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)

The distribution of beta-amyloid precursor protein (APP) was examined immunocytochemically in rats subjected to focal cerebral ischemia by permanent occlusion of the middle cerebral artery. At 4 and 7 days post-occlusion, APP immunoreactivity was preferentially localized within axonal swellings, dystrophic neurites and neuronal perikarya all along the periphery of the infarct. Immunolabeling was observed with antibodies generated against N-terminal, midregion, and C-terminal domains of APP. No immunoreactivity was observed with antisera directed against beta-amyloid protein (beta A4) itself. This pathological accumulation of APP is consistent with alterations of APP recently described in other models of neurodegeneration and implies a role for this protein in the response to CNS injury.
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PMID:Amyloid precursor protein accumulates in regions of neurodegeneration following focal cerebral ischemia in the rat. 145 15

Alterations of beta/A4 amyloid protein precursor (APP) were investigated immunohistochemically in the gerbil brain after transient global ischemia and subsequent reperfusion. Marked accumulation of this protein peaking at 24 h occurred in the neurons of the CA3 and paramedian region of the hippocampus as well as layers III, V and VI of the cerebral cortex. On the contrary, the accumulation was not observed in the neurons of the CA1 region. These results indicate that distribution of APP is altered depending on tissue viabilities after cerebral ischemia.
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PMID:Regional accumulation of amyloid beta/A4 protein precursor in the gerbil brain following transient cerebral ischemia. 149 78

An induction of amyloid precursor protein (APP) mRNA was examined in a middle cerebral artery occlusion model of rats using Northern blot analyses. The level of tubulin mRNA was measured as an internal standard. With persistent focal ischemia, APP mRNA species which contain a Kunitz-type protease inhibitor (KPI) domain were induced in the rat cerebral cortex from 1 to 21 days after the insult with a maximum at 4 days, while total amounts of APP mRNA did not change. No change was observed in the level of tubulin mRNA. These results suggest a selective role of APP species which contain the KPI domain in focal cerebral ischemia.
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PMID:Selective induction of Kunitz-type protease inhibitor domain-containing amyloid precursor protein mRNA after persistent focal ischemia in rat cerebral cortex. 190 58

Microglial cell activation is a rapidly occurring cellular response to cerebral ischaemia. Microglia proliferate, are recruited to the site of lesion, upregulate the expression of several surface molecules including major histocompatibility complex class I and II antigens, complement receptor and the amyloid precursor protein (APP) as well as newly expressed cytokines, e.g. interleukin-1 and transforming growth factor beta 1. The ischaemia-induced production of APP may contribute to amyloid deposition in the aged brain under conditions of hypofusion. Ultrastructurally, microglia transform into phagocytes removing necrotic neurons but still respecting the integrity of eventually surviving neurons even in the close vicinity of necrotic neurons. Microglial activation starts within a few minutes after ischaemia and thus precedes the morphologically detectable neuronal damage. It additionally involves a transient generalized response within the first 24 hours post-ischaemia even at sites without eventual neuronal cell death. In functional terms, the microglial reaction appears to be a double-edged sword in ischaemia. Activated microglia may exert a cytotoxic effector function by releasing reactive oxygen species, nitric oxide, proteinases or inflammatory cytokines. All of these cytotoxic compounds may cause bystander damage following ischaemia. Pharmacological suppression of microglial activation after ischaemia has accordingly attenuated the extent of cell death and tissue damage. However, activated microglia support tissue repair by secreting factors such as transforming growth factor beta 1 which may limit tissue damage as well as suppress astroglial scar formation. In line with ultrastructural observations microglial activation in ischaemia is a strictly controlled event. By secreting cytokines and growth factors activated microglia most likely serve seemingly opposed functions in ischaemia, i.e. maintenance as well as removal of injured neurons. Post-ischaemic pharmacological modulation of microglial intervention in the cascade of events that lead to neuronal necrosis may help to improve the structural and functional outcome following CNS ischaemia.
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PMID:Reactive microglia in cerebral ischaemia: an early mediator of tissue damage? 749 96

The distribution of beta-amyloid protein precursor (APP) was investigated immunocytochemically in rats subjected to global cerebral ischemia (GCI) induced by cardiac arrest. Rats underwent 10 min of GCI with 3, 6, and 12 h and 2 and 7 days of survival. APP immunostaining was found extracellular and intracellularly. Multiple extracellular APP immunoreactive deposits around and close to the vessels appeared as soon as 3 h after GCI. Extracellular accumulation of APP occurred frequently in the hippocampus, cerebral and cerebellar cortex, basal ganglia and thalamus and rarely in the brain stem. These deposits were labelled with antibodies against the N-terminal, beta-amyloid peptide, and C-terminal domains of APP. Our data suggests that either proteolytically cleaved fragments of the full-length APP or the entire APP molecule accumulates extracellularly after GCI. This findings may not only implicate the participation of APP in postischemic tissue damage but also suggest the involvement of pathomechanisms operating in ischemia in Alzheimer's disease pathology.
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PMID:Complete cerebral ischemia with short-term survival in rats induced by cardiac arrest. I. Extracellular accumulation of Alzheimer's beta-amyloid protein precursor in the brain. 752 11

