Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To clarify possible roles in the pathogenesis of ischemic brain edema, identification and quantitative analysis of hydroxy-eicosatetraenoic acids (HETEs) in rat brains exposed to middle cerebral artery occlusion were carried out using high-performance liquid chromatography. Rat brain sampling was done by in situ freezing 24 and 72 hours after occlusion. Only a small amount of 15-HETE was found in control rat brains. Twenty-four hours after ischemia, 11-HETE appeared, and the amount of 15-HETE tended to increase. Seventy-two hours after ischemia, when brain edema reached its maximum, 5-, 8-, 9-, 11-, 12-, and 15-HETEs were identified, and the amounts of all HETEs except 8- and 12-HETE were significantly increased. The detection of 5-HETE in ischemic rat brain indicates the simultaneous production of leukotrienes in the same brain area. The above results support the view that lipoxygenase products may play significant roles in the formation of ischemic brain edema.
Stroke
PMID:Identification and quantitative analysis of hydroxy-eicosatetraenoic acids in rat brains exposed to regional ischemia. 356 8

Using the rat middle cerebral artery occlusion model, alterations in the eicosanoid synthetic capacity of brain microvessels following ischemia were studied by radiochromatography. Brain microvessels of normal rats predominantly produced hydroxyacids with relatively small amounts of PGD2 and PGE2 from exogenous arachidonic acid. Confirmation that hydroxyacids and prostaglandins were products respectively of lipoxygenase(s) and cyclooxygenase was obtained by experiments using indomethacin and eicosatetraynoic acid. The eicosanoid synthetic capacity of the brain microvessel, especially of hydroxyacids, was significantly enhanced 24 and 72 hours after the onset of ischemia. Because this is the phase of maximum edema in the present model, enhanced eicosanoid production in the brain microvessel may be involved in the mechanisms that underly ischemic brain edema.
Stroke
PMID:Ischemic brain edema following occlusion of the middle cerebral artery in the rat. II: Alteration of the eicosanoid synthesis profile of brain microvessels. 396 53

The roles of PGI2 and TXA2 in recurring reduction of carotid artery and cerebral blood flow induced by partial constriction of the common carotid artery and cerebral blood flow induced by partial constriction of the common carotid artery were examined in anesthetized dogs. The recurring reduction was eliminated by OKY 046 and 1580 which inhibit TX synthetase, acetylsalicylic acid which inhibits cyclo-oxygenase and lipoxygenase, PGI2 and by papaverine which enhances PGI synthesis. But the recurring reduction was not eliminated by phentolamine. The recurring reduction was induced by epinephrine which activates phospholipase A2 and cyclo-oxygenase and causes platelet aggregation. It was also induced by tranylcypromine which inhibits PGE2 synthetase and, although infrequently, by TXA2. The recurring reduction was also induced by indomethacin that inhibits cyclo-oxygenase. The indomethacin-induced recurring reduction, however, was eliminated not by OKY 046 and 1580 but by PGI2. It is suggested that TXA2 acted as an inducer and PGI2 as an inhibitor in the recurring reduction of carotid artery and cerebral blood flow.
Stroke
PMID:Role of prostaglandin I2 and thromboxane A2 in recurring reduction of carotid and cerebral blood flow in dogs. 702 92

3,4-Dihydro-3,3-dimethyl-isoquinoline-2-oxide (MDL 101,002) is a conformationally constrained cyclic analog of the known spin trap alpha-phenyl N-tert-butyl nitrone (PBN). Because of PBN's ability to scavenge free radicals, MDL 101,002 is currently being evaluated in stroke models as a means to ameliorate the oxidative insult associated with reperfusion injury. To augment our understanding of the radical scavenging mechanism of this potential drug, MDL 101,002 was incubated with soybean lipoxygenase in the presence of linoleic acid to study the interaction between MDL 101,002 and free radicals formed during lipid peroxidation. Analysis of the reaction mixture was performed by high performance liquid chromatography using normal phase conditions with detection by atmospheric pressure chemical ionization mass spectrometry (APCI-MS). Similar to the work by Iwahashi et al. [Arch. Biochem. Biophys., 1991, 285, 172], who studied the spin trap alpha-(4-pyridyl-1-oxide)-N-tert-butyl nitrone (4-POBN), an adduct that suggested the trapping of pentyl radicals by MDL 101,002 was observed. However, the apparent molecular ion for this adduct (246 Da) was 1 Da lower than would be predicted if a pentyl radical had simply added to MDL 101,002. In addition, the adduct exhibited significant absorbance at 304 nm, consistent with the unsaturated nitrone structure of MDL 101,002. To account for these observations, it is postulated that, after the initial capture of a pentyl radical, subsequent abstraction of a hydrogen atom by a neighboring radical occurs to regenerate a nitrone (1-pentyl analog of MDL 101,002). We present evidence for this adduct and offer a mechanism for its formation. These findings indicate that mass spectroscopic analysis of stable nitrone radical adducts may be useful in the identification of radical-dependent damage in vivo and possibly in clinical development of MDL 101,002 as an antioxidant pharmaceutical.
 ...
PMID:Evidence for a novel pentyl radical adduct of the cyclic nitrone spin trap MDL 101,002. 911 49

