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

Pitavastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, is a potent cholesterol-lowering drug that reduces the risk of myocardial infarction and stoke. In this study, we examined its neuroprotective effects against hippocampal CA1 neuronal damage following transient cerebral ischemia in gerbils. Forebrain ischemia was induced by occlusion of bilateral common carotid arteries for 5 min. Pitavastatin, at a dose of 3, 10 or 30 mg/kg, was administered orally twice a day for 5 consecutive days and transient cerebral ischemia was induced in mice 1 h after the last treatment with pitavastatin. Histopathological observations showed that neuronal damage to the hippocampal CA1 neurons, which was observed 5 days after ischemia in animals, was prevented by pitavastatin treatment. Immunohistochemical staining for copper/zinc superoxide dismutase (SOD) and manganese SOD decreased in the hippocampal CA1 sector of gerbils 2 days after ischemia when histological neuronal destruction was not yet found, but was clearly observed in pitavastatin-treated animals. These results indicate that pitavastatin can protect dose-dependently against ischemia-induced neuronal damage and that the mechanism of the neuroprotection may be related to the preservation of SODs, especially copper/zinc-SOD. This in part explains how pitavastatin therapy, which targets free radicals, has beneficial effects against disorders including ischemic stroke.
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PMID:Pitavastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, reduces hippocampal damage after transient cerebral ischemia in gerbils. 1533 28

Review of results of experimental and clinical studies indicates that the penumbra of physiologically impaired but potentially salvageable tissue surrounding the central core of focal cerebral ischemia that develops shortly after onset of major conducting vessel occlusion is complex and dynamic with severity and duration thresholds for hypoxic stress and injury that are specific to tissue site, cell type, molecular pathway or gene expression investigated and efficiency of collateral or residual flow and reperfusion. Imaging methods that have been utilized in vivo to identify penumbra and predict response to reperfusion and other protective therapies include magnetic resonance spectroscopy, diffusion- and perfusion-MRI as well as positron emission tomography. However, resolution of focal lesions characterized by lactic acidosis or cellular edema does not predict tissue survival, and imaging thresholds for resuscitation after reperfusion have not been determined experimentally. HSP-70 stress protein induction represents an endogenous protective mechanism that occurs in penumbra but not core neurones. A robust protective effect has been demonstrated during focal ischemia in transgenic mice overexpressing HSP-70 perhaps by suppressing early cytochrome c release. Delayed manganese mediated striatal neurodegeneration can be detected with T1 MRI after brief episodes of transient focal ischemia. Future studies may define endogenous cytotoxic and cytoprotective molecular penumbras that can be exploited to improve outcome after temporary focal ischemia.
Stroke 2004 Nov
PMID:Molecular identification of the ischemic penumbra. 1548 32

Divalent manganese ion (Mn2+) has been reported to be a useful contrast agent for functional MRI, through a technique named activity-induced manganese-dependent MRI (AIM). In AIM, signal enhancement is related to functional increases in calcium influx, and therefore AIM is, thus far, the only MRI method able to map brain activation in vivo independently of the surrogate hemodynamic changes used in functional MRI. Because of its high signal-to-noise ratio (SNR) and high sensitivity, AIM allows the use of multi-slice or three-dimensional MRI techniques to map functional activity at high spatial resolution. In the present review, we define AIM as a functional MRI tool based on the administration of divalent ionized manganese through an open or disrupted blood-brain barrier (BBB). The adequacy and efficacy of AIM in detecting neural activation is described in light of supporting experiments on inhibition of calcium channels, FOS expression, and on direct comparison to BOLD- and perfusion-based functional MRI. Two main applications of AIM, mapping brain activation in rat somatosensory cortex, as well stroke research based on the well-established middle cerebral artery occlusion model, are described in detail. Methodological problems associated with a strong dependence on anesthetic conditions, potential corruption due to disruption of the BBB, and unspecific increase of the baseline signal due to acoustical noise are discussed. Finally, recommended preparation methods and experimental protocols for AIM are introduced.
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PMID:Manganese-enhanced magnetic resonance imaging (MEMRI) of brain activity and applications to early detection of brain ischemia. 1561 55

We present the results of the first theoretical investigation of salen-manganese complexes as synthetic catalytic scavengers of hydrogen peroxide molecules that mimic catalase enzymes. Catalase mimics can be used as therapeutic agents against oxidative stress in treatment of many diseases, including Alzheimer's disease, stroke, heart disease, aging, and cancer. A ping-pong mechanism approach has been considered to describe the H2O2 dismutation reaction. The real compounds reacting with a peroxide molecule were utilized in our BP density functional calculations to avoid uncertainties connected with using incomplete models. Part I of the dismutation reaction-converting a peroxide molecule into a water molecule with simultaneous oxidation of the metal atom of the catalyst-can be done quite effectively at the Mn catalytic center. To act as catalytic scavengers of hydrogen peroxide, the oxomanganese salen complexes have to be deoxidized during part II of the dismutation reaction. It has been shown that there are two possible reaction routes for the second part of the dismutation reaction: the top and the side substrate approach routes. Our results suggest that the catalyst could be at least temporarily deactivated (poisoned) in the side approach reaction route due to the formation of a kinetically stable intermediate. Overall, the side approach reaction route for the catalyst recovery is the bottleneck for the whole dismutation process. On the basis of the detailed knowledge of the mode of action of the (salen)MnIII catalase mimics, we suggest and rationalize structural changes of the catalyst that should lead to better therapeutic properties. The available experimental data support our conclusions. Our findings on the reaction dismutation mechanism could be the starting point for further improvement of salen-manganese complexes as synthetic catalytic scavengers of reactive oxygen species.
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PMID:(salen)MnIII compounds as nonpeptidyl mimics of catalase. Mechanism-based tuning of catalase activity: a theoretical study. 1573 83

