composed of cysteine biosynthesis enzymes, ATP sulfurylase and O-acetylserine sulfhydrylase, each with its own catalytic function and from whose interactions emerge new function: the hydrolysis of ATP. The hydrolysis is kinetically and energetically linked to the chemistry catalyzed by ATP sulfurylase, the first enzyme in the cysteine biosynthetic pathway, in such a way that each molecule of ATP hydrolyzed, each stroke of the pump, produces 1 equivalent of that enzyme's product. These findings integrate cysteine metabolism and broaden our understanding of the ways in which higher order allostery is used to effect free energy transfer.
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PMID:Cysteine biosynthetic enzymes are the pieces of a metabolic energy pump. 1208

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebrovascular disease leading to cognitive decline and dementia. CADASIL usually begins with migraine in about one third of the patients. More severe manifestations, transient ischemic attacks or recurrent strokes, appear between 30 and 50 years of age. CADASIL, however, may be diagnosed well before the first stroke on the basis of characteristic white matter hyperintensities upon magnetic resonance imaging and presence of pathognomonic granular osmiophilic material in arterial walls, including dermal arteries, since the arteriopathy is generalized. Gradual destruction of vascular smooth muscle cells (VSMC) leads to progressive wall thickening and fibrosis and luminal narrowing in small and medium-sized penetrating arteries. The reduced cerebral blood flow finally causes lacunar infarcts, mainly in the basal ganglia and fronto-temporal white matter, which lead to cognitive deficits and dementia of the subcortical vascular type. CADASIL is caused by single missense mutations or small deletions in Notch3 gene encoding a transmembrane receptor Notch3, of which upon ligand binding a nuclear signaling protein is generated by regulated intramembrane proteolysis. Notch signaling is essential during development, regulating cellular differentiation. In adults Notch3 is expressed only in VSMCs and it may promote cell survival by inhibiting apoptosis, but its exact function is unknown. Mutations result in either a gain or loss of one (or rarely, 3) cysteine residue(s) in one of the 34 epidermal growth factor-like repeats in the extracellular amino-terminal region of Notch3. It is as yet unclear which disturbance in the Notch signaling pathway leads to the characteristic vascular pathology of CADASIL.
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PMID:CADASIL: a common form of hereditary arteriopathy causing brain infarcts and dementia. 1214 5

Homocysteinemia in humans is associated with vascular complications that increase the risk for atherosclerosis and stroke. Animal studies have shown that the disease is multifactorial and includes lesions associated with the elastin component of the extracellular matrix. In the following experiments we have used the aortas from rapidly growing chicks to assess the cause of the elastin defects resulting from homocysteinemia. Day-old chicks were fed diets containing varying amounts of DL-methionine, DL-homocysteine, homocysteine thiolactone or DL-cysteine for periods up to 9 wk. Three weeks after feeding 2% DL-methionine the plasma methionine was elevated > 20-fold, whereas plasma homocysteine was more than 3-fold normal plasma values. The aortas showed severe histopathology, evidenced by the pronounced separation of elastic lamellae with marked smooth muscle proliferation and, in some instances, aneurysms. There was no evidence of decreased desmosine content or a significant reduction in lysyl oxidase in the aortas from the treated groups compared to those from controls. Increasing other dietary factors such as the vitamins required for methionine metabolism had no effect on the development of the vascular lesions. Twenty to 30% of the chicks fed the high methionine diets exhibited severe neurological problems, expressed as tonic contractions or seizures. Electron microscopy revealed disordered aortic elastic fibrils, associated with either an absence of or disrupted assembly of microfibrils. Immunohistochemical studies demonstrated a loss of fibrillin-2 immunoreactivity in the aortas of chicks fed 2% methionine. The studies suggest that elevated plasma methionine or its metabolites disrupt normal microfibril configuration, leading to the assembly of aberrant elastic fibers.
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PMID:Fibrillin-2 defects impair elastic fiber assembly in a homocysteinemic chick model. 1216 53

