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

Stroke is a severe and prevalent syndrome for which there is a great need for treatment, including agents to block the cascade of brain injury that occurs in the hours after the onset of ischemia. Reactive oxygen species (ROS) have been implicated in this destructive process, but antioxidant enzymes such as superoxide dismutase (SOD) have been unsatisfactory in experimental stroke models. This study is an evaluation of the effectiveness of salen-manganese complexes, a class of synthetic SOD/catalase mimetics, in a rat focal ischemia model involving middle cerebral artery occlusion. We focus on EUK-134, a newly reported salen-manganese complex demonstrated here to have greater catalase and cytoprotective activities and equivalent SOD activity compared with the previously described prototype EUK-8. The administration of EUK-134 at 3 hr after middle cerebral artery occlusion significantly reduced brain infarct size, with the highest dose apparently preventing further infarct growth. EUK-8 was also protective but substantially less effective. These findings support a key role for ROS in the cascade of brain injury after stroke, even well after the onset of ischemia. The enhanced activity of EUK-134 suggests that, in particular, hydrogen peroxide contributes significantly to this injury. Overall, this study suggests that synthetic SOD/catalase mimetics might serve as novel, multifunctional therapeutic agents for stroke.
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PMID:Synthetic combined superoxide dismutase/catalase mimetics are protective as a delayed treatment in a rat stroke model: a key role for reactive oxygen species in ischemic brain injury. 943 81

We measured hydroxyl radical (.OH) levels in blood, superoxide dismutase (SOD) activity in red blood cells (RBC) relative to both total protein (RBC-SOD/P) and Cu,Zn-SOD protein (RBC-SOD/SOD), SOD activity in plasma (plasma-SOD), and Cu,Zn-SOD protein relative to total RBC protein (Cu,Zn-SOD/P) in 22 patients with probable dementia of the Alzheimer type (DAT group, mean age 74.8+/-9.4 years), 16 with probable vascular dementia (VAD group, mean age 76.9+/-6.7 years) and 19 non-demented controls (control group, mean age 73.5+/-6.2 years). Levels of .OH in the DAT and VAD groups were significantly (P<0.01 and P<0.001, respectively) higher, whereas the values of RBC-SOD/P and RBC-SOD/SOD in these two groups (both P<0.001) and Cu,Zn-SOD/P in the DAT group (P<0.001) were significantly lower than the corresponding control values. Members of the VAD group with risk factors for stroke (RF+ group) showed significantly higher .OH levels than members of the VAD group without risk factors (RF- group; P<0.01) and the control group (P<0.001). RBC-SOD/P and RBC-SOD/SOD values in the RF+ group were significantly (both P<0.01) lower than the corresponding control values. There were no significant differences among the VAD, RF+ and control groups with respect to Cu,Zn-SOD/P values, or between the RF- and control groups for any measured parameter. We conclude that oxidative stress plays a role in the brain damage seen in both DAT and VAD, and that the causes of decreased SOD activity in RBC differ between DAT and VAD patients.
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PMID:Free radicals and superoxide dismutase in blood of patients with Alzheimer's disease and vascular dementia. 945 82

As stroke is a major cause of disability and death in the western world, there is great interest in the basic mechanisms by which ischemia/reperfusion (I/R) causes damage. To this end, extensive research has been carried out which identifies reactive oxygen species (ROS) as key participants in brain damage resultant from I/R. Brain tissue is protected from ROS damage by antioxidant enzymes, such as superoxide dismutase (SOD) and glutathione peroxidase (GP). Overexpression of SOD in transgenic mice has already been demonstrated to confer protection against I/R damage in murine stroke models. We are using transgenic mice overexpressing the intracellular form of glutathione peroxidase (GP1) to determine the protective capacity of overexpression of this enzyme on stroke damage. 1 h of focal cerebral ischemia followed by 24 h of reperfusion was induced using the intraliminal suture method. Volume of infarction was reduced by 48% in GP1 mice compared to nontransgenic littermates. Brain edema was reduced by 33%. Behavioral deficits agreed with histologic data. Overexpression of glutathione peroxidase confers significant protection against I/R damage in our stroke model possibly through direct scavenging of ROS or through the influencing of signalling mechanisms which lead to tissue damage.
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PMID:Overexpression of human glutathione peroxidase protects transgenic mice against focal cerebral ischemia/reperfusion damage. 947 16

