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)

Calpain I, an intracellular cysteine protease, has been implicated in the neurodegeneration following an episode of cerebral ischemia. In this paper, we report on a series of peptidomimetic ketomethylene and carbamethylene inhibitors of recombinant human calpain I (rh calpain I). Our study reveals that the -NHCO-moiety (possible hydrogen-bonding site) at the P2-P3 region of a potent tripeptide or a dipeptide inhibitor of calpain I is not a strict requirement for enzyme recognition. Compounds 7d ((R)-2-isobutyl-4-oxo-4-(9-xanthenyl)butanoic acid ((S)-1-formyl-3-methyl)butyl amide), 31 ((R)-2-isobutyl-4-(2-sulfonylnaphthyl)butyric acid ((S)1-formyl-3-methyl)butyl amide) and 34 ((R)-2-isobutyl-4-(2-sulfoxylnaphthyl)butyric acid ((S)-1-formyl-3-methyl)butyl amide) which exhibited good activity in the enzyme assay, also inhibited calpain I in a human cell line.
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PMID:Exploration of the importance of the P2-P3-NHCO-moiety in a potent di- or tripeptide inhibitor of calpain I: insights into the development of nonpeptidic inhibitors of calpain I. 962 65

The time course of oxidative stress following cerebral ischemia and reperfusion has been obscure, although oxygen-derived free radicals have been postulated to play an important role in the progression of reperfusion injury. We have examined the time profile of hydrogen peroxide (H2O2) generation in the rat cortex following incomplete forebrain ischemia and reperfusion. We used 20 male Sprague-Dawley rats anesthetized with alpha-chloralose and urethane. A closed cranial window was created in the temporoparietal skull, and 2'-7'-dichlorofluorescein (DCF), a sensitive fluorescent probe for H2O2, was loaded intracellularly by the superfusion technique. We simultaneously monitored DCF fluorescence and reflectance from the cortex with an in vivo fluoromicroscope having two photomultiplier tubes, and subtracted the hemodynamic artifact from DCF fluorescence. Incomplete forebrain ischemia was induced by temporal ligation of both common carotid arteries combined with hypotension. The results showed that corrected DCF fluorescence remained unchanged during ischemia, but increased following reperfusion, indicating enhanced H2O2 generation. Pretreatment by intraperitoneal injection of catalase attenuated H2O2 generation significantly. that H2O2 generation is mainly enhanced following reperfusion.
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PMID:In vivo fluorometric measurement of cerebral oxidative stress using 2'-7'-dichlorofluorescein (DCF). 965 19

Because melatonin is a cerebral vasoconstrictor agent, we tested whether it could shift the lower limit of cerebral blood flow autoregulation to a lower pressure level, by improving the cerebrovascular dilatory reserve, and thus widen the security margin. Cerebral blood flow and cerebrovascular resistance were measured by hydrogen clearance in the frontal cortex of adult male Wistar rats. The cerebrovasodilatory reserve was evaluated from the increase in the cerebral blood flow under hypercapnia. The lower limit of cerebral blood flow autoregulation was evaluated from the fall in cerebral blood flow following hypotensive hemorrhage. Rats received melatonin infusions of 60, 600, or 60,000 ng . kg-1 . h-1, a vehicle infusion, or no infusion (n = 9 rats per group). Melatonin induced concentration-dependent cerebral vasoconstriction (up to 25% of the value for cerebrovascular resistance of the vehicle group). The increase in vasoconstrictor tone was accompanied by an improvement in the vasodilatory response to hypercapnia (+50 to +100% vs. vehicle) and by a shift in the lower limit of cerebral blood flow autoregulation to a lower mean arterial blood pressure level (from 90 to 50 mmHg). Because melatonin had no effect on baseline mean arterial blood pressure, the decrease in the lower limit of cerebral blood flow autoregulation led to an improvement in the cerebrovascular security margin (from 17% in vehicle to 30, 55, and 55% in the low-, medium-, and high-dose melatonin groups, respectively). This improvement in the security margin suggests that melatonin could play an important role in the regulation of cerebral blood flow and may diminish the risk of hypoperfusion-induced cerebral ischemia.
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PMID:Melatonin improves cerebral circulation security margin in rats. 968 6

Uric acid is a well-known natural antioxidant present in fluids and tissues throughout the body. Oxyradical production and cellular calcium overload are believed to contribute to the damage and death of neurons that occurs following cerebral ischemia in victims of stroke. We now report that uric acid protects cultured rat hippocampal neurons against cell death induced by insults relevant to the pathogenesis of cerebral ischemia, including exposure to the excitatory amino acid glutamate and the metabolic poison cyanide. Confocal laser scanning microscope analyses showed that uric acid suppresses the accumulation of reactive oxygen species (hydrogen peroxide and peroxynitrite), and lipid peroxidation, associated with each insult. Mitochondrial function was compromised by the excitotoxic and metabolic insults, and was preserved in neurons treated with uric acid. Delayed elevations of intracellular free calcium levels induced by glutamate and cyanide were significantly attenuated in neurons treated with uric acid. These data demonstrate a neuroprotective action of uric acid that involves suppression of oxyradical accumulation, stabilization of calcium homeostasis, and preservation of mitochondrial function. Administration of uric acid to adult rats either 24 hr prior to middle cerebral artery occlusion (62.5 mg uric acid/kg, intraperitoneally) or 1 hr following reperfusion (16 mg uric acid/kg, intravenously) resulted in a highly significant reduction in ischemic damage to cerebral cortex and striatum, and improved behavioral outcome. These findings support a central role for oxyradicals in excitotoxic and ischemic neuronal injury, and suggest a potential therapeutic use for uric acid in ischemic stroke and related neurodegenerative conditions.
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PMID:Uric acid protects neurons against excitotoxic and metabolic insults in cell culture, and against focal ischemic brain injury in vivo. 972 32

