Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have demonstrated that melatonin is a scavenger of oxyradicals and peroxynitrite and an inhibitor of nitric oxide (NO) production. NO, peroxynitrite (formed from NO and superoxide anion), and poly (ADP-Ribose) synthetase (PARS) have been implicated as mediators of neuronal damage following focal ischemia. In the present study, we have investigated the effects of melatonin treatment in Mongolian gerbils subjected to cerebral ischemia. Treatment of gerbils with melatonin (10 mg kg(-1), 30 min before reperfusion and 1, 2, and 6 hr after reperfusion) reduced the formation of post-ischemic brain edema, evaluated by water content. Melatonin also attenuated the increase in the brain levels malondialdehyde (MDA) and the increase in the hippocampus of myeloperoxidase (MPO) caused by cerebral ischemia. Positive staining for nitrotyrosine was found in the hippocampus of Mongolian gerbils subjected to cerebral ischemia. Hippocampus tissue sections, from Mongolian gerbils subjected to cerebral ischemia, also showed positive staining for PARS. The degrees of staining for nitrotyrosine and for PARS were markedly reduced in tissue sections obtained from animals that received melatonin. Melatonin treatment increased survival and reduced hyperactivity linked to neurodegeneration induced by cerebral ischemia and reperfusion. Histological observations of the pyramidal layer of CA-1 showed a reduction of neuronal loss in animals that received melatonin. These results show that melatonin improves brain injury induced by transient cerebral ischemia.
 ...
PMID:Protective effects of melatonin in ischemic brain injury. 1106 44

The activity of peripheral phagocytes to generate reactive oxygen species (ROS) was studied in healthy individuals and patients with ischaemic stroke. The aim was to clarify the relationship between phagocyte activity, the time elapsed after the onset of disease and stroke severity. The total and extracellular production of ROS were evaluated by luminol chemiluminescence. Simultaneously the plasma oxidant activity was determined. When stimulated by opsonized zymosan, phagocytes in patients with stroke (regardless of its severity) showed fast activation. The total ROS generation increased over time in all stroke cases studied. However, the extracellular ROS generation was found to be greater in patients with severe stroke than in those with mild neurological deficiency. When stimulated by formyl-methionyl-leucyl-phenylalanine, the total oxidative phagocyte capacity (regardless of stroke severity) increased over time, but there was no change in the amount of extracellularly generated ROS. In patients with stroke the oxidant activity of plasma was enhanced. We conclude that circulating phagocytes in patients with ischaemic stroke are primed for enhanced ROS production by opsonin receptor-mediated stimulation and for increased secretion of myeloperoxidase by opsonin receptor-independent stimulation. The enhanced extracellular generation of ROS through opsonin receptor-dependent stimulation may be considered an oxidative stress biomarker in cerebral ischaemia.
 ...
PMID:Changes in phagocyte activity in patients with ischaemic stroke. 1175 38

Peroxynitrite is responsible for nitration in vivo, whereas myeloperoxidase can also catalyze protein nitration in the presence of high NO2(-) levels. Recent reports of myeloperoxidase-mediated enzyme inactivation or lipid peroxidation have suggested a role of myeloperoxidase in various pathological conditions. To clarify the role of myeloperoxidase in ischemic brain injury, the authors measured nitrotyrosine formation and infarct volume in myeloperoxidase-deficient or wild-type mice subjected to 2-hour focal cerebral ischemia-reperfusion. Twenty-four hours after reperfusion, infarct volume was significantly larger in myeloperoxidase-deficient mice than in wild-type mice (81 +/- 20 mm(3) vs. 52 +/- 13 mm(3), P < 0.01), and nitrotyrosine levels in the infarct region were higher in myeloperoxidase-deficient mice than in wild-type mice (13.4 +/- 6.1 microg/mg vs. 9.8 +/- 4.4 microg/mg, P = 0.13). Fourteen hours after reperfusion, the nitrotyrosine level was significantly higher in myeloperoxidase-deficient mice than in wild-type mice (3.3 +/- 2.9 microg/mg vs. 1.4 +/- 0.4 microg/mg, P < 0.05). The authors conclude that the absence of myeloperoxidase increases ischemic neuronal damage in vivo, and that the myeloperoxidase-mediated pathway is not responsible for the nitration reaction in cerebral ischemia-reperfusion.
 ...
PMID:Deficiency of myeloperoxidase increases infarct volume and nitrotyrosine formation in mouse brain. 1180 93

