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

Tumor necrosis factor (TNF)-alpha stimulated interleukin (IL)-6 release and induced the phosphorylation of myosin phosphatase targeting subunit (MYPT)-1, a Rho-kinase substrate. The IL-6 release was significantly suppressed by Y-27632 and fasudil, Rho-kinase inhibitors. Although IkappaB inhibitor suppressed the TNF-alpha-induced IL-6 release, the Rho-kinase inhibitors did not affect the TNF-alpha-induced IkappaB phosphorylation. TNF-alpha induced the phosphorylation of p38 mitogen-activated protein (MAP) kinase, stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK), and p44/p42 MAP kinase. The TNF-alpha-induced IL-6 release was suppressed by SB203580, a p38 MAPK inhibitor, or SP600125, a SAPK/JNK inhibitor, but not by PD98059, a MAP kinase/extracellular signal-regulated kinase kinase inhibitor. The Rho-kinase inhibitors attenuated the TNF-alpha-induced phosphorylation of both p38 MAP kinase and SAPK/JNK. Rho-kinase, which has been used for the clinical treatment of cerebral vasospasms, may be involved in other central nervous system (CNS) disorders such as traumatic injury, stroke, neurodegenerative disease and neuropathic pain. TNF-alpha, a proinflammatory cytokine that affects the CNS through cytokines, such as IL-6, release from neurons, astrocytes and microglia. Therefore, we investigated the involvement of Rho-kinase in the TNF-alpha-induced IL-6 release from rat C6 glioma cells. These results strongly suggest that Rho-kinase regulates the TNF-alpha-induced IL-6 release at a point upstream from p38 MAPK and SAPK/JNK in C6 glioma cells. Therefore, Rho-kinase inhibitor may be considered to be a new clinical candidate for the treatment of CNS disorders in addition to cerebral vasospasms.
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PMID:Involvement of Rho-kinase in tumor necrosis factor-alpha-induced interleukin-6 release from C6 glioma cells. 1942 47

Chondroitin sulphate (CS) is a natural glycosaminoglycan present in the extracellular matrix and is formed by the 1-3 linkage of D-glucuronic acid to N-acetylgalactosamine. In chondrocytes, CS diminishes interleukin-1 beta(IL-1beta)-induced increases in p38 mitogen-activated protein kinase (p38MAPK) and signal-regulated kinase 1/2 (Erk1/2) phosphorylation, and decreases nuclear factor-kappaB (NF-kappaB) nuclear translocation and as a consequence, reduces the formation of pro-inflammatory cytokines, IL-1beta and TNF-alpha, and pro-inflammatory enzymes, such as phospholipase A2 (PLA2), cyclooxygenase 2 (COX-2) and nitric oxide synthase-2 (NOS-2). The mechanism of action of CS explains its beneficial effect on the cartilage, synovial membrane and subchondral bone. On the other hand, in vivo, CS given orally prevents hepatic NF-kappaB nuclear translocation, suggesting that systemic CS may elicit an anti-inflammatory effect in many tissues besides the articulation. There is preliminary evidence showing that in human beings, CS may be of benefit in other diseases where inflammation is an essential marker, such as psoriasis and atherosclerosis. The review of the literature suggest that CS might also be of interest for the treatment of other diseases with an inflammatory and/or autoimmune character, such as inflammatory bowel disease, degenerative diseases of the central nervous system and stroke, multiple sclerosis and other autoimmune diseases.
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PMID:Immunomodulatory and anti-inflammatory effects of chondroitin sulphate. 1952 43