The mode of neuronal death caused by cerebral ischemia and reperfusion appears on the continuum between the poles of catastrophic necrosis and apoptosis: ischemic neurons exhibit many biochemical hallmarks of apoptosis but remain cytologically necrotic. The position on this continuum may be modulated by the severity of the ischemic insult. The ischemia-induced neuronal death is an active process (energy dependent) and is the result of activation of cascades of detrimental biochemical events that include perturbion of calcium homeostasis leading to increased excitotoxicity, malfunction of endoplasmic reticulum and mitochondria, elevation of oxidative stress causing DNA damage, alteration in proapoptotic gene expression, and activation of the effector cysteine proteases (caspases) and endonucleases leading to the final degradation of the genome. In spite of strong evidence showing that brain infarction can be reduced by inhibiting any one of the above biochemical events, such as targeting excitotoxicity, up-regulation of an antiapoptotic gene, or inhibition of a down-stream effector caspase, it is becoming clear that targeting a single gene or factor is not sufficient for stroke therapeutics. An effective neuroprotective therapy is likely to be a cocktail aimed at all of the above detrimental events evoked by cerebral ischemia and the success of such therapeutic intervention relies upon the complete elucidation of pathways and mechanisms of the cerebral ischemia-induced active neuronal death.
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PMID:Molecular mechanisms of cerebral ischemia-induced neuronal death. 1245 47

We reviewed 12 patients from 11 Japanese families diagnosed as having CADASIL from 1998 to 2001. The age of onset of focal neurologic deficits ranged from 38 to 71 years (mean: 50.4 +/- 9.8 years). Japanese CADASIL patients rarely had migraine and frequently presented with symptoms of dementia at diagnosis. Notch3 mutations were concentrated in exons 3, 4, and 5. Cysteine was replaced by another amino acid or vice versa in the majority of Japanese CADASIL patients. However, in 2 families, the mutations were not related to cysteine. In the prospective study, 2030 patients with stroke were hospitalized in 6 hospitals with stroke units in the Kumamoto district from 1999 to 2001. Among them, 14 patients fulfilled the criteria of being less than 60 years of age, showing lacunar strokes and/or TIA, presence of a family history, and no risk factors of stroke. One of these 14 patients was diagnosed as having CADASIL by DNA analysis. However, if hyperlipidemia was excluded from the list, 16 patients fulfilled the criteria and 2 patients were diagnosed as having CADASIL by DNA analysis. It was suspected that the incidence of CADASIL is not so rare in Japan. There were some families with CADASIL-like features, but without Notch3 mutations or GOM, suggesting the need for genetic analysis in the future.
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PMID:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and CADASIL-like disorders in Japan. 1248 Jul 61

Primary brain injury in stroke is followed by an excitotoxic cascade, oxidative stress and further neural damage. Glutathione is critical and depleted in oxidative stress. Since cysteine is limiting in glutathione synthesis, this study investigated the effect of dietary sulfur amino acid (SAA) deficiency on neural damage in a rat model of global hemispheric hypoxia-ischemia (GHHI). Animals were fed with SAA deficient ("deficient") or control diet for 3 days, subjected to right common carotid artery ligation and hypoxia, and diet continued for 3 more days. Histologically evaluated neural damage at 7 days post hypoxia-ischemia was greater in "deficient" rats, shown by mean (+/- SEM) global and hippocampal grid scores of 2.5 +/- 0.7 and 34.9 +/- 9.3%, respectively, vs. controls' scores of 0.1 +/- 0.1 and 0.1 +/- 0.1%, respectively. Mean brain (+/- SEM) reduced glutathione was not different between groups at 6h post hypoxia-ischemia, but was decreased in "deficient" animals 3 days later in neocortex (1.46 micromoles/g wet weight +/- 0.05 vs. 1.67 +/- 0.04 in controls) and thalamus (1.60 micromoles/g wet weight +/- 0.05 vs. 1.78 +/- 0.03 in controls). Administration of a cysteine precursor to "deficient" animals did not ameliorate neural damage. These findings suggest that well-nourished but not "deficient" animals tolerate a mild brain insult. The decline in brain glutathione in the "deficient" animals may be one of several contributing mechanisms.
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PMID:The effects of dietary sulfur amino acid deficiency on rat brain glutathione concentration and neural damage in global hemispheric hypoxia-ischemia. 1250 70

