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

Lectin-like oxidized low-density lipoprotein receptor (LOX-1) is a newly identified endothelial cell surface major receptor for oxidatively modified low-density lipoprotein. Progression of arthrosclerosis in the donor organ after organ transplantation is a major problem. We hypothesized that ischemia-reperfusion induces LOX-1. After 1 h ischemia of bilateral kidneys plus 3, 6, or 12 h reperfusion, we first revealed that LOX-1 mRNA expression was increased in renal cortex and medulla at 6 h after reperfusion, which was decreased by L-arginine supplement. Plasma nitric oxide (NO) end-product nitrite plus nitrate and inducible nitric oxide synthase (NOS) expression were increased after reperfusion of 6 h. However, NOS substrate L-arginine did not augment but markedly decreased plasma NO end product, because L-arginine supplement suppressed inducible NOS expression in kidney. We hypothesized that available L-arginine is depleted by ischemia-reperfusion, leading to inducible NOS induction. Ischemia decreased L-arginine levels in kidney and L-arginine supplement increased NO end products in renal cortex in the earliest phase of reperfusion. These results disclosed for the first time that a deficiency in L-arginine by ischemia reperfusion causes uncoupling of constitutive NOS, which induces inducible NOS and LOX-1, implying why L-arginine is effective for stroke or transplantation in preventing atherosclerotic progress.
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PMID:Induction of LOX-1 and iNOS expressions by ischemia-reperfusion of rat kidney and the opposing effect of L-arginine. 1266 76

Ischemic cerebrovascular disease (stroke) is one of the leading causes of death and long-time disability. Ischemia/reperfusion to any organ triggers a complex series of biochemical events, which affect the structure and function of every organelle and subcellular system of the affected cells. The purpose of this study was to investigate the therapeutic efficacy of N-acetyl cysteine (NAC), a precursor of glutathione and a potent antioxidant, to attenuate ischemia/reperfusion injury to brain tissue caused by a focal cerebral ischemia model in rats. A total of 27 male Sprague-Dawley rats weighing 250-300 g were used in this study. Focal cerebral ischemia (45 min) was induced in anesthetized rats by occluding the middle cerebral artery (MCA) with an intra-luminal suture through the internal carotid artery. The rats were scored post-reperfusion for neurological deficits. They were then sacrificed after 24 h of reperfusion and infarct volume in the brain was assessed by 2,3,5-triphenyl tetrazolium chloride (TTC). Brain sections were immunostained for tumor necrosis factor (TNF-alpha) and inducible nitric oxide synthase (iNOS). Animals treated with NAC showed a 49.7% (S.E.M.=1.25) reduction in brain infarct volume and 50% (S.E.M.=0.48) reduction in the neurological evaluation score as compared to the untreated animals. NAC treatment also blocked the ischemia/reperfusion-induced expression of tumor necrosis factor and inducible nitric oxide synthase. The data suggest that pre-administration of NAC attenuates cerebral ischemia and reperfusion injury in this brain ischemia model. This protective effect may be as a result of suppression of TNF-alpha and iNOS.
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PMID:N-Acetyl cysteine protects against injury in a rat model of focal cerebral ischemia. 1269 31

