Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We observed temporal changes in NACP (precursor protein of non-Abeta component of Alzheimer's disease amyloid), a presynaptic protein a.k. a. alpha-synuclein, in the hippocampus after 5 min ischemia. Intense NACP immunoreactivity was seen transiently around cerebral blood vessels in the CA1 subfield on day 4, and NACP-positive unusual tubal and chain-like structures developed on month 6. We suggest that the changes in NACP may play an important role in the ischemic pathogenesis.
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PMID:Changes in presynaptic protein NACP/alpha-synuclein in an ischemic gerbil hippocampus. 955 70

Macrophage scavenger receptors (MSR) are implicated in the development of atherosclerosis and amyloid b-protein deposition in Alzheimer's disease. However, histopathological studies of MSR expression in human tissues have been hampered by a lack of specific antibodies. Using MSR-deficient mice, we successfully raised a novel monoclonal antibody against human MSR together with high-titer antisera. These antibodies specifically recognized human tissue macrophages and human MSR protein purified from differentiated THP1 cells. In normal brain, MSR staining was mainly distributed to the perivascular cells, which correspond to Mato's fluorescent granular perithelial cells (Mato cells). In the lesions of ischemia and Alzheimer's disease, a subset of microglia stained positive for MSR. These novel antibodies are useful tools for analysis of MSR expression in human tissues.
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PMID:Immunohistochemical evidence for a macrophage scavenger receptor in Mato cells and reactive microglia of ischemia and Alzheimer's disease. 958 84

A brief period of bilateral carotid occlusion (BCO)-induced forebrain ischemia in gerbils triggers neuronal degeneration and the subsequent expression of amyloid precursor protein (APP), b-amyloid protein (b-AP), and apolipoprotein E (APO-E) in the selectively vulnerable CA1 region of the hippocampus. The increase in immunoreactivity is secondary to the postischemic degeneration of the CA1 neurons and is largely astrocyte-derived as evidenced by a simultaneous increase in glial fibrillary acidic protein (GFAP) staining. Oxygen radical-induced lipid peroxidation has been strongly suggested to play a role in postischemic neuronal damage and Alzheimer's disease. Recent literature suggests a possible link between early oxidative stress and APP overexpression. Therefore, the present investigation examined the effect of two novel brain-penetrating pyrrolopyrimidine lipid peroxidation inhibitors (PNU-101033E and PNU-104067F) on CA1 neurodegeneration and the subsequent increase in APP, b-AP, APO-E, and GFAP immunostaining at 4 days after a 5-minute episode of forebrain ischemia. Using an antibody for lipid peroxidation-derived malondialdehyde (MDA)-modified proteins, the authors also examined the effects of PNU-104067F on MDA immunostaining 2 days after ischemia, before completion of the neuronal loss. At 2 days, the authors also evaluated microglial activation using an antibody to surface major histocompatibility complex class II antigen expressed by activated microglia. Gerbils were treated at 30 mg/kg orally 30 minutes before the BCO and 2 hours after ischemia, followed by daily dosing for the next day (microglia and MDA) and the successive 3 days for APP, b-AP, APO-E, and GFAP immunostaining. APP and APO-E staining was significantly suppressed by 50% and 66%, respectively, with either compound. b-AP immunoreactivity was decreased 56% with both compounds, and GFAP expression was significantly decreased 53% (PNU-101033E) and 60.5% (PNU-104067F). There was a concomitant partial sparing of the CA1 hippocampal neurons by both PNU-101033E and PNU-104067F (P < .01) as determined by cresyl violet histochemistry. PNU-104067F significantly inhibited lipid peroxidation-derived MDA immunostaining and microglia activation (P < .05) at 48 hours after ischemia. Brain-penetrable lipid peroxidation inhibitors may provide attenuation of various glial response proteins after ischemic injury, probably secondary to neuronal protection.
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PMID:Neuroprotective efficacy and mechanisms of novel pyrrolopyrimidine lipid peroxidation inhibitors in the gerbil forebrain ischemia model. 959 46