Sitosterolemia is an autosomal recessive disorder caused by mutations in the ABCG5 or ABCG8 half-transporter genes. These mutations disrupt the mechanism that distinguishes between absorbed sterols and is most prominently characterized by hyperabsorption and impaired biliary elimination of dietary plant sterols. Sitosterolemia patients retain 15-20% of dietary plant sterols, whereas normal individuals absorb less than 1-5%. Normotensive Wistar Kyoto inbred (WKY inbred), spontaneously hypertensive rat (SHR), and stroke-prone spontaneously hypertensive rat (SHRSP) strains also display increased absorption and decreased elimination of dietary plant sterols. To determine if the genes responsible for sitosterolemia in humans are also responsible for phytosterolemia in rats, we sequenced the Abcg5 and Abcg8 genes in WKY inbred, SHR, and SHRSP rat strains. All three strains possessed a homozygous guanine-to-thymine transversion in exon 12 of the Abcg5 gene that results in the substitution of a conserved glycine residue for a cysteine amino acid in the extracellular loop between the fifth and sixth membrane-spanning domains of the ATP binding cassette half-transporter, sterolin-1. The identification of this naturally occurring mutation confirms that these rat strains are important animal models of sitosterolemia in which to study the mechanisms of sterol trafficking.
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PMID:A missense mutation in the Abcg5 gene causes phytosterolemia in SHR, stroke-prone SHR, and WKY rats. 1261 6

There is increasing evidence that some neuronal death after brain ischaemia is mediated by the action of cysteine-requiring aspartate-directed proteases (caspases), the proteases responsible for apoptosis in mammals, although this form of neuronal death is not always accompanied by the morphological changes that are typical of apoptosis in other tissues. Caspase-mediated neuronal death is more extensive after transient than permanent focal brain ischaemia and may contribute to delayed loss of neurons from the penumbral region of infarcts. The activation of caspases after brain ischaemia is largely consequent on the translocation of Bax, Bak, and other BH3-only members of the Bcl-2 family to the mitochondrial outer membrane and the release of cytochrome c, procaspase-9, and apoptosis activating factor-1 (Apaf-1) from the mitochondrial intermembrane space. How exactly ischaemia induces this translocation is still poorly understood. NF-kappaB, the c-jun N-terminal kinase-c-Jun pathway, p53, E2F1, and other transcription factors are probably all involved in regulating the expression of BH3-only proteins after brain ischaemia, and mitochondrial translocation of Bad from sequestering cytosolic proteins is promoted by inactivation of the serine-threonine kinase, Akt. Other processes that are probably involved in the activation of caspases after brain ischaemia include the mitochondrial release of the second mitochondrial activator of caspases (Smac) or direct inhibitor-of-apoptosis-binding protein with low pI (DIABLO), the accumulation of products of lipid peroxidation, a marked reduction in protein synthesis, and the aberrant reentry of neurons into the cell cycle. Non-caspase-mediated neuronal apoptosis may also occur, but there is little evidence to date that this makes a significant contribution to brain damage after ischaemia. The intracellular processes that contribute to caspase-mediated neuronal death after ischaemia are all potential targets for therapy. However, anti-apoptotic interventions in stroke patients will require detailed evaluation using a range of outcome measures, as some such interventions seem simply to delay neuronal death and others to preserve neurons but not neuronal function.
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PMID:Apoptosis and brain ischaemia. 1265 66


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