Proton MR spectroscopy has greatly enhanced our understanding of the in vivo pathophysiology of ischemic cerebrovascular disease. This article focuses on 1H MR spectrum changes in the setting of cerebral ischemia and infarction and shows how proton spectroscopy has improved our understanding of these disease processes. The role of 1H MR spectroscopy in cerebral ischemia without infarction, hypoxia-ischemic encephalopathy, and vascular dementia are also reviewed.
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PMID:Proton MR spectroscopy in ischemic stroke and other vascular disorders. 976 48

The effects of mild (33 degrees C) and moderate (29 degrees C) hypothermia were investigated to determine which temperature was more effective against compression-induced cerebral ischemia. Eighteen cats were anesthetized. The animals were divided into three groups according to deep-brain temperature (control, 37 degrees C; mild hypothermia, 33 degrees C; and moderate hypothermia, 29 degrees C). Intracranial pressure (ICP) and cerebral blood flow (CBF) were monitored, the latter by hydrogen clearance. Arteriovenous oxygen difference (AVDO2) and cerebral venous oxygen saturation (ScvO2) were measured in blood samples from the superior sagittal sinus. The cerebral metabolic rate of oxygen (CMRO2) and the cerebral metabolic rate of lactate (CMR lactate) were calculated. Extracellular glutamate was measured by microdialysis. ICP was increased by inflation of an epidural balloon until CBF became zero, and this ischemia was maintained for 5 min, after which the balloon was quickly deflated. All parameters were recorded over 6 h. Evans blue was injected to examine vascular permeability changes. CBF was decreased by 56% by mild hypothermia and by 77% by moderate hypothermia. Mild hypothermia had a coupled metabolic suppression whereas moderate hypothermia significantly increased AVDO2 and decreased ScvO2, producing a low CBF/CMRO2 (relative ischemia). After balloon deflation, all three groups showed reactive hyperemia, which was significantly reduced by mild and moderate hypothermia. CBF then decreased to 50% of pre-inflation values and ScvO2 decreased (post-ischemic hypoperfusion). CBF/CMRO2, ScvO2, and AVDO2 did not differ significantly between the three groups. After balloon deflation, all three groups showed increased CMR lactate, which was significantly reduced by mild and moderate hypothermia. Extracellular glutamate increased in control animals (3.8 +/- 1.72 microM), an effect most effectively suppressed in the mild hypothermia group (1.0 +/- 0.46 microM). Damaged tissue volumes as indicated by Evans blue dye extravasation were 729 +/- 89 mm3 in control, 247 +/- 56 mm3 in mild hypothermia, and 267 +/- 35 mm3 in moderate hypothermia animals. These data suggest that mild hypothermia (33 degrees C) might be the optimal brain temperature to treat compression-related cerebral ischemia.
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PMID:Effects of mild (33 degrees C) and moderate (29 degrees C) hypothermia on cerebral blood flow and metabolism, lactate, and extracellular glutamate in experimental head injury. 986 37

We have previously provided evidence that two transition metal cations, Zn2+ and Cu2+, can alter the conformation of nerve growth factor (NGF), rendering it unable to bind to its receptors or to activate signal transduction pathways. In the present study, we have assessed the influence of Zn2+ and Cu2+ on NGF-mediated protection from an oxidative insult. Exposure of rat pheochromocytoma (PC12) cells to hydrogen peroxide resulted in an increase in cell death via apoptosis, which was inhibited by NGF. Zn2+ and Cu2+, when added to cultures at a concentration of 100 microM, prevented NGF-mediated survival-promoting effects. Neither of these ions had an effect on basal cell viability (in the absence of NGF) after an oxidative insult. These results demonstrate that Zn2+ and Cu2+ can selectively inhibit NGF-mediated resistance to an oxidative stress, and have significant implications for neuronal function under both physiological and pathological (e.g. cerebral ischemia) conditions.
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PMID:Zinc and copper inhibit nerve growth factor-mediated protection from oxidative stress-induced apoptosis. 1002 71

