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

Enriched populations of human microglial cells were isolated from mixed cell cultures prepared from embryonic human telencephalon tissues. Human microglial cells exhibited cell type-specific antigens for macrophage-microglia lineage cells including CD11b (Mac-1), CD68, B7-2 (CD86), HLA-ABC, HLA-DR and ricinus communis aggulutinin lectin-1 (RCA-1), and actively phagocytosed latex beads. Gene expression and protein production of cytokines, chemokines and cytokine/chemokine receptors were investigated in the purified populations of human microglia. Normal unstimulated human microglia expressed constitutively mRNA transcripts for interleukin- 1beta (IL-1beta) -6, -8, -10, -12, -15, tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, and monocyte chemoattractant protein-1 (MCP-1), while treatment with lipopolysaccharide (LPS) or amyloid beta peptides (Abeta) led to increased expression of mRNA levels of IL-8, IL-10, IL-12, TNF-alpha, MIP-1alpha, MIP-1beta, and MCP-1. Human microglia, in addition, expressed mRNA transcripts for IL-1RI, IL-1RII, IL-5R, IL-6R, IL-8R, IL-9R, IL-10R, IL-12R, IL-13R, and IL-15R. Enzyme-linked immunosorbent assays (ELISA) showed increased protein levels in culture media of IL-1beta, IL-8, TNF-alpha, and MIP-1alpha in human microglia following treatment with LPS or Abeta. Increased TNF-alpha release from human microglia following LPS treatment was completely inhibited with IL-10 pretreatment, but not with IL-6, IL-9, IL-12, IL-13, or transforming growth factor-beta (TGF-beta). Present results should help in understanding the basic microglial biology, but also the pathophysiology of activated microglia in neurological diseases such as Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, stroke, and neurotrauma.
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PMID:Cytokines, chemokines, and cytokine receptors in human microglia. 1211 20

Transforming growth factor-beta1 (TGF-beta1) plays a central role in the response of the brain to different types of injury. Increased TGF-beta1 has been found in the central nervous system of patients with acute or chronic disorders such as stroke or Alzheimer disease. To further define the molecular targets of TGF-beta1 in cerebral tissues, a selection of high-density cDNA arrays was used to characterize the mRNA expression profile of 7,000 genes in transgenic mice overexpressing TGF-beta1 from astrocytes as compared with the wild-type line. Selected findings were further evaluated by reverse transcription-polymerase chain reactions from independent transgenic and wild-type mice. Furthermore, the expression pattern of seven selected genes such as Delta-1, CRADD, PRSC-1, PAI-1, Apo-1/Fas, CTS-B, and TbetaR-II were confirmed in either cultured cortical neurons or astrocytes following TGF-beta1 treatment. The authors' observations enlarge the repertoire of known TGF-beta1-modulated genes and their possible involvement in neurodegenerative processes.
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PMID:Transforming growth factor-beta1-modulated cerebral gene expression. 1221 17

Within the last few years, there has been a growing interest in the neuroprotective effects of estrogen and the possible beneficial effects of estrogen in neurodegenerative diseases such as stroke, Alzheimer disease, and Parkinson disease. Here, we review the progress in this field, with a particular focus upon estrogen-induced protection from stroke-induced ischemic damage. The important issue of whether clinically relevant selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene and estrogen replacement therapy can exert neuroprotection is also addressed. Although the mechanism of estrogen and SERM neuroprotection is not clearly resolved, we summarize the leading possibilities, including 1) a genomic estrogen receptor-mediated pathway that involves gene transcription, 2) a nongenomic signaling pathway involving activation of cell signalers such as mitogen-activated protein kinases and/or phosphatidylinositol-3-kinase /protein kinase B, and 3) a nonreceptor antioxidant free-radical scavenging pathway that is primarily observed with pharmacological doses of estrogen. The role of other potential mediatory factors such as growth factors and the possibility of an astrocyte role in neuroprotection is also discussed.
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PMID:Protective effects of estrogen and selective estrogen receptor modulators in the brain. 1239 Aug 66