Shichimotsu-koka-to (SKT) has been prescribed to treat patients with essential and renal hypertension. We investigated the effects of SKT on renal lesions in stroke-prone spontaneously hypertensive rats (SHRSPs). SHRSPs were given an extract of SKT by mixing it with drinking water, from 8 through 29 weeks of age, so that the average intake of SKT extract was about 1.5 g/kg/d. At 29 weeks of age, the kidneys of SHRSPs exhibited proliferative arteritis characterized by the proliferation of smooth muscle cells in the interlobular arteries, dilation and degeneration of renal tubules, infiltration of inflammatory cells and hemorrhage, with partial swelling or necrotizing of glomeruli. In particular, arteritis and periarteritis were noted. The treatment of SHRSPs with SKT ameliorated this morphological damage in the kidney and significantly decreased urea nitrogen in the serum. Treatment with SKT also strongly decreased the xanthine oxidase (XOD) activity and significantly increased the superoxide dismutase (SOD) activity in the kidney of SHRSPs; consequently, these values became close to those in normotensive Wistar Kyoto rats (WKYs). These results indicate that treatment with SKT ameliorated the histopathological damage and change in activity of enzymes related to free radicals in the kidney of SHRSPs, which may be important mechanisms for SKT for protecting SHRSPs from renal dysfunction.
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PMID:Preventive effects of Shichimotsu-koka-to on renal lesions in stroke-prone spontaneously hypertensive rats. 978 38

Cerebral ischemia followed by oxygen reperfusion induces apoptosis in hippocampal neurons in stroke-prone spontaneously hypertensive rats (SHRSP) but not in Wistar Kyoto rats (WKY). The overproduction of oxygen-free radicals that occurs in the tissues of SHRSP is implicated in reoxygenation injury after hypoxia. Antioxidants inhibit reoxygenation injury in hippocampal slices, and temporal cortices in Alzheimer's disease increase sensitivity to oxygen-free radicals. Because this sensitivity may contribute to the development of the disease, we have studied hypoxia and oxygen reperfusion using cortical neurons isolated from WKY and SHRSP (at 15 days of gestation). We have tried to determine whether cortical neurons are damaged under these conditions, and whether neurons from SHRSP are more vulnerable than those from WKY. We have tried also to verify whether neuronal damage is minimized by vitamin E using the following techniques: (a) Trypan blue staining, (b) in situ staining of apoptosis, (c) ultrastructural examination, and (d) measurement of lactic dehydrogenase (LDH) activity in the bathing medium. Furthermore, we have examined the mechanisms involved in the development of neuronal damage and have studied ways of minimizing it. We demonstrated that 36 hours of hypoxia significantly increased the rate of cell death in SHRSP (p < 0.01), although 12 to 24 hours of hypoxia did not increase cell death in either WKY or SHRSP. In addition, 6 to 36 hours of hypoxia and 1.5 to 5 hours of oxygen reperfusion heavily damaged cells of both WKY and SHRSP, and most became apoptotic or necrotic. In contrast, cells incubated with 50 to 300 microg/ml of vitamin E remained intact, although 10 to 20 microg/ml of vitamin E did not totally preserve the cells. Moreover, vitamin E protected the neurons from high concentrations of sodium nitroprusside (nitric oxide donor) in a dose-dependent manner. Vitamin E, when added to the cells, increased in concentration in a time-dependent manner over a 24-hour period and in a dose-dependent manner below 200 microg/ml, and it was detected mostly in the mitochondria. We also demonstrated that serial treatments with allopurinol (a xanthine oxidase inhibitor) or superoxide dismutase preserved neurons during hypoxia and oxygen reperfusion. These data indicate that SHRSP neurons are weaker than WKY neurons in long-term hypoxia; oxygen radical generation occurs in the early minutes after reperfusion, and then the oxygen-free radicals cause heavy damage to the cells; and antioxidants including vitamin E react with the radicals, thereby preventing apoptosis and necrosis. Therefore, antioxidants appear to be the most important agents in lowering oxygen-free radical damage in cortical neurons.
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PMID:Vitamin E prevents apoptosis in cortical neurons during hypoxia and oxygen reperfusion. 984 Jun 16