Excessive activation of N-methyl-D-aspartate (NMDA) receptor channels (NRs) is a major cause of neuronal death associated with stroke and ischemia. Cerebellar granule neurons in vivo, but not in culture, are relatively resistant to toxicity, possibly owing to protective effects of glia. To evaluate whether NR-mediated signaling is modulated when developing neurons are cocultured with glia, the neurotoxic responses of rat cerebellar granule cells to applied NMDA or glutamate were compared in astrocyte-rich and astrocyte-poor cultures. In astrocyte-poor cultures, significant neurotoxicity was observed in response to NMDA or glutamate and was inhibited by an NR antagonist. Astrocyte-rich neuronal cultures demonstrated three significant differences, compared with astrocyte-poor cultures: (a) Neuronal viability was increased; (b) glutamate-mediated neurotoxicity was decreased, consistent with the presence of a sodium-coupled glutamate transport system in astrocytes; and (c) NMDA- but not kainate-mediated neurotoxicity was decreased, in a manner that depended on the relative abundance of glia in the culture. Because glia do not express NRs or an NMDA transport system, the mechanism of protection is distinct from that observed in response to glutamate. No differences in NR subunit composition (evaluated using RT-PCR assays for NR1 and NR2 subunit mRNAs), NR sensitivity (evaluated by measuring NR-mediated changes in intracellular Ca2+ levels), or glycine availability as a coagonist (evaluated in the presence and absence of exogenous glycine) were observed between astrocyte-rich and astrocyte-poor cultures, suggesting that glia do not directly modulate NR composition or function. Nordihydroguaiaretic acid, a lipoxygenase inhibitor, blocked NMDA-mediated toxicity in astrocyte-poor cultures, raising the possibility that glia effectively reduce the accumulation of highly diffusible and toxic arachidonic acid metabolites in neurons. Alternatively, glia may alter neuronal development/phenotype in a manner that selectively reduces susceptibility to NR-mediated toxicity.
 ...
PMID:Glia modulate NMDA-mediated signaling in primary cultures of cerebellar granule cells. 979 24

The haemodynamic responses to arachidonic acid (AA) have been investigated in seven groups of anaesthetized rats. Sodium arachidonate was infused intravenously for 4 or 20 min, and arterial blood pressure was recorded continuously. Cardiac output and organ blood flow were measured by microspheres. Infusion of arachidonate caused first a fast drop in arterial blood pressure, thereafter it increased steadily for 5-15 min towards a pressure about 25 mmHg above control level. The high pressure was maintained for at least 1 h. Repeated infusions of arachidonate gave similar responses. Inhibition of cyclo-oxygenase by indomethacin prevented the initial pressure drop to arachidonate, but not the sustained increase in pressure. Arterial pressure, total vascular resistance and blood flow in the kidneys, adrenals and spleen were significantly reduced, whereas cardiac output was not changed 4 min after start infusion of arachidonate. However, average blood pressure was significantly increased 22 and 35 min after start infusion (from 103.9 +/- 2.9 to 128.1 +/- 6.1 and 135.8 +/- 4.6 mmHg). Mean vascular resistance increased simultaneously (from 3.5 +/- 0.2 to 4.7 +/- 0.4 and 5.2 +/- 0.4 mmHg 100 mL-1), while cardiac output, stroke volume and heart rate were maintained or slightly reduced. The renal blood flow was significantly lowered (from average 4.9 +/- 0.1 to 3.3 +/- 0.2 and 4.0 +/- 0.2 mL min-1). Indomethacin did not prevent the changes in vascular resistance or organ blood flow recorded after 20-35 min. On the other hand, inhibition of both cyclo-oxygenase, lipoxygenase and the cytochrome P450 pathways by eicosatetrayonic acid (ETYA) normalized all haemodynamic parameters. Likewise, the rise in pressure was prevented by 17-octadecynoic acid (17-ODYA), an inhibitor of the cytochrome P450 enzyme activity. Thus, arachidonate infusion caused a transient decrease, and then a sustained increase in arterial pressure and vascular resistance, and a long-lasting reduction in renal blood flow, possibly owing to release of a cytochrome P450 dependent vasoconstrictor metabolite of AA.
 ...
PMID:Sustained increase in arterial blood pressure and vascular resistance induced by infusion of arachidonic acid in rats. 1097 Dec 17