Cells in the brain deploy multiple mechanisms to maintain the integrity of nerve cell circuits, and to facilitate responses to environmental demands and promote recovery of function after injury. The mechanisms include production of neurotrophic factors and cytokines, expression of various cell survival-promoting proteins (e.g. protein chaperones, antioxidant enzymes, Bcl-2 and inhibitor of apoptosis proteins), protection of the genome by telomerase and DNA repair proteins, and mobilization of neural stem cells to replace damaged neurons and glia. The aging process challenges such neuroprotective and neurorestorative mechanisms, often with devastating consequences as in Alzheimer's disease (AD), Parkinson's and Huntington's diseases and stroke. Genetic and environmental factors superimposed upon the aging process can determine whether brain aging is successful or unsuccessful. Mutations in genes that cause inherited forms of AD (amyloid precursor protein (APP) and presenilins), Parkinson's disease (alpha-synuclein and parkin) and trinucleotide repeat disorders (e.g. huntingtin and the androgen receptor) overwhelm endogenous neuroprotective mechanisms. On the other hand, neuroprotective mechanisms can be bolstered by dietary (caloric restriction, and folate and antioxidant supplementation) and behavioral (cognitive and physical activities) modifications. At the cellular and molecular levels, successful brain aging can be facilitated by activating a hormesis response to which neurons respond by upregulating the expression of neurotrophic factors and stress proteins. Neural stem cells that reside in the adult brain are also responsive to environmental demands, and appear capable of replacing lost or dysfunctional neurons and glial cells, perhaps even in the aging brain. The recent application of modem methods of molecular and cellular biology to the problem of brain aging is revealing a remarkable capacity within brain cells for adaptation to aging and resistance to disease.
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PMID:Neuroprotective and neurorestorative signal transduction mechanisms in brain aging: modification by genes, diet and behavior. 1239 75

In this review, we consider comparative aspects of the biology and pathology of oxygen radicals in neurodegenerative disease and how these findings have influenced our concept of oxidative stress. The common definition of oxidative stress is a breach of antioxidant defenses by oxygen radicals leading to damage to critical molecules and disrupted physiology. Inherent in this definition is that oxidative stress is an unstable situation, for if there is net damage, viability of the system decreases with time, leading to disequilibria and death. While this circumstance defines acute conditions, such as stroke and head trauma which result in dysfunction and death, it does not fit physiological situations or chronic diseases closely aligned to normal physiology. Therefore, we propose that oxidative modifications in Alzheimer disease may actually serve as a homeostatic response to stress resulting in a shift of neuronal priority from normal function to basic survival. This phenomenon is comparable to normal physiological conditions of metabolic decrease, such as those seen in hibernation and estivation. Thus, Alzheimer disease could be seen as part of normal aging that includes additional pathology due to inadequate homeostatic response.
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PMID:Comparative biology and pathology of oxidative stress in Alzheimer and other neurodegenerative diseases: beyond damage and response. 1245 79

Alzheimer's disease (AD) is more prevalent following an ischemic or hypoxic episode, such as stroke. Indeed, brain levels of amyloid precursor protein (APP) and the cytotoxic amyloid beta peptide (Abeta) fragment are enhanced in these patients and in animal models following experimental ischaemia. We have investigated the effect of chronic hypoxia (CH; 2.5% O2, 24 h) on processing of APP in the human neuroblastoma, SH-SY5Y. We demonstrate that constitutive and muscarinic-receptor-enhanced secretion of the alpha-secretase cleaved fragment of APP, sAPPalpha, was reduced by approximately 60% in CH cells. The caspase inhibitor BOC-D(Ome)FMK did not reverse this effect of CH, and CH cells were as viable as controls, based on MTT assays. Thus, loss of sAPPalpha is not related to cell death or caspase processing of APP. Pre-incubation with antioxidants did not reverse the effect of CH, and the effect could not be mimicked by H2O2, discounting the involvement of reactive oxygen species in hypoxic loss of sAPPalpha. CH did not affect muscarinic activation of extracellular-signal regulated kinase. However, expression of ADAM 10 (widely believed to be alpha-secretase) was decreased approximately 50% following CH. Thus, CH selectively decreases processing of APP by the alpha-secretase pathway, most likely by decreasing levels of ADAM 10.
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PMID:Altered processing of amyloid precursor protein in the human neuroblastoma SH-SY5Y by chronic hypoxia. 1247 81

Cerebrovascular deposition of the amyloid beta-protein (Abeta) is a common pathologic event in patients with Alzheimer's disease (AD) and certain related disorders. Such an Abeta vascular deposition occurs primarily in the medial layer of the cerebral vessel wall in an assembled fibrillar state. These deposits are associated with several pathological responses, including degeneration of the smooth muscle cells in the cerebral vessel wall. Severe cases of cerebrovascular Abeta deposition are also accompanied by loss of vessel wall integrity and hemorrhagic stroke. Although the reasons for this pathological consequence are unclear, altered proteolytic mechanisms within the cerebral vessel wall may be involved. We analyzed cerebral Abeta deposition in brains with AD and Dutch-type hereditary cerebral hemorrhage with amyloidosis (HCHWA-D) on the basis of two amyloid species of Abeta(40) and Abeta(42/43) using specific monoclonal antibodies. Compared to Abeta deposition in senile plaques, the molecular composition of Abeta was distinguishable, indicating that the Abeta(40) species is the main component for vascular amyloid. Furthermore, we found Abeta(42/43) immunoreactivity was also much increased in amyloid angiopathy of all cases with HCHWA-D. Taken together, amyloid angiopathy in HCHWA-D may share an Abeta(42)-driven deposition mechanism with plaque amyloid, resulting in enhanced Abeta(40) deposition.
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PMID:Enhanced Abeta40 deposition was associated with increased Abeta42-43 in cerebral vasculature with Dutch-type hereditary cerebral hemorrhage with amyloidosis (HCHWA-D). 1248 Jul 45