Oxidative insults, whether over-excitation, excessive release of glutamate or ATP caused by stroke, ischemia or inflammation, exposure to ionizing radiation, heavy-metal ions or oxidized lipoproteins may initiate various signaling cascades leading to apoptotic cell death and neurodegenerative disorders. Among the various reactive oxygen species (ROS) generated in the living organism, hydroxyl and peroxynitrite are the most potent and can damage proteins, lipids and nucleic acids. It appears that some natural antioxidants (tocopherol, ascorbic acid and glutathione) and defense enzyme systems (superoxide dismutase, catalase and glutathione peroxidase) may provide some protection against oxidative damage. Recent findings indicate several polyphenols and antioxidant drugs (probucol, seligilline) are effective in protecting the cells from ROS attack. Further development of these antioxidant molecules may be of value in preventing the development of neurodegenerative diseases.
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PMID:Oxidative stress and neurodegenerative disorders. 984 43

BACKGROUND AND PURPOSE--Endothelin-1, in concentrations similar to that present in cerebrospinal fluid after fluid percussion brain injury (FPI), increases superoxide anion (O2-) production. Endothelin-1 also contributes to altered cerebral hemodynamics after FPI through impairment of ATP-sensitive K+ (KATP) channel function through protein kinase C (PKC) activation. Generation of O2- additionally occurs after FPI. Nitric oxide and cGMP elicit pial artery dilation through KATP channel activation. The present study was designed to determine whether PKC activation generates O2-, which, in turn, could link such activation to impaired KATP channel function after FPI. METHODS--Injury of moderate severity (1.9 to 2.1 atm) was produced by the lateral FPI technique in anesthetized newborn pigs equipped with a closed cranial window. Superoxide dismutase-inhibitable nitroblue tetrazolium (NBT) reduction was determined as an index of O2- generation. RESULTS--Phorbol 12, 13-dibutyrate (10(-6) mol/L), a PKC activator, increased superoxide dismutase-inhibitable NBT reduction from 1+/-1 to 37+/-5 pmol/mm2. Staurosporine (10(-7) mol/L), a PKC antagonist, blocked the NBT reduction after phorbol 12,13-dibutyrate and blunted the NBT reduction observed after FPI (1+/-1 to 15+/-2 versus 1+/-1 to 5+/-1 pmol/mm2 after FPI in the absence versus presence of staurosporine). Exposure of the cerebral cortex to a xanthine oxidase O2--generating system increased NBT reduction in a manner similar to FPI and blunted pial artery dilation to the KATP channel agonists cromakalim and calcitonin gene-related peptide, the nitric oxide releasers sodium nitroprusside and S-nitroso-N-acetylpenicillamine, and the cGMP analogue 8-bromo-cGMP (10+/-1% and 21+/-1% versus 4+/-1% and 9+/-1% for 10(-8) and 10(-6) mol/L cromakalim before and after activated oxygen-generating system exposure). CONCLUSIONS--These data show that PKC activation increases O2- production and contributes to such production observed after FPI. These data also show that an activated system that generates an amount of O2- similar to that observed with FPI blunted pial artery dilation to KATP channel agonists and nitric oxide/cGMP. These data suggest, therefore, that O2- generation links PKC activation to impaired KATP channel function after FPI.
Stroke 1999 Jan
PMID:Superoxide generation links protein kinase C activation to impaired ATP-sensitive K+ channel function after brain injury. 988 Apr 4