The neurons that accumulate beta/A4 amyloid protein precursor (APP) after transient cerebral ischemia were characterized by comparing their distribution with those destined to suffer delayed neuronal death or those with induction of 72-kDa heat-shock protein. With immunohistochemistry of APP in gerbil brains, no alterations were detected after ischemia for 2 min and subsequent reperfusion for up to 7 days, whereas after ischemia for 3 min and reperfusion for 48 h, a small number of neurons, intensely immunoreactive for APP, were found to be scattered in the CA1 subfield of the hippocampus and the layer V/VI of the frontoparietal cortex. After reperfusion for 24 h following ischemia for 5 or 15 min, a large number of densely stained neurons appeared in the subiculum, and CA3 subfield of the hippocampus, and layers III and V/VI of the frontoparietal cortex. The majority of these neurons did not undergo delayed neuronal death after reperfusion for 72 h and thereafter. APP and heat-shock protein were upregulated in the same regions, but mostly in distinct neurons. These results indicate that APP accumulates in the neurons marginating the regions destined to die, and the majority of these neurons seem to survive after ischemic insult.
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PMID:Temporal profiles of accumulation of amyloid beta/A4 protein precursor in the gerbil after graded ischemic stress. 801 2

Transient global forebrain ischemia induces in rat brain a large increase of expression of the immediate early genes c-fos and c-jun and of the mRNAs for the 70-kDa heat-shock protein and for the form of the amyloid beta-protein precursor including the Kunitz-type protease-inhibitor domain. At 24 hr after ischemia, this increased expression is particularly observed in regions that are vulnerable to the deleterious effects of ischemia, such as pyramidal cells of the CA1 field in the hippocampus. In an attempt to find conditions which prevent the deleterious effects of ischemia, representatives of three different classes of K+ channel openers, (-)-cromakalim, nicorandil, and pinacidil, were administered both before ischemia and during the reperfusion period. This treatment totally blocked the ischemia-induced expression of the different genes. In addition it markedly protected neuronal cells against degeneration. The mechanism of the neuroprotective effects involves the opening of ATP-sensitive K+ channels since glipizide, a specific blocker of that type of channel, abolished the beneficial effects of K+ channel openers. The various classes of K+ channel openers seem to deserve attention as potential drugs for cerebral ischemia.
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PMID:K+ channel openers prevent global ischemia-induced expression of c-fos, c-jun, heat shock protein, and amyloid beta-protein precursor genes and neuronal death in rat hippocampus. 841 18

Several diseases related to brain aging seem to be due to neuronal loss and decreased synaptic functions. Therefore it is important to clarify the cellular and molecular mechanism of age-related-neuronal death and -reduction in synaptic activities in the brain. I here review recent advances in cellular and molecular studies on neuronal death and the decrease in synaptic functions. Neuronal death is caused not only with physiological aging but also by several pathological states such as 1) results from abnormal metabolism of beta APP (Alzheimer's disease), 2) increased level of extraneuronal glutamate and intracellular Ca2+/NO (cerebral ischemia), and 3) appearance of neurotoxic MPP+ (1-methyl-4-phenyl-pyridinium ion) (Parkinson's disease) etc. From neurotoxicological aspect of neuro-glial interaction, I introduce recent findings on signaling pathways of NO synthase induction in glial cells and cytotoxic action of NO in neurons. Furthermore I also describe and discuss our findings obtained in the brain of old rats as well as in senescence accelerated mice (accelerated aging substrain of AKR/J-mouse) regarding age-related changes in synaptic activity and neurotransmittor receptor-mediated signaling system.
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PMID:[Neurochemical aspect of brain aging--neuronal death and decreased synaptic functions]. 875 25

Brains from patients with Alzheimer's disease contain amyloid plaques which are composed of beta-amyloid peptide and are considered to play a causal role in the neuropathology of this disease. The origin of beta-amyloid peptide in brain parenchyma and vessels of Alzheimer's disease patients is not known. This study examined the permeability of the blood-brain barrier to beta-amyloid peptide in rats subjected to single or repeated episodes of global cerebral ischaemia followed by i.v. injections of human synthetic beta-amyloid-(1-42)-peptide. Rats receiving beta-amyloid peptide after ischaemia demonstrated multifocal and widespread accumulation of beta-amyloid peptide in hippocampus, cerebral cortex and occasionally in white matter. beta-Amyloid peptide penetration involved arterioles, veins and venules. Neuronal, glial and pericyte bodies were observed filled with beta-amyloid peptide. Direct evidence that soluble human beta-amyloid-(1-42)-peptide crosses the blood-brain barrier and enters the brain from the circulation is thus provided for the first time.
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PMID:Evidence of blood-brain barrier permeability/leakage for circulating human Alzheimer's beta-amyloid-(1-42)-peptide. 881 45

Studies of ischemic brain injury in cell culture, animal models, and humans have revealed inter- and intra-cellular signaling pathways that increase resistance to cell degeneration and death. Brain injury induces expression of many different growth factors and cytokines which can protect neurons against insults relevant to the pathogenesis of ischemic brain injury including excitotoxicity, hypoxia, hypoglycemia, acidosis, and pro-oxidants. Neuroprotective signal transduction pathways elicit changes that promote the maintenance of cellular ion homeostasis and/or suppress the accumulation of free radicals. For example: basic fibroblast growth factor suppresses expression of a glutamate receptor protein and induces antioxidant enzymes; tumor necrosis factor induces expression of a Ca(2+)-binding protein and Mn-superoxide dismutase; and secreted forms of beta-amyloid precursor protein hyperpolarize neurons by activating K+ channels. Transcriptional regulation involves activation of tyrosine phosphorylation cascades and NFkB. Interestingly, similar neuroprotective pathways can be activated by moderate levels of cell "stress" such as that induced by glutamate in cell culture or a brief period of cerebral ischemia in vivo. Novel rapid and delayed intracellular neuroprotective signaling mechanisms are being revealed, such as the regulation of Ca2+ influx by actin filaments and the induction of genes by Ca2+ and radicals. New therapeutic approaches arising from this research include low molecular weight lipophilic compounds that activate neurotrophic factor signaling pathways and agents that selectively depolymerize actin.
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PMID:Neuroprotective signal transduction: relevance to stroke. 906 43


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