Aspirin is not only one of the best-documented medicines in the world, but also one of the most frequently used drugs of all times. In addition to its role as an analgesic, aspirin is being increasingly used in the prophylaxis of ischemic heart disease and strokes. The prevalence of aspirin intolerance is around 5 to 6%. Up to 20% of the asthmatic population is sensitive to aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) and present with a triad of rhinitis, sinusitis, and asthma when exposed to the offending drugs. This syndrome is referred to as aspirin-induced asthma (AIA). The pathogenesis of AIA has implicated both the lipoxygenase (LO) and the cyclooxygenase (COX) pathways. By inhibiting the COX pathway, aspirin diverts arachidonic acid metabolites to the LO pathway. This also leads to a decrease in the levels of prostaglandin (PG) E(2), the anti-inflammatory PG, along with an increase in the synthesis of cysteinyl leukotrienes (LTs). Evidence suggests that patients with AIA have increased activity of LTC(4) synthase, the rate-limiting enzyme in the cysteinyl LT synthesis, in their bronchial biopsy specimens, thereby tilting the balance in favor of inflammation. LT-modifying drugs are effective in blocking the bronchoconstriction provoked by aspirin and are used in the treatment of this condition. Aspirin desensitization has a role in the management of AIA, especially in patients who need prophylaxis from thromboembolic diseases, myocardial infarction, and stroke. This review covers the latest understanding of pathogenesis, clinical features, and management of AIA.
 ...
PMID:Aspirin and asthma. 1108 3

Free fatty acids (FFAs) are elevated in the brain following both ischemic and traumatic injury. Phospholipase activation, with the subsequent release of FFAs from membrane phospholipids, is the likely mechanism. In addition to phospholipases A1, B, C, and D, there are at least 19 groups of PLA2, including multiple cytosolic, calcium independent, and secretory isoforms. Phospholipase activity can be regulated by calcium, by phosphorylation, and by agonists binding to G-protein-coupled receptors. These enzymes normally function in the physiological remodeling of cellular membranes, whereby FFAs are removed by phospholipase activity and then reacylated with a different FFA. However, reductions in the cell's ability to maintain normal metabolic function and the resultant fall in ATP levels can cause the failure of reacylation of membrane phospholipids. Alterations to membrane phospholipids would be expected to compromise many cellular functions, including the ability to accumulate excitotoxic amino acids. This review presents evidence for a central role of phospholipases and their products in the etiology of damage following injury to the brain. Phospholipase expression and activity is increased in animal models of cerebral ischemia and trauma. FFA release from the in vivo rat brain is reduced following the application of selective phospholipase inhibitors, and this inhibition also decreases the severity of cortical damage following forebrain ischemia, focal (middle cerebral artery occlusion) ischemia, and cerebral trauma. Mice with knockouts of PLA2 have decreased infarct volumes. Human data demonstrate a correlation between the elevation of CSF FFAs and worsened outcome following stroke, traumatic brain injury, and subarachnoid hemorrhage. The released FFAs, especially arachidonic and docosahexaenoic acids, together with the production of lysophospholipids, can initiate a chain of events which may be responsible for the development of neuronal damage. Inhibitors of both cyclooxygenase and lipoxygenase pathways have been shown to reduce cerebral deficits following ischemia and trauma. These results suggest therapeutic strategies to reduce morbidity following cerebral injury using selective inhibitors of phospholipases, cyclooxygenases, and lipoxygenases, underlining the need for further investigation of their role in the development of cerebral damage.
 ...
PMID:The role of phospholipases, cyclooxygenases, and lipoxygenases in cerebral ischemic/traumatic injuries. 1451 63

