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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proteolytic modifications of amyloid precursor protein (APP) play key roles in the development of Alzheimer's disease. However, each specific in vivo process has not yet been fully resolved in spatial terms because the orthodox approach employing electrophoretic analysis requires homogenization of samples and thus provides limited information on the localization of the process. To acquire such spatial information for the primary process involved in beta-amyloidogenesis, we have designed and developed a novel antibody exclusively specific to APP fragments possessing the exact amino terminus of the major beta-amyloid (A beta) peptide. Use of this antibody revealed that cleavage of APP at the amino terminal position of the A beta sequence is a normal steady-state process in gerbil hippocampus. Furthermore, nonfatal transient (10 min) forebrain ischemia followed by reperfusion enhanced the initial beta-amyloidogenic reaction mainly in pyramidal cells of CA1 sector and of dentate gyrus prior to and along with delayed neuronal degeneration. The APP fragments accumulated in cell bodies and dendrites of the neurons. These results suggest that beta-amyloidogenesis may involve a process that is also activated in postischemic brain and that ischemia-like conditions may contribute to pathogenic A beta accumulation.
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PMID:Spatial resolution of the primary beta-amyloidogenic process induced in postischemic hippocampus. 819 61

It has been suggested that microglia, a type of glial cells in the central nervous system, play various important roles in normal and pathologic brains. In this article, we discussed the association or roles of microglia in injury and in brain diseases such as Alzheimer's disease, AIDS dementia complex, multiple sclerosis and ischemia. Furthermore, microglia-derived cytotoxic products and other secretory factors were summarized. In addition to the pathological aspects, secretory factors that showed neurotrophic effects were described with special reference to their physiological significance in the neuronal growth, neuronal function and regeneration processes. Accumulated evidence suggests that microglia are associated with not only brain pathology but also normal physiology in the brain.
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PMID:Functional roles of microglia in the brain. 823 23

The suspected involvement of the beta-amyloid precursor protein (beta APP) in the etiology of Alzheimer's disease (AD) has been strengthened by recent genetic evidence, but pursuit of the mechanisms involved will initially require basic cell biology approaches. Several studies have concentrated on toxic activities of beta-amyloid peptide (beta AP) itself, illuminating its contributions to excitotoxicity and calcium-mediated degeneration in general. We now know that generation of beta AP from beta APP also compromises the production of an important set of trophic factors: the secreted forms of beta APP (APPS), which may act--ironically--by conferring protection from calcium-mediated insults. Therefore, conditions which contribute to the formation of beta AP (possibly including ischemia) not only produce an agent which exacerbates calcium-mediated cell death, but also reduce the levels of one of the few factors able to rescue calcium homeostasis. The implications of these postulates and their relationship to the process of aging are discussed.
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PMID:beta-Amyloid precursor protein mismetabolism and loss of calcium homeostasis in Alzheimer's disease. 823 76

We studied changes in the spatial and temporal distribution of the beta amyloid precursor protein (APP) of Alzheimer's disease (AD) in experimental ischemic brain injury. Rats with repeated reversible occlusions of one middle cerebral artery showed striking APP reactivity in astrocytic processes in perifocal regions and adjacent white matter. APP reactive dystrophic axons and neurons were also evident in the cortex and hippocampus ipsilateral to the MCA occlusion. Such changes were similarly apparent in animals subjected to partial forebrain ischemia induced by bilateral occlusion of the carotid arteries. Our studies suggest that focal ischemic insults or chronic hypoperfusion leads to increased accumulation or induction of APP in surviving cellular elements that may relate to the processes involved in beta amyloid deposition in AD.
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PMID:The amyloid precursor protein in ischemic brain injury and chronic hypoperfusion. 823 81

The effects of a new acetylcholinesterase inhibitor, ENA-713, on ischemia-induced changes in acetylcholine, monoamines, and their metabolites, were studied in the gerbil. ENA-713 (0.2 mg/kg) or saline was administered intraperitoneally to gerbils 30 min before induction of cerebral ischemia by bilateral carotid occlusion. Pretreatment with ENA-713 mitigated the ischemia-induced abnormalities of the cholinergic, dopaminergic and serotoninergic systems in the gerbil brain, although it had virtually no effect on acetylcholine, monoamines, or their metabolites in any region of the normal gerbil brain. These findings suggest that ENA-713 has beneficial effects against ischemia-induced cerebral disorders. Thus, ENA-713 seems to be promising as a preventive or therapeutic agent for cerebrovascular dementia due to cerebral ischemia and might be useful for the treatment of Alzheimer-type dementia which is associated with multiple neurotransmitter abnormalities in the brain.
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PMID:Effects of the acetylcholinesterase inhibitor ENA-713 on ischemia-induced changes in acetylcholine and aromatic amine levels in the gerbil brain. 825 Jun 45

