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

Lipid peroxidation of membranes by oxygen free radicals has been implicated in various disease states. Different antioxidants and iron chelators have been used to reduce lipid peroxidation. Lazaroids have been used for the acute treatment of central nervous system disorders such as trauma and ischemia wherein lipid peroxidative processes take place. In this study we evaluated the effect of lazaroids (U-78518F and U-74389F) on the release of acid phosphatase activity and formation of malondialdehyde (MDA) in rat liver lyosomes subjected to exogenously generated oxygen free radicals. There was a significant increase in the acid phosphatase release and MDA formation in the presence of oxygen free radicals. This was prevented by both the lazaroids. In a separate study the effect of lazaroid U-74389F was seen on the zymosan-stimulated polymorphonuclear (PMN) leukocyte-derived chemiluminescence. The PMN leukocyte chemiluminescent activity was attenuated by the lazaroid in a dose-dependent manner. These studies suggest that lazaroids may inhibit lipid peroxidation and stabilize the membrane.
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PMID:Protective effects of lazaroids against oxygen-free radicals induced lysosomal damage. 784 65

Reperfusion injury is believed to represent an important facet of brain disease initiated by ischemia. With the continued improvement toward clinically relevant animal models of stroke and cerebrovascular injury, more direct evidence for reperfusion injury after brain ischemia will be obtained. Experimental studies should consider which outcome measures are most clinically relevant and utilize chronic histopathological and behavioral assessments to monitor outcome. Recent data indicate a complex and time-dependent sequence of microvascular and cellular responses to brain injury. The potential for pathophysiological events occurring at different reperfusion periods indicates that multiple therapeutic windows may exist for brain protection. Thus, it is conceivable that successful therapeutic strategies may ultimately involve several agents directed at the early, intermediate, and late phases of reperfusion. Finally, it should be stressed that reperfusion injury may represent a chronic condition that could potentially participate in a wide range of central nervous system disorders including those associated with normal aging.
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PMID:Morphological manifestations of reperfusion injury in brain. 803 Aug 62

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

Recent evidence suggests that neurons and glia can synthesize and secrete cytokines, which play critical roles in maintaining homeostasis in the central nervous system (CNS) by mediating the interaction between cells via autocrine or paracrine mechanisms. Circulating cytokines and soluble receptors also regulate neuronal function via endocrine mechanisms. Disturbance of the cytokine-mediated interaction between cells may lead to neuronal dysfunction and/or cell death and contribute to the pathogenesis of the CNS diseases (e.g., ischemia, Alzheimer's disease and HIV encephalopathy). Defining the molecular pathways of cytokine dysregulation and neurotoxicity may help to elucidate potential therapeutic interventions for many devastating CNS diseases.
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PMID:Cytokines in the central nervous system: regulatory roles in neuronal function, cell death and repair. 864 60

Central nervous system has a low antioxidative capacity, which is formed mainly by ascorbic acid. Therefore the cerebral tissue is threatened by the increased formation of free radicals and their metabolites (ROS--reactive oxygen species). ROS are formed such as in reperfusion phase after ischemia and in catecholamine metabolism, in oxidative stress due to hyperglycaemia. Polyunsaturated fatty acids (PUFA) are peroxidased by ROS; proteins and DNK are damaged as well. Free radicals are involved in etiology and pathogenesis of many CNS diseases, such as neuritis, Alzheimer disease, Parkinson disease, Huntington disease, aging and atherosclerosis of the brain, epilepsy, etc. During the antioxidant therapy it is necessary to consider the types of ROS, their origin and their mode of action, whether to administer hydrophilic or lipophilic antioxidants, eventually chelate agents, etc. Hydrophylic antioxidants are acting very soon after the administration, whereas the lipophilic ones reach their target tissues with a great delay. Therefore it is better to apply them preferentially like a prevention, if possible. Enzymatic antioxidants (SOD, GSPHx and catalase and others) are usually acting only for a short time. The methods of estimation of free radicals attacks are discussed as well their possible pathophysiological effects.
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PMID:[Free radicals in the central nervous system]. 866 12

Gd-DTPA has a T1 shortening effect that enhances the contrast in MRI and is widely used for the clinical evaluation of CNS diseases, though it is not suitable for the detection of cerebral ischemic regions during the superacute stage. Superparamagnetic iron oxide particles have a T2 shortening effect on relaxation time, reducing signal intensity on T2-weighted MRI in normal cerebral tissue. From this perspective we tested the feasibility of detecting ischemic lesions during the superacute stage using superparamagnetic iron oxide particles-enhanced MRI. Male Sprague-Dawley rats were anesthetized using pentobarbital and the left middle cerebral artery was permanently occluded (lt.-PMCAO) using a modified version of the Koizumi method. After lt.-PMCAO, 100 mumoles Fe/kg, 1 ml/kg magnetite, superparamagnetic iron oxide particles, (magnetite-injected group, n = 9) or physiological saline (vehicle-injected group, n = 9) was injected into the femoral vein. T2-weighted MR images were performed at designated time points immediately after injection of magnetite or vehicle on a 6.34 T MR unit. Additionally, in separate animals coronal sections of the brain were stained with 4% 2, 3, 5 triphenyl-tetrazolium-chloride (TTC) to confirm the infarct region. In the magnetite-injected group, a high signal area at the region of lt.-MCA was visible within-20 to 30 min following lt.-PMCAO, whereas in the vehicle-injected group no high signal ischemic area could be confirmed until 3 h after lt.-PMCAO. Infarction was noticed in the TTC staining 3 h following lt.-PMCAO. In this study magnetite injection allowed the detection of ischemia in the occluded MCA area on T2-weighted MRI during the superacute stage. These results suggest that ischemia during the superacute stage can be evaluated using magnetite enhanced MRI.
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PMID:[Usefulness of magnetite as an MRI contrasting agent in an experimental cerebral ischemic model. Evaluation of lesion detecting time]. 965 3