Microglial cells are the prime effectors in immune and inflammatory responses of the central nervous system (CNS). During pathological conditions, the activation of these cells helps restore CNS homeostasis. However, chronic microglial activation endangers neuronal survival through the release of various proinflammatory molecules and neurotoxins. Thus, negative regulators of microglial activation have been considered as potential therapeutic candidates to target stroke and neurodegenerative diseases. Chunghyuldan, a combinatorial drug consisting of Scutellariae Radix, Coptidis Rhizoma, Phellodendri Cortex, Gardeniae Fructus, and Rhei Rhizoma, has an inhibitory effect on stroke recurrence in patients with small-vessel disease. It has also been reported to confer antihypertensive, antihyperlipidemic, and antiinflammatory effects. The aim of this study was to examine whether Chunghyuldan suppresses microglial activation. Chunghyuldan was effective at inhibiting LPS-induced nitric oxide (NO) release from rat brain microglia. Real-time reverse transcriptase PCR analysis revealed that pretreatment of rat brain microglia with Chunghyuldan attenuated the LPS-induced expression of mRNAs encoding inducible NO synthase, tumor necrosis factor (TNF)-alpha, interleukin-1beta, and cyclooxygenase-2. In rat brain microglia, Chunghyuldan reduced the LPS-stimulated production of TNF-alpha and prostaglandin E2. In addition, Chunghyuldan significantly decreased LPS-induced phosphorylation of the ERK1/2 and p38 signaling proteins. These results suggest that Chunghyuldan provide neuroprotection by reducing the release of various proinflammatory molecules from activated microglia.
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PMID:Chunghyuldan attenuates brain microglial inflammatory response. 1952 39

TNF-alpha has been reported to be relevant in stroke-induced neuronal death. However the precise function of TNF-alpha in brain ischemia remains controversial since there are data supporting either a detrimental or a protective effect. Here we show that TNF-alpha is released after oxygen-glucose deprivation (OGD) of cortical cultures and is a major contributor to the apoptotic death observed without affecting the OGD-mediated necrotic cell death. In this paradigm, apoptosis depends on TNF-alpha-induced activation of caspase-8 and -3 without affecting the activation of caspase-9. By using knock-out mice for TNF-alpha receptor 1, we show that the activation of both caspase-3 and -8 by TNF-alpha is mediated by TNF-alpha receptor 1. The pro-apoptotic role of TNF-alpha in OGD is restricted to neurons and microglia, since astrocytes do not express either TNF-alpha or TNF-alpha receptor 1. Altogether, these results show that apoptosis of cortical neurons after OGD is mediated by TNF-alpha/TNF-alpha receptor 1.
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PMID:Activation of caspase-8 by tumour necrosis factor receptor 1 is necessary for caspase-3 activation and apoptosis in oxygen-glucose deprived cultured cortical cells. 1955 59

Increased levels of cytokines have been reported after resuscitation from cardiac arrest. We hypothesized that proinflammatory cytokines, released in response to ischemia/reperfusion, increase following resuscitation and play a role in post-cardiac arrest myocardial dysfunction. Ventricular fibrillation (VF) was induced by coronary occlusion in 20 swine. After 7 min of VF, resuscitation was performed as per guidelines. Plasma levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 were measured 15 min after the start of resuscitation in all animals and at intervals of 6 h in resuscitated animals. Intravascular pressures and cardiac output (CO) were also recorded. TNF-alpha abruptly increased after resuscitation, peaking at 15 min following return of spontaneous circulation, and declined to baseline levels after 3 h. IL-1beta increased more slowly, reaching a maximum 2 h after reperfusion. IL-6 concentrations were not significantly different from control values at any time point. Males demonstrated greater elevations of TNF-alpha and IL-1beta than females. Stroke work was significantly depressed at all time points with a nadir at 15-30 min after reperfusion, corresponding to the peak TNF-alpha values. The anti-TNF-alpha antibody infliximab attenuated the decrease in myocardial function observed 30 min after reperfusion. TNF-alpha increases during recovery from cardiac arrest are associated with depression of left ventricle (LV) function. The effect of TNF-alpha can be attenuated by anti-TNF-alpha antibodies.
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PMID:Cardiac function and the proinflammatory cytokine response after recovery from cardiac arrest in swine. 1964 9