A major goal of the second International Workshop on "Brain Uptake and Utilization of Fatty Acids, Lipids and Lipoproteins: Application to Neurological Disorders" was the identification of important future research areas that would lead to accelerated and systematic progress in the field. Major themes identified for future research include the following: (1) Rigorous research protocols for fatty acid (FA) studies should be established to overcome errors introduced by small differences in chain length and degree of unsaturation. (2) Using cellular integration models consisting of endothelial cells, astrocytes, and neurons, investigation of functional lipidomics, cell-specific signaling by lipids, and nutritional considerations should be undertaken. (3) Educational programs should be undertaken for women of childbearing age on the health benefits of omega3 long chain (LC) polyunsaturated fatty acids (PUFA) from fish consumption vs risks of mercury in fish. (4) Studies of the "flip-flop" model of passive diffusion should be extended to include other quantitative measures, such as the sizes of different fatty acid pools. (5) Investigations to establish physiologic roles and concentrations of omega3 LC-PUFA in various compartments of the brain should be undertaken. (6) Further studies should be carried out to illuminate the role and behavior of tight junctions in the microvascular endothelium of the blood-brain barrier and astrocytes, with emphasis on developing new LC-PUFA and lipid-based carriers of biomolecules across this barrier. (7) Roles and localization of very low density lipoproteins, low density lipoprotein (LDL), and the LDL receptor in the brain and their interactions with omega3 LC-PUFA, cholesterol, apolipoprotein E1-4, and their derivatives in Alzheimer's disease (AD) should be assessed. (8) Investigation of intraneuronal synthesis of DHA and its effects on signal transduction, apoptosis, and neurite growth stimulation should be undertaken. (9) Nutrition-based behavioral affects of EPA and DHA, particularly with respect to the omega6:omega3 FA ratio, gene regulation, neurodevelopment, and conversion to bioactive molecules by cyclooxygenases (COX) and lipoxygenase, should be explored. (10) Further assessment of brain lipid metabolism and neurodevelopment should be performed in DHA-deficient rodent models, including the use of imaging techniques. (11) Potential toxic effects of COX overexpression and the possible consequences of DHA over-supplementation in various neurological and neurodevelopmental disorders should be characterized. (12) The relationship between LC-PUFA, stroke, and AD should be clarified, and neurogenetic metabolic diseases that could benefit from supplementation with omega3 LC-PUFA such as DHA should be identified.
 ...
PMID:Brain uptake and utilization of fatty acids, lipids & lipoproteins: recommendations for future research. 1790 59

This review focuses on the morphological features of atherosclerosis and the involvement of oxidative stress in the initiation and progression of this disease. There is now consensus that atherosclerosis represents a state of heightened oxidative stress characterized by lipid and protein in the vascular wall. Reactive oxygen species (ROS) are key mediators of signaling pathways that underlie vascular inflammation in atherogenesis, starting from the initiation of fatty streak development, through lesion progression, to ultimate plaque rupture. Plaque rupture and thrombosis result in the acute clinical complications of myocardial infarction and stroke. Many data support the notion that ROS released from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, myeloperoxidase (MPO), xanthine oxidase (XO), lipoxygenase (LO), nitric oxide synthase (NOS) and enhanced ROS production from dysfunctional mitochondrial respiratory chain, indeed, have a causatory role in atherosclerosis and other vascular diseases. Moreover, oxidative modifications in the arterial wall can contribute to the arteriosclerosis when the balance between oxidants and antioxidants shifts in favour of the former. Therefore, it is important to consider sources of oxidants in the context of available antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase and transferases thiol-disulfide oxidoreductases and peroxiredoxins. Here, we review also the mechanisms in which they are involved in order to accelerate the pace of the discovery and facilitate development of novel therapeutic approaches.
 ...
PMID:Atherosclerosis and oxidative stress. 1807 94


<< Previous 1 2 3 4 Next >>