Recent studies have shown a close association between reactive oxygen species and DNA fragmentation and that delayed neuronal death after transient forebrain ischemia manifests as DNA fragmentation-like apoptosis. We examined the effect of indomethacin on ischemic-induced delayed hippocampal neuronal death in gerbils using the TUNEL staining method, since indomethacin is neuroprotective in a variety of degenerative processes, such as Alzheimer's disease. Indomethacin (5 mg/kg, i.p.), administered 5 min before the ischemic insult, significantly decreased the number of TUNEL-positive hippocampal CA1 pyramidal neurons and delayed the appearance of TUNEL-positive neurons. Our results indicate that indomethacin is effective in inhibiting DNA fragmentation after transient forebrain ischemia.
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PMID:Indomethacin inhibits delayed DNA fragmentation of hippocampal CA1 pyramidal neurons after transient forebrain ischemia in gerbils. 959 92

The Transforming Growth Factor-betas (TGF-beta) are a group of multifunctional proteins whose cellular sites of production and action are widely distributed throughout the body, including the central nervous system (CNS). Within the CNS, various isoforms of TGF-beta are produced by both glial and neural cells. When evaluated in either cell culture or in vivo models, the various isoforms of TGF-beta have been shown to have potent effects on the proliferation, function, or survival of both neurons and all three glial cell types, astrocytes, microglia and oligodendrocytes. TGF-beta has also been shown to play a role in several forms of acute CNS pathology including ischemia, excitotoxicity and several forms of neurodegenerative diseases including multiple sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease.
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PMID:TGF-beta in the central nervous system: potential roles in ischemic injury and neurodegenerative diseases. 962 Jun 42

Axonal injury following cerebral ischaemia has attracted less attention than damage in grey matter. However, it is becoming increasingly recognised that axons are highly vulnerable to focal ischaemia [D. Dewar, D.A. Dawson, Changes of cytoskeletal protein immunostaining in myelinated fibre tracts after focal cerebral ischaemia in the rat, Acta. Neuropathol., 93 (1997) 71-77] [2]; [L. Pantoni, J.H. Garcia, J.A. Gutierrez, Cerebral white matter is highly vulnerable to ischemia, Stroke, 27 (1996) 1641-1647] [10]; [P. S. Yam, T. Takasago, D. Dewar, D.I. Graham, J. McCulloch, Amyloid precursor protein accumulates in white matter at the margin of a focal ischaemic lesion, Brain Res., 760 (1997) 150-157] [15]. Since white matter does not contain neuronal cell bodies or synapses it is likely that the mechanisms of injury and strategies for its protection are different from those in grey matter. In order that the effect of therapeutic intervention on the protection of axons can be assessed, a method by which axonal injury can be mapped and quantified is required. For this purpose, we investigated immunocytochemical methods using amyloid precursor protein (APP) following permanent middle cerebral artery occlusion in the rat. APP is transported by fast anterograde axonal transport [E.H. Koo, S.S. Sisodia, D.R. Archer, L.J. Martin, A. Weidemann, K. Beyreuther, P. Fischer, C.L. Masters, D.L. Price, Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport, Proc. Natl. Acad. Sci. U.S.A. 87 (1990) 1561-1565] [7] and has been shown to accumulate following a variety of insults to axons, indicative of dysfunction of axonal transport [R.N. Kalaria, S.U. Bhatti, E.A. Palatinsky, D.H. Pennington, E.R. Shelton, H.W. Chan, G. Perry, W.D. Lust, Accumulation of the beta amyloid precursor protein at sites of ischemic injury in rat brain, Neuroreport, 4 (1993) 211-214] [4]; [T. Kawarabayashi, M. Shoji, Y. Harigaya, H. Yamaguchi, S. Hirai, Expression of APP in the early stage of brain damage, Brain Res., 563 (1991) 334-338] [5]; [N. Otsuka, M. Tomonaga, K. Ikeda, Rapid appearance of beta-amyloid precursor protein immunoreactivity in damaged axons and reactive glial cells in rat brain following needle stab injury, Brain Res., 568 (1991) 335-338] [9]; [K. Shigematsu, P. L. McGeer, Accumulation of amyloid precursor protein in neurons after intraventricular injection of colchicine, Am. J. Pathol., 140 (1992) 787-794] [12]. We have been able to map the topographical relationship between APP accumulation and region of infarction using immunocytochemistry and image analysis techniques. Additionally, using a semi-quantitative scoring system, we have demonstrated that there is a relationship between the amount of APP accumulation and the volume of infarction following middle cerebral artery occlusion. These methods will be useful in the future for the assessment of therapeutic interventions on the protection of axons following ischaemic injury.
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PMID:Topographical and quantitative assessment of white matter injury following a focal ischaemic lesion in the rat brain. 963 Jul