Recent studies have suggested that the calcium antagonists have an antiatherogenic antioxidant property. The effects of the calcium antagonists on reactive oxygen species (ROS)-related enzymes, however, remain unknown. We hypothesized that the calcium antagonists inhibit oxidative stress in the hearts of stroke-prone spontaneously hypertensive rats (SHRSP) through the ROS-scavenging enzymes known as superoxide dismutases (SODs). Male 12-week-old Wister-Kyoto rats (WKY) and SHRSP were used for the study. SHRSP were randomized and treated for 6 weeks with a vehicle, amlodipine (5 mg/kg/day), or enalapril (10 mg/kg/day). NAD(P)H oxidase activity was measured by a luminescence assay, and SOD activity was measured spectrophotometrically. Protein expressions were analyzed by immunoblots. Both drugs showed equipotent effects on systolic blood pressure, left ventricular hypertrophy and fibrosis, the wall-to-lumen ratio, the manganese SOD activity, ROS, and the endothelial NO synthase expression in the SHRSP hearts. Furthermore, amlodipine significantly restored copper/zinc-containing SOD (Cu/ZnSOD) expression and its activity in SHRSP hearts to a level equal to that of WKY more effectively than did enalapril (p <0.05), whereas enalapril downregulated NAD(P)H oxidase activity more than did amlodipine (p <0.05) in the SHRSP hearts. Furthermore, amlodipine restored Cu/ZnSOD expression and its activity in SHRSP hearts to a level equal to that in WKY hearts, and this restoration was significantly more effective than that by enalapril (p <0.05); on the other hand, enalapril induced a greater downregulation of NAD(P)H oxidase activity in SHRSP hearts than did amlodipine (p <0.05). Thus, amlodipine may inhibit vascular remodeling and oxidative stress in the SHRSP heart by efficiently upregulating Cu/ZnSOD, suggesting that the calcium antagonist may exhibit an antiatherogenic antioxidative action beyond blood-pressure lowering through the restoration of Cu/ZnSOD activity in the heart in cases of hypertension.
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PMID:Calcium antagonist reduces oxidative stress by upregulating Cu/Zn superoxide dismutase in stroke-prone spontaneously hypertensive rats. 1582 70

Curcumin is a natural antioxidant isolated from the medicinal plant Curcuma longa Linn. We previously reported that manganese complexes of curcumin (Cp-Mn) and diacetylcurcumin (DiAc-Cp-Mn) exhibited potent superoxide dismutase (SOD)-like activity in an in vitro assay. Nitric oxide (NO) is a free radial playing a multifaceted role in the brain and its excessive production is known to induce neurotoxicity. Here, we examined the in vivo effect of Cp-Mn and DiAc-Cp-Mn on NO levels enhanced by kainic acid (KA) and L-arginine (L-Arg) in the hippocampi of awake rats using a microdialysis technique. Injection of KA (10 mg/kg, i.p.) and L-Arg (1000 mg/kg, i.p.) significantly increased the concentration of NO and Cp-Mn and DiAc-Cp-Mn (50 mg/kg, i.p.) significantly reversed the effects of KA and L-Arg without affecting the basal NO concentration. Following KA-induced seizures, severe neuronal cell damage was observed in the CA1 and CA3 subfields of hippocampal 3 days after KA administration. Pretreatment with Cp-Mn and DiAc-Cp-Mn (50 mg/kg, i.p.) significantly attenuated KA-induced neuronal cell death in both CA1 and CA3 regions of rat hippocampus compared with vehicle control, and Cp-Mn and DiAc-Cp-Mn showed more potent neuroprotective effect than their parent compounds, curcumin and diacetylcurcumin. These results suggest that Cp-Mn and DiAc-Cp-Mn protect against KA-induced neuronal cell death by suppression of KA-induced increase in NO levels probably by their NO scavenging activity and antioxidative activity. Cp-Mn and DiAc-Cp-Mn have an advantage to be neuroprotective agents in the treatment of acute brain pathologies associated with NO-induced neurotoxicity and oxidative stress-induced neuronal damage such as epilepsy, stroke and traumatic brain injury.
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PMID:Prevention of kainic acid-induced changes in nitric oxide level and neuronal cell damage in the rat hippocampus by manganese complexes of curcumin and diacetylcurcumin. 1626 25