Animal models of focal ischaemia induced by middle cerebral artery occlusion (MCAO) provide most evidence for cellular inflammatory responses in stroke. Permanent MCAO results in a modest neutrophil infiltration at 24 h after ischaemia, predominantly around arterial vessels at the margins of infarction, whereas MCAO with subsequent reperfusion is associated with substantial infiltration by neutrophils throughout the entire infarct. Several studies show that C-reactive protein (CRP), an inflammatory marker, is associated with stroke outcomes and future vascular events. Several drugs, especially hydroxymethylglutaryl coenzyme A reductase inhibitors (statins), have been demonstrated to reduce hsCRP levels independently of their effects on plasma cholesterol. Various cytokines were shown to be expressed in the injured brain. Recent investigations demonstrated that mRNAs of above cytokines were induced in the ischemic rat brain. TNF-alpha is a pleiotropic cytokine that mediates key roles in many physiological and pathological cellular processes including acute and chronic inflammation, programmed cell death or apoptosis, anti-tumor responses, and infection. Pharmaceutical industry to search a small molecule TNF inhibitor have taken multiple strategies. Significant protection after in vivo oral use of SB-239063 from brain injury and neurological deficits was observed in one study. In the same study significant protection from brain injury and neurological deficits was also demonstrated due to i.v post-stroke treatment with the same compound. Leukocyte-endothelial adhesion process consists of several steps, beginning with rolling of the leukocyte on the endothelial surface until it has slowed down to such a degree that it sticks to the endothelium. Treatment with a murine anti-ICAM-1 antibody (enlimomab) has been investigated in patients with acute ischemic stroke in the Enlimomab Acute Stroke Trial (EAST). Unfortunately, the case fatality rate in this trial was significantly higher in the enlimomab patient group than in the placebo group. Furthermore, experimental data have shown that focal cerebral ischemia induces a time-dependent activation of granulocytes, lymphocytes, and macrophages. Dissipation of ATP by CD39 reduced P2X7 receptor stimulation and thereby suppressed baseline leukocyte alphaMbeta2-integrin expression. As alphaMbeta2-integrin blockade reversed the postischemic, inflammatory phenotype of Cd39-/- mice, these data suggest that phosphohydrolytic activity on the leukocyte surface suppresses cell-cell interactions that would otherwise promote thrombosis or inflammation.
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PMID:Inflammation as a therapeutic target in acute ischemic stroke treatment. 1984 65

Cerebral ischaemia is a common occurrence in a range of pathological conditions, including stroke and traumatic brain injury. Two of the components in ischaemia are tissue hypoxia and the release of pro-inflammatory agents such as TNF-alpha. The role of TNF-alpha in an ischaemic/hypoxic episode is still controversial, although deleterious effects of pro-inflammatory cytokines in the area of injury are well documented. One of the prime adaptive mechanisms in response to hypoxia is the cellular activation of adenosine 1 receptors (A1Rs), which inhibits excitatory synaptic transmission. In the present study we have examined the effect of TNF-alpha application on synaptic transmission during hypoxic exposure and re-oxygenation using extracellular recordings in the CA1 region of the rat hippocampal slice. Hypoxia caused a reversible depression of the field EPSP (29.6+/-9.7% of control, n=5), which was adenosine A(1) receptor-dependent (85.7+/-4.3%, in the presence of DPCPX (200 nM), the adenosine A(1) receptor antagonist). DPCPX inhibited the maintenance of long-term potentiation obtained 30 min post hypoxia (143.8+/-8.2% versus 96.4+/-10.6% respectively, 1h post tetanus; n=5; p<0.005). In TNF-alpha (150 pM) treated slices hypoxic depression was similar to controls but a reduction in fEPSP slope was observed during re-oxygenation (66.8+/-1.4%, n=5). This effect was reversed by pre-treatment with SB 203580 (1 microM), a p38 MAP kinase inhibitor (91.8+/-6.9%, n=5). These results demonstrate a novel p38 MAPK dependent role for TNF-alpha in attenuating synaptic transmission after a hypoxic episode.
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PMID:Tumor necrosis factor-alpha impairs the recovery of synaptic transmission from hypoxia in rat hippocampal slices. 1994