Nuclear factor-kappaB (NFkappaB) is a transcription factor that is activated after cerebral ischemia. NFkappaB activation leads to the expression of many inflammatory genes involved in the pathogenesis of stroke. The authors previously showed that mild hypothermia is protective even when cooling begins 2 h after stroke onset. In the present study, they examined the influence of hypothermia on NFkappaB activation. Rats underwent 2 h of transient middle cerebral artery occlusion. Brains were cooled to 33 degrees C immediately after or 2 h after occlusion, and maintained for 2 h. After normothermic ischemia (brain temperature at 38 degrees C), NFkappaB cytoplasmic expression, nuclear translocation, and binding activity were observed as early as 2 h in the ischemic hemisphere and persisted at 24 h. Hypothermia decreased NFkappaB translocation and binding activity but did not alter overall expression. Hypothermia also affected the levels of NFkappaB regulatory proteins by suppressing phosphorylation of NFkappaB's inhibitory protein (IkappaB-alpha) and IkappaB kinase (IKK-gamma) and decreasing IKK activity, but did not alter overall IKK levels. Hypothermia suppressed the expression of two NFkappaB target genes: inducible nitric oxide synthase and TNF-alpha. These data suggest that the protective effect of hypothermia on cerebral injury is, in part, related to NFkappaB inhibition due to decreased activity of IKK.
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PMID:Mild hypothermia inhibits nuclear factor-kappaB translocation in experimental stroke. 1277 74

Ebselen is a seleno organic compound with antioxidant and anti-inflammatory properties, which is under clinical trials for the treatment of ischemic stroke. In this study, we attempted to correlate the protective effects of ebselen and the inducible nitric oxide synthase (iNOS) immunocontent in hippocampal slices submitted to oxygen-glucose deprivation (OGD), since the exacerbated production of nitric oxide by iNOS plays a role in the mechanisms of cellular death in ischemic insults. Ebselen (10 microM) protected slices from the deleterious effects of OGD (as assessed by MTT assay) only when present during all the recovery period (180 min). Moreover, ebselen added 5 and 15 min after the beginning of recovery only partially protected the slices from cellular death, while when added 30 min after the beginning of recovery no protection was observed. OGD increased the immunocontent of iNOS, and this increase was abolished also only when ebselen was present during all the recovery period. Our results indicate that the neuroprotective effect of ebselen could be related to this decrease in the iNOS immunocontent.
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PMID:Neuroprotective effect of ebselen on rat hippocampal slices submitted to oxygen-glucose deprivation: correlation with immunocontent of inducible nitric oxide synthase. 1285 May 58

Massive cutaneous burn combined with smoke inhalation causes high mortality in fire victims. Cyclo-oxygenase (COX) and inducible nitric oxide (NO) synthase (iNOS) have been shown to be up-regulated in burn injury. Ketorolac, a non-steroidal, anti-inflammatory agent (NSAID), inhibits prostaglandin and thromboxane synthesis through inhibition of COX. NSAIDs have been shown to down-regulate iNOS. Thus we hypothesized that treatment with ketorolac would attenuate burn/smoke-related cardiopulmonary derangements. We conducted a fully controlled long-term laboratory investigation in an Intensive Care Unit setting. Eighteen female sheep were surgically prepared for chronic study. After a recovery period of 5 days, a tracheotomy was performed under ketamine/halothane anaesthesia. Sheep were given a 40% total body surface third-degree burn and insufflated with cotton smoke (48 breaths, <40 degrees C). Sheep were divided into three groups: sham (not injured and not treated; n =6), control (injured, but not treated; n =6) and treated (injured and administered ketorolac 60 mg/day; n =6). The sham group had stable cardiopulmonary and systemic haemodynamics. Control animals showed depressed cardiopulmonary function, decreased pulmonary gas exchange, increased pulmonary microvascular leakage and decreased left ventricle stroke work index with elevated left atrial pressure. Systemic vascular leak in control animals was evidenced by robust haemoconcentration (haematocrit and fluid net balance). Treatment with ketorolac prevented all of these morbidities. Post-treatment with ketorolac also resulted in significant inhibition of elevated plasma nitrite/nitrate levels in control animals. These results suggest that ketorolac may ameliorate cardiopulmonary morbidity, at least in part, by inhibiting excessive NO.
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PMID:Ketorolac attenuates cardiopulmonary derangements in sheep with combined burn and smoke inhalation injury. 1292 81