In the human brain and spinal cord, neurons degenerate after acute insults (e.g., stroke, cardiac arrest, trauma) and during progressive, adult-onset diseases [e.g., amyotrophic lateral sclerosis, Alzheimer's disease]. Glutamate receptor-mediated excitotoxicity has been implicated in all of these neurological conditions. Nevertheless, effective approaches to prevent or limit neuronal damage in these disorders remain elusive, primarily because of an incomplete understanding of the mechanisms of neuronal death in in vivo settings. Therefore, animal models of neurodegeneration are crucial for improving our understanding of the mechanisms of neuronal death. In this review, we evaluate experimental data on the general characteristics of cell death and, in particular, neuronal death in the central nervous system (CNS) following injury. We focus on the ongoing controversy of the contributions of apoptosis and necrosis in neurodegeneration and summarize new data from this laboratory on the classification of neuronal death using a variety of animal models of neurodegeneration in the immature or adult brain following excitotoxic injury, global cerebral ischemia, and axotomy/target deprivation. In these different models of brain injury, we determined whether the process of neuronal death has uniformly similar morphological characteristics or whether the features of neurodegeneration induced by different insults are distinct. We classified neurodegeneration in each of these models with respect to whether it resembles apoptosis, necrosis, or an intermediate form of cell death falling along an apoptosis-necrosis continuum. We found that N-methyl-D-aspartate (NMDA) receptor- and non-NMDA receptor-mediated excitotoxic injury results in neurodegeneration along an apoptosis-necrosis continuum, in which neuronal death (appearing as apoptotic, necrotic, or intermediate between the two extremes) is influenced by the degree of brain maturity and the subtype of glutamate receptor that is stimulated. Global cerebral ischemia produces neuronal death that has commonalities with excitotoxicity and target deprivation. Degeneration of selectively vulnerable populations of neurons after ischemia is morphologically nonapoptotic and is indistinguishable from NMDA receptor-mediated excitotoxic death of mature neurons. However, prominent apoptotic cell death occurs following global ischemia in neuronal groups that are interconnected with selectively vulnerable populations of neurons and also in nonneuronal cells. This apoptotic neuronal death is similar to some forms of retrograde neuronal apoptosis that occur following target deprivation. We conclude that cell death in the CNS following injury can coexist as apoptosis, necrosis, and hybrid forms along an apoptosis-necrosis continuum. These different forms of cell death have varying contributions to the neuropathology resulting from excitotoxicity, cerebral ischemia, and target deprivation/axotomy. Degeneration of different populations of cells (neurons and nonneuronal cells) may be mediated by distinct or common causal mechanisms that can temporally overlap and perhaps differ mechanistically in the rate of progression of cell death.
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PMID:Neurodegeneration in excitotoxicity, global cerebral ischemia, and target deprivation: A perspective on the contributions of apoptosis and necrosis. 967 Dec 59