Stroke is a major cause of disability and leading cause of death in the northern hemisphere. Only recently it became evident that cerebral ischemia not only leads to brain tissue damage and subsequent local inflammation but also to a dramatic loss of peripheral blood T-cells with subsequent infections. However, only scarce information is available on the activation status of surviving T cells. This study therefore addressed the functional consequences of immunological changes induced by stroke in humans. For this purpose peripheral blood T-cells were isolated from 93 stroke patients and the expression of activation makers was determined. In addition ex vivo stimulation assays were applied to asses the functionality of T cells derived from blood of stroke patients. Compared to healthy controls, stroke patients demonstrated an enhanced surface expression of HLA-DR (p<0.0001) and CD25 (p = 0.02) on T cells, revealing that stroke leads to T cell activation, while CTLA-4 remained undetectable. In vitro studies revealed that catecholamines inhibit CTLA-4 upregulation in activated T cells. Ex vivo, T cells of stroke patients proliferated unimpaired and released increased amounts of the proinflammatory cytokine TNF-alpha (p<0.01) and IL-6 (p<0.05). Also, in sera of stroke patients HMGB1 concentrations were increased (p = 0.0002). The data demonstrate that surviving T cells in stroke patients remain fully functional and are primed towards a TH1 response, in addition we provide evidence that catecholamine mediated inhibition of CTLA-4 expression and serum HMGB1 release are possible mediators in stroke induced activation of T cells.
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PMID:Functional status of peripheral blood T-cells in ischemic stroke patients. 2009 Sep 32

Psoriasis is a chronic inflammatory, immune-mediated skin disease, which may cause significant deterioration in the quality of life. Recent evidence indicates that psoriasis and psoriatic arthritis are frequently associated with cardiometabolic diseases including myocardial infarction, stroke, diabetes, obesity, dyslipidemia and non-alcoholic fatty liver disease. Although the causal relationship between cardiometabolic comorbidities and psoriasis has not yet been completely proven, it appears that obesity is a relevant risk factor for the development of psoriasis and metabolic syndrome. In addition, moderate to severe psoriasis itself is a risk factor for cardiovascular disease and the metabolic syndrome. Some common genetic traits as well as inflammatory mechanisms may underlie the development of psoriasis and cardiometabolic comorbidities. The presence of comorbidities has important implications in the global approach to patients with psoriasis. Traditional systemic anti-psoriatic agents could negatively affect cardiometabolic comorbidities, and may have important interactions with drugs commonly used by psoriasis patients. In contrast, the recent findings that the risk of myocardial infarction is markedly reduced in rheumatoid arthritis patients who respond to anti-TNF-alpha therapy compared with non-responders supports the hypothesis that the anti-inflammatory effect of TNF-alpha blockers might potentially reduce the cardiovascular risk also in psoriasis patients. Finally, patients with moderate to severe psoriasis should be treated promptly and effectively, should also be encouraged to drastically correct their modifiable cardiovascular risk factors, in particular obesity and smoking habit.
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PMID:Cardiometabolic comorbidities and the approach to patients with psoriasis. 2009 57

Inflammation, which is known to be detrimental to the neurological outcome during the acute phase after ischemia, provides a potential preventative or therapeutic approach for acute stroke. Lipoxins are endogenous lipoxygenase derived eicosanoids and evokes protective actions in a range of pathophysiologic processes. Here, we evaluated the efficacy of 5 (S), 6 (R)-lipoxin A(4) methyl ester (LXA(4) ME), a stable synthetic analogue of lipoxin A(4) in cerebral ischemia reperfusion injury in rats. Transient focal cerebral ischemia was induced by middle cerebral artery occlusion for 2h. Intracerebroventricular administration of LXA(4) ME immediately after onset of ischemia ameliorated neurological dysfunctions, reduced infarction volume and attenuated neuronal apoptosis. Moreover, Treatment with LXA(4) ME suppressed neutrophils infiltration and lipid peroxidation levels; inhibited the activation of microglia and astrocytes; reduced the expression of pro-inflammatory cytokines TNF-alpha and IL-1beta; and up-regulated the expression of anti-inflammatory cytokines IL-10 and TGF-beta1 in the ischemic brain. In addition, activation of NF-kappaBeta was inhibited by LXA(4) ME treatment. These results demonstrate that treatment of LXA(4) ME affords strong neuroprotective effect against cerebral ischemia reperfusion injury, and that these effects might be associated with its anti-inflammatory property.
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PMID:Lipoxin A4 analogue protects brain and reduces inflammation in a rat model of focal cerebral ischemia reperfusion. 2013 64


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