This investigation examined the effectiveness of a serine protease inhibitor (LEX032) when used as a cerebral protective agent after ischemia. Focal cerebral ischemia in the rat was produced by intravascular occlusion of the middle cerebral artery for a period of 30 min. Just prior to thread withdrawal (i.e., reperfusion), rats received an iv bolus administration of either vehicle or LEX032 (50 mg/kg), an optimal dose chosen based on previous studies. Somatosensory evoked potentials (SSEP's) were monitored prior to, during, and for a period of 60 min after removal of occlusion. The animals were allowed to recover for 24 h after the ischemic insult. Cortical activity in the occluded region, as assessed by SSEPs, returned much sooner in the LEX032-treated animals (10 +/- 6 min) than in the untreated animals (40 +/- 25 min). On a scale ranging from 0 to 3, with three indicating the most severely injured, the LEX032 animals had a significantly better neurologic score (1.0 +/- 0.9) than the untreated animals (2.3 +/- 0.5) 24 h after ischemia. The improved neurobehavior was related to a 55% reduction in brain injury as assessed by TTC staining. LEX032-treated animals had significantly (P < 0.01) smaller infarcts (115 +/- 40 mm3) compared to vehicle-treated animals (263 +/- 13 mm3). In a separate group of animals (n = 6/group), leukocyte infiltration, as evaluated by tissue myeloperoxidase activity (MPO U/g tissue wt), was also significantly (P < 0.05) lower in the LEX032-treated animals (1.4 +/- 0.3) compared to vehicle-treated animals (3.6 +/- 0.7). This data demonstrates that LEX032 reduces brain injury and suggests that serine protease inhibitors may reduce ischemia/reperfusion injury by decreasing leukocyte activation and migration.
 ...
PMID:LEX032, a novel recombinant serpin, protects the brain after transient focal ischemia. 1196 9

Stroke, or ischaemic brain damage, is of great geriatric importance being the third most common cause of death after cancer and heart diseases in developed countries. Despite such high frequency, its management has received inadequate attention. Many studies have shown the role of free radicals in the pathogenesis of ischaemic brain damage. Search for safe and effective antioxidant and free radial scavenger agents, therefore, appear to be a promising approach for stroke therapy. Gold, widely used in modern medicine for the treatment of rheumatoid arthritis, is highly valued for various medicinal uses in Indian systems of medicine. Traditional gold preparations are attributed with tonic/rejuvenating and antioxidant properties. Our earlier studies revealed interesting analgesic, immunostimulant, adaptogenic and glycogen sparing properties in these preparations, but their effects in cerebral ischaemia have not been investigated. This prompted us to initiate the present study using global and focal models of ischaemia in albino rats. Enzymatic parameters (lipid peroxidase, reduced glutathione, catalase, glutathione reductase, glutathione-S-transferase, glutatione peroxidase, superoxide dismutase, and glucose-6-phosphate dehydrogenase) were employed to assess ischaemic brain damage and its modulation. Significant restoration of altered values to near normal levels by Ayurvedic Swarna Bhasma and Unani Kushta Tila Kalan (25 mg/kg, orally for 10 days), suggest potentials for gold preparations in cerebrovascular diseases. The preparations deserve more scientific attention for possible therapeutic exploitation.
 ...
PMID:Antioxidant/restorative effects of calcined gold preparations used in Indian systems of medicine against global and focal models of ischaemia. 1207 6