Disturbances in the normal homeostasis of the central nervous system induce a localized activation of microglia. This activation serves to isolate pathological processes from surrounding, intact nervous tissue. Concomitantly, healthy or minimally damaged nerve cells nearby may be negatively influenced by potent molecules released by activated microglia. This situation appears to exist e.g. in ischemia, multiple sclerosis and Alzheimer's disease. Pharmacologic regulation of microglial activity is therefore a rational approach to treatment of many central nervous system disorders.
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PMID:[Microglia--new target cells for neurological therapy]. 1101 96

In recent years, oxidative stress has been implicated in a variety of degenerative processes, diseases, and syndromes. Some of these include atherosclerosis, myocardial infarction, stroke, and ischemia/reperfusion injury; chronic and acute inflammatory conditions such as wound healing; central nervous system disorders such as forms of familial amyotrophic lateral sclerosis (ALS) and glutathione peroxidase-linked adolescent seizures; Parkinson's disease and Alzheimer's dementia; and a variety of other age-related disorders. Among the various biochemical events associated with these conditions, emerging evidence suggests the formation of superoxide anion and expression/activity of its endogenous scavenger, superoxide dismutase (SOD), as a common denominator. This review summarizes the function of SOD under normal physiological conditions as well as its role in the cellular and molecular mechanisms underlying oxidative tissue damage and neurological abnormalities. Experimental evidence from laboratory animals that either overexpress (transgenics) or are deficient (knockouts) in antioxidant enzyme/protein levels and the genetic SOD mutations observed in some familial cases of ALS are also discussed.
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PMID:Role of superoxide dismutases in oxidative damage and neurodegenerative disorders. 1219 1

Acid sphingomyelinase (ASMase) and NF-kappaB participate in tumor necrosis factor alpha (TNFalpha) signal transduction. Mice in which the genes encoding ASMase or the p50 subunit of NF-kappaB are disrupted have been reported to be less vulnerable than wild-type mice to focal brain ischemia. We now demonstrate selective diminution in expression of GluR1, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate-type glutamate receptor (AMPA-GluR) protein subunit, in these two groups of knockout mice. To confirm that neuronal GluR1 expression is regulated by ASMase and NF-kappaB, and to learn whether this regulation has pathophysiological significance, we treated cultured human NT2-N neurons with TNFalpha. This induced GluR1 expression and increased susceptibility of the neurons to kainate necrosis. Both induction of GluR1 and heightened vulnerability to kainate were blocked by inhibiting ASMase or by antisense knockdown of NF-kappaB p50. We conclude that TNFalpha can sensitize neurons to excitotoxic necrosis by inducing expression of GluR1 via an ASMase- and NF-kappaB-dependent mechanism. TNFalpha levels are frequently elevated during ischemia and other CNS diseases in which excitotoxicity contributes to neuronal loss. Our results suggest that inhibiting TNFalpha signal transduction will diminish neuronal necrosis in these diseases.
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PMID:Tumor necrosis factor alpha increases neuronal vulnerability to excitotoxic necrosis by inducing expression of the AMPA-glutamate receptor subunit GluR1 via an acid sphingomyelinase- and NF-kappaB-dependent mechanism. 1246 May 58

The functional changes of astrocytes are deeply involved in neurodegenerating processes of various CNS diseases. ATP is released during various neuronal damages such as brain ischemia and may control astrocyte functions. We examined the effect of ATP on the production of nitric oxide in the cultured astrocytes from rat embryo. The astrocytes were stimulated by lipopolysaccharide instead of pathological activation in vivo. Nitric oxide production was evaluated by the fluorometric assay of nitrite accumulated in the medium. The expression of inducible nitric oxide synthase was analyzed by Western blotting. Nitric oxide production induced by 1 ng/ml lipopolysaccharide was enhanced by ATP with maximal enhancement of three- to four-fold; a half-effective concentration was about 0.3 mM. In the absence of ATP, half-effective concentration of lipopolysaccharide on nitric oxide production was about 3 ng/ml; however, half-effective concentration shifted to 0.3 ng/ml in the presence of 1.5-mM ATP. Several other P2 receptor agonists (uridine triphosphate, ADP, adenosine monophosphate, 2'- and 3'-O - (4-benzoylbenzoyl)-ATP, and 2-methylthioATP) showed a similar enhancing effect, and an antagonist, ATP-2',3'-dialdehyde, showed an inhibiting effect. Western blotting analysis revealed that the extent of lipopolysaccharide-induced expression of nitric oxide synthase increased several-fold by the addition of ATP; half-effective concentration was about 0.5 mM. These results suggest that the extracellular ATP plays an important role as a transmitter and regulates astrocyte functions via a certain P2 receptor and that such a change in astrocyte function is involved in either protection or aggravation in neurodegenerative processes.
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PMID:Potentiation by ATP of lipopolysaccharide-stimulated nitric oxide production in cultured astrocytes. 1260 90


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