In vitro studies suggest that ischemic injury of cerebral white matter is mediated by nonsynaptic cellular mechanisms, such as Ca2+ entry into axons through reversal of the Na+ -Ca2+ exchanger. The authors investigated extracellular Ca2+ concentration in relation to tissue depolarization (direct current potential) in vivo using ion-selective electrodes in cortical gray and subcortical white matter of alpha-chloralose-anesthetized cats during 120 minutes of global cerebral ischemia. On induction of ischemia, regional CBF, as measured by hydrogen clearance, ceased. The direct current potential decreased rapidly within minutes in gray matter and with little time delay in white matter. Extracellular Ca2+ concentration decreased just as quickly in gray matter. In white matter, in contrast, extracellular Ca2+ increased in the first 20 to 30 minutes, and a delayed and much slower decline, compared with gray matter, was observed thereafter, reaching a minimal level only about 60 minutes after occlusion. Our results suggest that smaller and delayed transmembrane shifts of Ca2+ are correlates of delayed ischemic membrane dysfunction in central white matter tracts, which may be explained by a lack of synaptic mechanisms.
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PMID:Breakdown of calcium homeostasis in relation to tissue depolarization: comparison between gray and white matter ischemia. 1041 34

Therapeutic cerebral hypothermia is widely used for the treatment of severe head injury and cerebral ischemia. The effects of cerebral hypothermia on the cerebral blood flow (CBF) and metabolism, and cerebral vasculature in the normal brain were investigated. Thirty-four adult cats were divided into four groups. CBF was monitored by hydrogen clearance. Arteriovenous oxygen difference (AVDO2) and cerebral venous oxygen saturation (ScvO2) were measured in blood samples from the superior sagittal sinus. The cerebral metabolic rate of oxygen (CMRO2) and cerebral vascular resistance (CVR) were calculated. The cerebral blood volume (CBV) was measured using technetium-99m-labeled human serum albumin in 12 cats. Deep cerebral temperature was cooled from 37 degrees C to 25 degrees C using a water-circulating blanket. In the hypothermia group (Group A: n = 10), CBF (51.2 +/- 8.3 ml 100 g-1 min-1 at 37 degrees C) decreased with lower brain temperature (6.1 +/- 2.7 at 25 degrees C). CMRO2 (2.24 +/- 0.75 ml 100 g-1 min-1 at 37 degrees C) was also decreased (0.52 +/- 0.20 at 25 degrees C). AVDO2 (4.3 +/- 1.0 ml 100 g-1 min-1 at 37 degrees C) increased significantly at 31 degrees C (6.6 +/- 1.8; p < 0.05) and ScvO2 (67.8 +/- 7.9% at 37 degrees C) decreased significantly at 29 degrees C (53.7 +/- 9.7; p < 0.05). CBV (5.3 +/- 1.2% at 37 degrees C) decreased significantly at 29 degrees C (3.7 +/- 1.0; p < 0.05) and CVR (3.2 +/- 0.7 mmHg ml-1 100 g-1 min-1 at 37 degrees C) increased significantly at 29 degrees C (13.8 +/- 5.2; p < 0.01). The combined effect of hypothermia with vasopressor (noradrenalin) (Group B: n = 6) or barbiturate (thiopental) administration (Group C: n = 6) on the cerebral metabolic parameters were also examined. Hypothermia with noradrenalin administration significantly improved the ischemic parameters (AVDO2 was 4.7 +/- 1.4 ml 100 g-1 min-1 at 31 degrees C and ScvO2 was 72.2 +/- 6.4% at 29 degrees C). However, hypothermia with barbiturate administration did not improve these metabolic parameters. These results suggest that hypothermia may cause vasoconstriction and misery perfusion in the brain. This potential risk of relative ischemia can be avoided by combination with vasopressor administration.
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PMID:Misery perfusion caused by cerebral hypothermia improved by vasopressor administration. 1049 21

The abrupt elevation in the levels of cyclooxygenase or lipoxygenase metabolites of arachidonic acid during cerebral ischemia contributes to neuronal injury. Recently, evidence has accumulated that both excitotoxic and apoptotic features can coexist in ischemia models in vitro and in vivo. In this study, we evaluated whether phenidone, an inhibitor of both cyclooxygenase and lipoxygenase, can provide protection against excitotoxin- or ischemia-induced neurotoxicity, including the staurosporine apoptosis model, in mouse cortical cultures. We examined the protective effect of phenidone against free radical injuries induced by arachidonic acid, hydrogen peroxide, xanthine/xanthine oxidase, Fe2+/ascorbic acid. Pre- and post-treatment with phenidone (300 microM for 24 h) moderately attenuated the neuronal injury induced by 50 microM kainate and oxygen/glucose deprivation (45 min) by 33% and 50%, respectively. It had no effect on NMDA induced injury (150 microM for 5 min). The maximum dose of phenidone (300 microM) reduced the oxidative injury induced by arachidonic acid (71% inhibition), hydrogen peroxide (95% inhibition), xanthine/xanthine oxidase (57% inhibition), and Fe2+/ascorbic acid (99% inhibition) neurotoxicity. Phenidone (300 microM) decreased staurosporine (100 nM)-induced apoptosis to 30%. These results suggest that phenidone may contribute to neuronal survival by modulating oxidative stress, which is involved in the excitotoxic and apoptotic processes occurring under ischemic conditions.
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PMID:Phenidone attenuates oxygen/glucose deprivation-induced neurotoxicity by antioxidant and antiapoptotic action in mouse cortical cultures. 1050 49


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