Ischemia-induced nerve cell death can partly be prevented by propentofylline, a pharmacon structurally related to xanthine derivates that interacts with the neuromodulatory function of endogenous adenosine. To evaluate a possible mechanism of neuroprotection by propentofylline, we studied its effect on the cellular production of reactive oxygen intermediates in microglial cells, which under pathological conditions can differentiate into brain macrophages, in comparison to peritoneal macrophages. Using a flow cytometric assay, we determined the intracellular formation of reactive oxygen intermediates by measuring the oxidation of the membrane-permeable and nonfluorescent dihydrorhodamine 123 to the cationic and intracellularly trapped, green fluorescent rhodamine 123 in single viable cells. Propentofylline at the therapeutic concentration of 50 microM completely inhibited the Ca(2+)-dependent Con A-induced increase in the production of reactive oxygen intermediates in peritoneal macrophages. In isolated and cultured microglial cells, which have a high spontaneous respiratory burst activity, the spontaneous production of reactive oxygen intermediates was reduced by approximately 30%. A phorbol 12-myristate 13-acetate-induced rise in the respiratory burst activity could not be inhibited by propentofylline in either cell type. An increased generation of reactive oxygen intermediates is thought to contribute to nerve cell death after brain ischemia, edema, and neurodegenerative diseases like Alzheimer's disease. These pathological conditions are all accompanied by an activation of microglial cells. We therefore suggest that the neuroprotective properties of propentofylline might in part be due to a modulation of the microglial production of potentially harmful reactive oxygen intermediates.
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PMID:Modulation of intracellular formation of reactive oxygen intermediates in peritoneal macrophages and microglia/brain macrophages by propentofylline. 826 50

Complex sets of nervous system functions are dependent on proper working of the synaptic apparatus, and these functions are regulated by diverse synaptic proteins that are distributed in various subcellular compartments of the synapse. The most extensively studied synaptic proteins are synaptophysin, the synapsins, growth associated protein 43 (GAP-43), SV-2, and p65. Moreover, synaptic terminals contain a great number of other proteins involved in calcium transport, neurotransmission, signaling, growth and plasticity. Probes against various synaptic proteins have recently been used to study synaptic alterations in human disease, as well as in experimental models of neurological disorders. Such probes are useful markers of synaptic function and synaptic population density in the nervous system. For the present, we will review the role of synaptic proteins in the following conditions: Alzheimer's disease (AD) and other disorders including ischemia, disorders where synapse-associated proteins are abnormally accumulated in the nerve terminals, synaptic proteins altered after denervation, and synaptic proteins as markers in neoplastic disorders. The study of the molecular alterations of the synapses and of plasticity might yield important clues as to the mechanisms of neurodegeneration in AD, and of the patterns of presynaptic and dendritic damage under diverse pathological conditions.
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PMID:The role of synaptic proteins in the pathogenesis of disorders of the central nervous system. 826 86

We surveyed 1,545 subjects--recruited into the UK Medical Research Council elderly hypertension treatment trial between 1982 and 1987--to detect incident cases of dementia, identifying 50 cases of dementia, including 31 cases of probable or possible Alzheimer's disease (AD). These we compared with 223 unimpaired, unmatched controls from the same population for exposure to familial, cardiovascular, educational, and geographic risk factors for dementia. Our study confirms the association of family history of dementia with dementia (odds ratio [OR] = 4.36) and AD (OR = 4.69), and of advanced age with dementia (OR = 2.81). Rural residence exerted a protective effect for dementia (OR = 0.21) and AD (OR = 0.28). We report near-significant associations between AD and dementia and several cardiovascular risk factors (ECG ischemia, systolic hypertension, and smoking) among subjects lacking a family history of dementia. We postulate the existence of a nonfamilial form of dementia transcending traditional categories of multi-infarct dementia and AD, more common among urban residents, and mediated through vascular pathology. Risk factors reported elsewhere but not confirmed in this study were advanced maternal age and winter season of birth.
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PMID:Risk factors for Alzheimer's disease and dementia: a case-control study based on the MRC elderly hypertension trial. 829 99

New highly-accurate stereological methods for estimating the total numbers of neurons in brain structures have been used to test for age-related neuron loss in the human hippocampal formation. Across the age range of 13 to 85 years, there was a substantial loss of neurons in the subiculum (52%) and in the hilus of the dentate gyrus (31%); the three remaining hippocampal subdivisions showed no significant change. These losses qualify as potential morphological correlates of senescent decline in relational memory in that they can be expected to compromise the functional integrity of a region of the brain known to be intimately involved in this type of memory. The regional pattern of neuron loss is similar in certain respects to the patterns of cell loss seen during the initial phases of ischemia and epilepsy and is fundamentally different from the pattern associated with Alzheimer's disease.
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PMID:Regionally specific loss of neurons in the aging human hippocampus. 836 10

Brain is a logical target of free radical damage, considering the large lipid content of myelin sheaths and the high rate of brain oxidative metabolism. Thus, the hypothesis that free radicals may be involved in the pathogenesis of certain CNS diseases has gained increasing popularity in recent years. In CNS ischemia-reperfusion injury, the role of free radicals appears to be well established, however, involvement of other factors, such as excitatory amino acids and prostaglandins, may also contribute to the production of neuronal necrosis following ischemia. Liberation of free iron appears to play a crucial role in the generation of reactive oxygen species in posttraumatic epilepsy. Although there is no direct evidence to indicate free radical involvement in the pathogenesis of Alzheimer's disease, brain trauma with release of iron, amyloid angiopathy and disturbances in blood-brain barrier function all appear to contribute to the development of ischemic episodes with free radical generation and neuronal degeneration. In Parkinson's disease, the substantia nigra appears to be under oxidative stress as evidenced by the findings of increased lipid peroxidation, reduced GSH levels, high concentration of iron and free radical generation via autocatalytic mechanisms within neuromelanin-containing catecholaminergic neurons. Regardless of the initial insult, a cascade of events involving both reactive oxygen radicals and mitochondrial metabolism is likely to contribute to cell injury.
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PMID:Oxygen, antioxidants and brain dysfunction. 837 80


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