Flavonoids, naturally occurring polyphenolic compounds, are known to inhibit both lipopolysaccharide (LPS) stimulated tumor necrosis factor alpha and interleukin 6 release which modulate the proinflammatory molecules that have been reported in many progressive neurodegenerative disorders, including Alzheimer's disease (AD), viral and bacterial meningitis, AIDS dementia complex, and stroke. The present experiments were performed to study the possible effects of exogenously administered flavonoids (apigenin-7-glucoside and quercetin) on the cognitive performance in aged and LPS-treated mice (an animal model for AD) using passive avoidance and elevated plus-maze tasks. Aged and LPS-treated mice showed poor retention of memory in step-through passive avoidance and in plus-maze tasks. Chronic administration of the flavonoids apigenin-7-glucoside (5-20 mg/kg i.p.) and quercetin (25-100 mg/kg i.p.) dose dependently reversed the age-induced and LPS-induced retention deficits in both test paradigms. However, flavonoids after chronic administration in young mice did not show any improvement of memory retention in both paradigms. Apigenin-7-glucoside showed more efficacy as compared with quercetin in both models that may be probably due to its greater efficacy to inhibit cyclooxygenase-2 and inducible nitric oxide synthase. Chronic treatment with flavonoids did not alter the locomotor activity in both young and aged mice; however, aged mice showed improvement of performance on Rota-Rod test. The results showed that chronic treatment with flavonoids reverses cognitive deficits in aged and LPS-intoxicated mice which suggests that modulation of cyclooxygenase-2 and inducible nitric synthase by flavonoids may be important in the prevention of memory deficits, one of the symptoms related to AD.
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PMID:Protective effect of flavonoids against aging- and lipopolysaccharide-induced cognitive impairment in mice. 1292 78

The activation of microglial cells is involved in the pathogenesis of a variety of neurodegenerative diseases, stroke and traumatic brain injuries. Recent studies suggest that protein acetylation can affect the extent of inflammatory responses. Our aim was to elucidate whether histone deacetylase inhibitors, inducers of protein hyperacetylation, regulate the inflammatory response in neural models of inflammation in vitro and whether neurone-glia interactions affect this regulation. Interestingly, we observed that histone deacetylase inhibitors, such as trichostatin A (TSA) and suberoylanilide hydroxamic acid, strongly potentiated the lipopolysaccharide (LPS)-induced inflammatory response in murine N9 and rat primary microglial cells as well in neural co-cultures and hippocampal slice cultures. TSA clearly potentiated the LPS-induced expression of interleukin (IL)-6 and inducible nitric oxide synthase mRNAs, as well as the secretion of cytokines IL-6, tumour necrosis factor-alpha and macrophage inflammatory protein (MIP)-2, and nitric oxide (NO). Co-culture and slice culture experiments showed that the presence of astrocytes and neurones did not stimulate or prevent the pro-inflammatory potentiation induced by histone deacetylase inhibitor in microglial cells. The potentiation of cytokine and NO responses was blocked by the nuclear factor kappa B (NF-kappa B) inhibitors caffeic acid phenethyl ester and helenalin, demonstrating that the NF-kappa B signalling pathway is involved. The DNA-binding activity of the NF-kappa B complex was strongly increased by LPS treatment but not enhanced by TSA. This suggests that potentiation of the inflammatory response is not dependent on the level of cytoplasmic NF-kappa B activation or DNA-binding activity but that site of action may be at the level of transcriptional regulation. Our results suggest that environmental stresses, ageing, diet and diseases that regulate protein acetylation status may also affect the inflammatory response.
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PMID:Regulation of microglial inflammatory response by histone deacetylase inhibitors. 1451 Nov 18