Regional distribution and age-related change of Mn-, Cu/Zn-superoxide dismutase (SOD) and constitutive type of nitric oxide synthase (NOS) activities in the brain were determined using stroke-prone spontaneously hypertensive rats (SHRSP). In the hippocampus (HIP), Mn- and Cu/Zn-SOD activities in SHRSP of 31-week-old were significantly lower than those of 15-week-old or normotensive rats (WKY). From Mn-SOD immunohistochemical staining of several subfields of the HIP, our results suggested that SHRSP hippocampal CA1 was more vulnerable to oxidative stress compared with WKY and other subfields. In the 31-week-old SHRSP cerebral cortex (CC), the activities of Mn-, Cu/Zn-SOD and NOS were significantly lower than those in WKY. At this age, most of the SHRSP developed cerebral injuries. These observations indicated that hypertensive vascular disease observed in the SHRSP CC resulted from the decreased antioxidant capacity that is closely associated with the development of stroke and, in turn, shortened life span.
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PMID:Age-related change of antioxidant capacities in the cerebral cortex and hippocampus of stroke-prone spontaneously hypertensive rats. 1050 47

Lot of advancement has taken place, not only in the management but also in the pathophysiology and imaging modalities in patients of stroke. Indolent chronic infections, particularly those due to H. pylori, have been identified as one of the risk factors. The mechanism of inflammation in inducing a precoagulant state has also been worked out. SPECT studies have detected ischaemic areas before appearance of CT abnormalities. CT angiography identifies abnormalities in the 'circle of willis' in posterior circulation strokes much better, and helps weigh the risk versus benefit of thrombolysis. With experiance in use of r-TPA, the list of contra indications and precautions has become longer than its indications. Newer drugs like lubeluzole and edselen have also been recommended. Various other drugs e.g. aptiganel hydrochloride, MDL 28170, 'basic fibroblast growth factor' and 'superoxide dismutase' are at an experimental stage. The concept of a 'stroke cocktail' may be in vogue soon. Controversies still exit regarding the exact indication of prophylactic anticoagulant and the 'international normalized ratio' (INR) to be achieved. Guidelines have been laid down for the approach to patients with asymptomatic carotid artery stenosis. However, the paramount message in stroke care is dissipation of the concept of 'brain attack', amongst the primary care medical and para-medical personnel.
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PMID:Ischaemic stroke: new frontiers. 1051 74

Organ injury caused by transient ischemia followed by reperfusion is associated with a number of clinically and environmentally induced conditions. Ischemia/reperfusion (I/R) conditions arise during surgical interventions such as organ transplantation and coronary bypass surgery, and in diseases such as stroke and cardiac infarct. The destructive effects of I/R arise from the acute generation of reactive oxygen species subsequent to reoxygenation, which inflict direct tissue damage and initiate a cascade of deleterious cellular responses leading to inflammation, cell death, and organ failure. This review summarizes existing and potential approaches for treatment that have been developed from research using model systems of I/R injury. Although I/R injury in the liver is emphasized, other organ systems share similar pathophysiological mechanisms and therapeutic approaches. We also review current knowledge of the molecular events controlling cellular responses to I/R injury, such as activation of AP-1 and NF-kappaB pathways. Therapeutic strategies aimed at ameliorating I/R damage are focused both on controlling ROS generated at the time of oxygen reperfusion and on intervening in the activated signal transduction cascades. Potential therapies include pharmacological treatment with small molecules, antibodies to cytokines, or free-radical scavenging enzymes, such as superoxide dismutase or catalase. Additionally, the use of gene therapy approaches may significantly contribute to the development of strategies aimed at inhibiting of I/R injury.
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PMID:Therapeutic approaches for ischemia/reperfusion injury in the liver. 1054 90


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