The Na(+)/H(+) exchanger (NHE) is activated during ischemia-reperfusion in an effort to restore intracellular pH to normal levels. The NHE is recognized to exist as a distinct protein in the plasma membranes of a variety of cells. We investigated the pharmacological effects of a Na(+)/H(+) exchanger inhibitor, SM-20220 (N-(aminoiminomethyl)-1-methyl-1-H-indole-2-carboxamide methanesulfonate), on ischemic brain damage, edema and neutrophil accumulation at 72 h after middle cerebral artery (MCA) occlusion in a rat MCA occlusion model. SM-20220 was intravenously administered as a bolus injection immediately after occlusion, followed by a continuous infusion over 2.5 h. At 72 h after occlusion, the infract area was measured using hematoxylin-eosin staining and, using the same slices, neutrophils in the brain were immuno-stained with anti-myeloperoxidase (n=11). In a separate study, rat behavior was scored and scaled, and brains removed for the determination of water content by the dry-weight method. SM-20220 significantly (P<0.05) attenuated cerebral infarct volume, water content, and the neutrophil accumulation at 72 h after the MCA occlusion, and ameliorated neurological deficits. SM-20220, an NHE inhibitor prevented the progress of cerebral ischemic damage and edema following MCA occlusion in rats though a possible mechanism that may be due to the inhibition of neutrophil accumulation. The NHE in neutrophils may enhance the progress of cerebral damage following cerebral ischemia-reperfusion.
 ...
PMID:SM-20220, a Na(+)/H(+) exchanger inhibitor: effects on ischemic brain damage through edema and neutrophil accumulation in a rat middle cerebral artery occlusion model. 1212 86

Matrix metalloproteinases (MMPs) are activated in focal cerebral ischemia. The activation of MMP-9 is involved in blood-brain barrier breakdown and tissue remodeling. The MMPs are released to the extracellular space, but the form and fate of secreted enzymes in brain are unknown. Using microdialysis in vivo, the authors studied whether ischemia-induced MMP-9 in brain tissue was related to free MMP-9 in the extracellular fluid. A microdialysis probe was placed into the right striatum and microdialysis was initiated 24 hours later in controls (n = 7). One hour prior to microdialysis, a group of rats (n = 7) was subjected to 1-hour occlusion of the right middle cerebral artery, followed by reperfusion. Dialysates were collected at discrete time points up to 24 hours, and subjected to zymography and Western blot analysis. The MMP-9 was released after ischemia and accumulated in the extracellular space at 24 hours (P < 0.05). Free MMP-9 forms include mainly the 95-kd proform, and, to a lesser extent, dimers and cleaved active forms (70 kd), but not the 88-kd form found in tissue. Probe implantation and microdialysis increased free MMP-9 in the dialysate. This increase was concomitant with neutrophil infiltration after the mechanical lesion, as myeloperoxidase was found by means of Western blot analysis in the brain hemisphere subjected to microdialysis (P < 0.005), and immunohistochemistry revealed the presence of myeloperoxidase stain surrounding the site of probe implantation. The results suggest that certain forms of MMP-9 are released and accumulate in the extracellular space after brain injury, and that vascular alterations and neutrophil recruitment elicit MMP-9 activation in the brain after focal ischemia and trauma.
 ...
PMID:Certain forms of matrix metalloproteinase-9 accumulate in the extracellular space after microdialysis probe implantation and middle cerebral artery occlusion/reperfusion. 1217 77