Free radicals are known to occur as natural by-products under physiological conditions and have been implicated in the neuronal loss observed in a variety of neuropathological conditions including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and ischemia. Oxyradical-induced cytotoxicity arises from both chronic and acute increases in reactive oxygen species which give rise to subsequent lipid peroxidation (LP). By reacting with polyunsaturated fatty acids in the the various cellular membranes, oxyradicals such as hydroxyl (OH.) and peroxynitrite (ONOO) give rise to a variety of lipid peroxidation products (LPP), including 4-hydroxynonenal (HNE) and malondialdehyde (MD). Once formed, these peroxidation metabolites have been demonstrated to have relatively long half-lives within cells (minutes to hours), allowing for multiple interactions with cellular components. Emerging data suggest that LP and LPP may underlie the neuronal alterations and neurotoxicity observed in numerous neurodegenerative conditions. Data supporting this involvement include the detection of LP and formation of LPP in a variety of neuropathological conditions including AD, ALS, PD, and ischemia. Secondly, direct application of LPP, either in vivo or in vitro, has been shown to be cytotoxic and mimic neuronal alterations observed in neuropathological conditions. Furthermore, prevention of LP and subsequent LPP formation have been demonstrated to be neuroprotective in a variety of neurodegenerative paradigms. Additionally, LP and LPP have been implicated in the modulation of a wide array of activities within the central nervous system including long term potentiation, neurite outgrowth, and proliferation. Understanding the mechanism(s) and involvement of LP in these processes will greatly enhance the understanding of oxyradical and ion homeostasis in neurophysiological and neuropathological conditions. The focus of this review is to describe the process by which lipid peroxidation occurs and establish a framework for its involvement in the central nervous system.
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PMID:Roles of lipid peroxidation in modulation of cellular signaling pathways, cell dysfunction, and death in the nervous system. 971 2

Neurotoxicity mediated by glutamate is thought to play a role in neurological disorders such a stroke, ischemia and slowly progressing neurodegenerative diseases. However, the contribution of excitotoxicity in neuronal death that occurs in Alzheimer's disease is still an open question. This paper briefly reviews the main lines of evidence supporting a participation of excess glutamatergic neurotransmission in the neurodegeneration of selective groups of neurons in this disease.
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PMID:Glutamic acid and Alzheimer's disease. 971 30

The regional selectivity and mechanisms underlying the toxicity of the serine/threonine protein phosphatase inhibitor okadaic acid (OA) were investigated in hippocampal slice cultures. Image analysis of propidium iodide-labeled cultures revealed that okadaic acid caused a dose- and time-dependent injury to hippocampal neurons. Pyramidal cells in the CA3 region and granule cells in the dentate gyrus were much more sensitive to okadaic acid than the pyramidal cells in the CA1 region. Electron microscopy revealed ultrastructural changes in the pyramidal cells that were not consistent with an apoptotic process. Treatment with okadaic acid led to a rapid and sustained tyrosine phosphorylation of the mitogen-activated protein kinases ERK1 and ERK2 (p44/42(mapk)). The phosphorylation was markedly reduced after treatment of the cultures with the microbial alkaloid K-252a (a nonselective protein kinase inhibitor) or the MAP kinase kinase (MEK1/2) inhibitor PD98059. K-252a and PD98059 also ameliorated the okadaic acid-induced cell death. Inhibitors of protein kinase C, Ca2+/calmodulin-dependent protein kinase II, or tyrosine kinase were ineffective. These results indicate that sustained activation of the MAP kinase pathway, as seen after e.g., ischemia, may selectively harm specific subsets of neurons. The susceptibility to MAP kinase activation of the CA3 pyramidal cells and dentate granule cells may provide insight into the observed relationship between cerebral ischemia and dementia in Alzheimer's disease.
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PMID:Regional selective neuronal degeneration after protein phosphatase inhibition in hippocampal slice cultures: evidence for a MAP kinase-dependent mechanism. 973 50


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