T1 signal hyperintensity is a common finding at magnetic resonance imaging of the sellar region. However, this signal intensity pattern has different sources, and its significance depends on the clinical context. Normal variations in sellar T1 signal hyperintensity are related to vasopressin storage in the neurohypophysis, the presence of bone marrow in normal and variant anatomic structures, hyperactive hormone secretion in the anterior pituitary lobe (eg, in newborns and pregnant or lactating women), and flow artifacts and magnetic susceptibility effects. Pathologic variations in T1 signal hyperintensity may be related to clotting of blood (in hemorrhagic pituitary adenoma, pituitary apoplexy, Sheehan syndrome, or thrombosed aneurysm) or the presence of a high concentration of protein (Rathke cleft cyst, craniopharyngioma, or mucocele), fat (lipoma, dermoid cyst, lipomatous meningioma), calcification (craniopharyngioma, chondroma, chordoma), or a paramagnetic substance (manganese, melanin). After treatment, T1 signal hyperintensity may result from the presence of materials used for surgical packing (gelatin sponge, fat); from compression of the cavernous sinus and reduction of the venous flow, caused by overpacking of the operative bed; or from hormone hypersecretion by a remnant of normal tissue in the anterior lobe of the pituitary gland.
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PMID:T1 signal hyperintensity in the sellar region: spectrum of findings. 1641 46

HEK293T cells overexpressing divalent metal transporter-1 (DMT1) were established to screen for small-molecule inhibitors of iron uptake. Using a fluorescence-based assay, we tested 2000 known bioactive compounds to find 3 small molecules that potently block ferrous iron uptake. One of the inhibitors, ebselen, is a seleno compound used in clinical trials as a protective agent against ischemic stroke. Ebselen inhibited Fe(II) uptake (IC(50) of approximately 0.22 microM), but did not influence Fe(III) transport or DMT1-mediated manganese uptake. An unrelated antioxidant, pyrrolidine dithiobarbamate (PDTC), also inhibited DMT1 activity (IC(50) of approximately 1.54 microM). Both ebselen and PDTC increased cellular levels of reduced glutathione. These observations indicate that Fe(II) transport by DMT1 can be modulated by cellular redox status and suggest that ebselen may act therapeutically to limit iron-catalyzed damage due to transport inhibition.
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PMID:Small-molecule screening identifies the selanazal drug ebselen as a potent inhibitor of DMT1-mediated iron uptake. 1698 86

Effective stroke therapies require recanalization of occluded cerebral blood vessels; however, early reperfusion can cause BBB (blood-brain barrier) injury, leading to cerebral oedema and/or devastating brain haemorrhage. These complications of early reperfusion, which result from excess production of ROS (reactive oxygen species), significantly limit the benefits of stroke therapies. Here, we summarize some of the findings that lead to the development of a novel animal model that facilitates identification of specific free radical-associated components of the reperfusion injury process and allows therapeutic interventions to be assessed. In this model, KO (knockout) mice containing 50% activity of the mitochondrial antioxidant manganese-SOD (superoxide dismutase) (SOD2-KO) undergo transient focal ischaemia followed by reperfusion. These animals have delayed (>24 h) BBB breakdown associated with activation of matrix metalloproteinase-9, inflammation and a high brain haemorrhage rate. These adverse consequences are absent from wild-type littermates, SOD2 overexpressors and minocycline-treated SOD2-KO animals. In addition, using microvessel isolations following in vivo ischaemia/reperfusion, we were able to show that the tight junction membrane protein, occludin, is an early and specific target in ROS-mediated microvascular injury. This new model is ideal for studying ischaemia/reperfusion-induced vascular injury and secondary brain damage and offers a unique opportunity to evaluate free radical-based neurovascular protective strategies.
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PMID:A new approach for the investigation of reperfusion-related brain injury. 1707 20

Loss of function and subsequent spontaneous recovery after stroke have been associated with physiological and anatomical alterations in neuronal networks in the brain. However, the spatiotemporal pattern of such changes has been incompletely characterized. Manganese-enhanced MRI (MEMRI) provides a unique tool for in vivo investigation of neuronal connectivity. In this study, we measured manganese-induced changes in longitudinal relaxation rate, R(1), to assess the spatiotemporal pattern of manganese distribution after focal injection into the intact sensorimotor cortex in control rats (n=10), and in rats at 2 weeks after 90-min unilateral occlusion of the middle cerebral artery (n=10). MEMRI data were compared with results from conventional tract tracing with wheat-germ agglutinin horseradish peroxidase (WGA-HRP). Distinct areas of the sensorimotor pathway were clearly visualized with MEMRI. At 2 weeks after stroke, manganese-induced changes in R(1) were significantly delayed and diminished in the ipsilateral caudate putamen, thalamus and substantia nigra. Loss of connectivity between areas of the sensorimotor network was also identified from reduced WGA-HRP staining in these areas on post-mortem brain sections. This study demonstrates that MEMRI enables in vivo assessment of spatiotemporal alterations in neuronal connectivity after stroke, which may lead to improved insights in mechanisms underlying functional loss and recovery after stroke.
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PMID:Changes in neuronal connectivity after stroke in rats as studied by serial manganese-enhanced MRI. 1717 75


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