Nitric oxide (NO) and reactive oxygen species are both implicated in neuronal death due to cerebral ischemia. BN 80933, an original compound associating an inhibitor of neuronal NO synthase with an antioxidant, has been shown to reduce functional and histological damage in rat submitted to cerebral ischemia. The aim of the present study was to confirm these results in mice and to further examine the effects of BN 80933 on inflammatory response, including blood-brain barrier (BBB) disruption, brain edema, and neutrophil infiltration after transient middle cerebral artery occlusion (MCAO). Intravenous administration of BN 80933 at 3 and 10 mg/kg 3 h after MCAO significantly reduced by 26 to 36% the infarct volume evaluated 24 and 48 h after ischemia, and improved the neurological score. Furthermore, BN 80933 at both dosages decreased by 42 to 75% the extravasation of Evans blue in brain parenchyma observed 24 h after ischemia. This reduction in BBB disruption was associated with decreased brain edema as demonstrated by the 37% reduction in brain water content induced by BN 80933 at 3 mg/kg 24 h after MCAO. Neutrophil infiltration in brain parenchyma, evaluated by the myeloperoxidase activity, was also reduced by 45 to 56% in animals treated with BN 80933 at 3 and 10 mg/kg. Together, these results extend the protective capacity of BN 80933 against brain ischemic injury and confirm that BN 80933 represents a promising treatment for stroke.
 ...
PMID:Neuroprotective effects of (S)-N-[4-[4-[(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl]-2-thiophenecarboximid-amide (BN 80933), an inhibitor of neuronal nitric-oxide synthase and an antioxidant, in model of transient focal cerebral ischemia in mice. 1273 Mar 57

Naloxone has been advanced as a potential neuroprotectant against ischemic injury. This study examined the involvement of classical opioid receptors in the reduction of middle cerebral arterial ligation-induced cortical infarction in rats. The infarct volume was significantly reduced after infusion of (-)-naloxone, but not its inert stereoisomer (+)-naloxone. Beta-funaltrexamine (beta-FNA), a mu opioid antagonist, also reduced ischemic infarct volume. Both (-)-naloxone and beta-FNA attenuated cerebral ischemia/reperfusion (I/R)-induced increases in neutrophil-associated myeloperoxidase activity and chemokine mRNA expression, including macrophage inflammatory protein-1 alpha and -2. However, (-)-naloxone and beta-FNA failed to decrease cerebral I/R-induced brain edema. The findings suggest that naloxone, acting through a blockade of mu opioid receptor activation, is beneficial to cerebral I/R insult in terms of reducing brain infarction, neutrophil accumulation, and chemokine expression.
 ...
PMID:Neuroprotection of naloxone against ischemic injury in rats: role of mu receptor antagonism. 1284 83

Reactive oxygen species produced by neutrophils contribute to the pathogenesis of focal cerebral ischemia/reperfusion injury and signal the inflammatory response. We have previously shown that honokiol, an active principle extracted from Magnolia officinalis, has a protective effect against focal cerebral ischemia/reperfusion injury in rats that paralleled a reduction in reactive oxygen species production by neutrophils. To elucidate the underlying mechanism(s) of the antioxidative effect of honokiol, peripheral neutrophils isolated from rats were activated with phorbol-12-myristate-13-acetate (PMA) or N-formyl-methionyl-leucyl-phenylalanine (fMLP) in the presence or absence of honokiol. In this study, we found that honokiol inhibited PMA- or fMLP-induced reactive oxygen species production by neutrophils by three distinct mechanisms: (1) honokiol diminished the activity of assembled-NADPH oxidase, a major reactive oxygen species producing enzyme in neutrophils by 40% without interfering with its protein kinase C (PKC)-dependent assembly; (2) two other important enzymes for reactive oxygen species generation in neutrophils, i.e., myeloperoxidase and cyclooxygenase, were also inhibited by honokiol by 20% and 70%, respectively; and (3) honokiol enhanced glutathione (GSH) peroxidase activity by 30%, an enzyme that triggers the metabolism of hydrogen peroxide (H2O2). These data suggested that honokiol, acting as a potent reactive oxygen species inhibitor/scavenger, could achieve its focal cerebral ischemia/reperfusion injury protective effect by modulating enzyme systems related to reactive oxygen species production or metabolism, including NADPH oxidase, myeloperoxidase, cyclooxygenase, and GSH peroxidase in neutrophils.
 ...
PMID:The anti-inflammatory effect of honokiol on neutrophils: mechanisms in the inhibition of reactive oxygen species production. 1295 55


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>