Acetylsalicylic acid (ASA) reduces the incidence of ischemic stroke mainly through its antithrombotic action; however, it also has a direct neuroprotective effect. The present study was designed to evaluate the effect of ASA on oxidative stress and the activity of nitric oxide synthase (NOS) in an in vitro model of hypoxia in rat brain slices. Rat brain slices were perfused with nitrogen (hypoxia) for a maximum of 120 min, after which we measured lipid peroxidation, glutathione levels, glutathione-related enzyme activities, and constitutive nitric oxide synthase (cNOS) and inducible nitric oxide synthase (iNOS) activities. In brain tissue subjected to hypoxia, ASA reduced oxidative stress and iNOS activity (all increased by hypoxia), but only when used at higher concentrations. The effects of salicylic acid (SA) were similar but more intense than were those of ASA. After oral administration, the effect of SA was much greater than that of ASA, and the decrease in cell death with SA was seen much more clearly. In view of the greater effect of SA compared to ASA on changes in oxidative stress parameters in a model of hypoxia, and higher brain concentrations of SA when it is administered alone than when ASA is given (undetectable levels), we conclude that SA plays an important role in the cytoprotective effect in brain tissue after ASA administration.
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PMID:Antioxidant effect of acetylsalicylic and salicylic acid in rat brain slices subjected to hypoxia. 1470 49

Free radicals and inflammatory mediators are involved in transient focal cerebral ischemia (FCI). Preadministration of N-acetylcysteine (NAC) has been found to attenuate the cerebral ischemia-reperfusion injury in a rat model of experimental stroke. This study was undertaken to investigate the neuroprotective potential of NAC administered after ischemic events in experimental stroke. FCI was induced for 30 min by occluding the middle cerebral artery (MCA). NAC (150 mg/kg) was administered intraperitoneally at the time of reperfusion followed by another dose 6 hr later. Animals were sacrificed after 24 hr of reperfusion. The cerebral infarct consistently involved the cortex and striatum. Infarction was assessed by staining the brain sections with 2,3,5-triphenyltetrazolium chloride. Animals treated with NAC showed a significant reduction in infarct area and infarct volume and an improvement in neurologic scores and glutathione level. Reduction in infarction was significant even when a single dose of NAC was administered at 6 hr of reperfusion. Immunohistochemical and quantitative real-time PCR studies demonstrated a reduction in the expression of proinflammatory cytokines such as tumor necrosis factor alpha (TNFalpha) and interleukin 1beta (IL-1beta) and inducible nitric oxide synthase (iNOS) in NAC compared to that in vehicle-treated animals. The expression of activated macrophage/microglia (ED1) and apoptotic cell death in ischemic brain was also reduced by NAC treatment. These results indicate that in a rat model of experimental stroke, administration of NAC even after ischemia onset protected the brain from free radical injury, apoptosis, and inflammation, with a wide treatment window.
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PMID:Administration of N-acetylcysteine after focal cerebral ischemia protects brain and reduces inflammation in a rat model of experimental stroke. 1511 24

The protective effects of estrogens have been widely reported in a number of animal and cell culture models, but the molecular mechanisms of this potent neuroprotective activity are not well understood. Both in vitro and in vivo studies indicate that in the central nervous system and peripheral tissues, estrogen treatment reduces cytokine production and inflammatory responses. Nuclear factor-kappa B (NFkappaB) plays an essential role in the regulation of post-ischemic inflammation, which is detrimental to recovery from an ischemic stroke. We investigated the role of NFkappaB in neuronal survival in rats that received transient middle cerebral artery (MCA) occlusion, and observed that this transient cerebral ischemia induced substantial apoptosis and inflammatory responses, including IkappaB phosphorylation, NF-kappaB activation and iNOS over-expression. 17 beta-estradiol (E2) treatment produced strong protective effects by reducing infarct volume, neuronal apoptosis, and inflammatory responses. These findings provide evidence for a novel molecular and cellular interaction between the sex hormone and the immunoresponsive system. These studies also provide evidence that suppression of post-ischemic inflammation may play a critical role in estrogen-mediated neuroprotection.
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PMID:Estrogen attenuates nuclear factor-kappa B activation induced by transient cerebral ischemia. 1514 51


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