We report a sporadic case of unusual cerebral amyloid angiopathy (CAA) with prominent capillary involvement. A 67-year-old doctor developed gait disturbance, resting tremor and rigidity. He was diagnosed to have Parkinson's disease, for which the treatment with levodopa was effective. Four years later he began to exhibit progressive cognitive decline and behavioral abnormalities consisting of hallucination and agitation. Subsequently, his condition steadily worsened and became bedridden with severe dementia, and he died eight years after the disease onset. During the clinical course, there had been no episode of stroke. Postmortem examinations revealed the typical pathology of Parkinson's disease with frequent cortical Lewy bodies in the amygdala. The most striking pathological feature of this patient was widespread CAA where prominent beta-amyloid (A beta) deposition was observed in the capillaries of the neocortex, most pronouncedly in the occipital lobe, as well as leptomeningeal and cerebral medium-sized and small vessels. Further, perivascular plaques were found in half of the amyloid-laden capillaries. Tau-positive dystrophic neurites were only sparsely detectable within a few perivascular plaques. Despite the severe A beta pathology, there was no microaneurysmal dilatation, fibrinoid necrosis or vascular occlusion. There was only one small ischemic lesion in the brain. The cerebral white matter was unremarkable. Senile plaques of neuritic type and neurofibrillary tangles were mostly limited to the hippocampal regions and, to a lesser degree, in the amygdaloid nucleus, which did not meet the neuropathological criteria of Alzheimer's disease. On the gene analyses, his apolipoprotein E (ApoE) genotyping was verified to be heterozygous epsilon 3/epsilon 4, and no mutation was seen in exons 16 and 17 of the amyloid precursor protein gene. Severe A beta capillary angiopathy as seen in our patient is exceptional in sporadic CAA. Further, A beta angiopathy of this patient was notable in the absence of an associated cerebrovascular disease despite prominent A beta deposition in the vessel walls. Regarding the development of his severe dementia, the limbic pathology of Lewy body disease might be one of the potential causes, but A beta angiopathy appears more likely because of its severity. We speculate that widespread A beta deposition disregulates the blood-brain barrier of the capillaries leading to a disturbance of the microcirculation throughout the cerebral cortex without obvious ischemic disintegration of the neuropil. We should take into consideration that A beta angiopathy can present as progressive dementia without cerebrovascular disease.
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PMID:[Sporadic cerebral amyloid angiopathy presenting with dementia and prominent capillary beta-amyloid deposition: a case report]. 1260 81

The authors searched for mutations in the beta-amyloid precursor protein in a Spanish family with a hereditary syndrome of hemorrhagic stroke, dementia, leukoencephalopathy, and occipital calcifications. DNA from two affected members demonstrated the Iowa amyloid precursor protein mutation previously identified as a cause of severe amyloid angiopathy without hemorrhagic stroke. These data point to other genetic or environmental factors that may determine the occurrence of symptomatic hemorrhage in amyloid angiopathy.
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PMID:Hemorrhagic stroke associated with the Iowa amyloid precursor protein mutation. 1265 73

Efforts in basic neuroscience and studies of rare hereditary neurological diseases are partly motivated by the hope that such work can lead to better understanding of and treatments for the common neurological disorders. An example is the progress that has resulted from identification of the genes that cause benign familial neonatal convulsions (BFNCs). Benign familial neonatal convulsions is a rare idiopathic, generalized epilepsy syndrome. In 1998, geneticists discovered that BFNC is caused by mutations in a novel potassium channel subunit, KCNQ2. Further work quickly revealed the sequences of 3 related brain channel genes KCNQ3, KCNQ4, and KCNQ5. Mutations in 2 of these genes were shown to cause BFNC (KCNQ3) and hereditary deafness (KCNQ4). Physiologists soon discovered that the KCNQ genes encoded subunits of the M-channel, a widely expressed potassium channel that mediates effects of modulatory neurotransmitters and controls repetitive neuronal discharges. Finally, pharmacologists discovered that the biological activities of 3 classes of compounds in development as treatments for Alzheimer disease, epilepsy, and stroke were mediated in part by effects on brain KCNQ channels. Cloned human KCNQ channels can now be used for high-throughput screening of additional drug candidates. Ongoing studies in humans and animal models will refine our understanding of KCNQ channel function and may reveal additional targets for therapeutic manipulation.
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PMID:M-channels: neurological diseases, neuromodulation, and drug development. 1270 61


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