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

Cytokines have been recognized to play an important role both in normal development of the brain, when they act as neurotrophic factors, as well as following injury. While both the cytokines and their receptors are synthesized and expressed in the brain normally (albeit at low levels), it has become clear that elevated levels are associated with many neurological disorders. In this review, we have chosen to present the data for only a few of the cytokines, including interleukin-1beta, interleukin-3, interleukin-6, interferon-gamma, transforming growth factor-beta, and tumor necrosis factor-alpha. Data are presented that suggest roles they may play in human disorders, including stroke, multiple sclerosis, Alzheimer's disease, and several psychiatric disorders. The results in human disease are compared with results obtained in a variety of transgenic animal models. The mouse models have very different disorders depending on whether a cytokine is overexpressed either peripherally or in either astrocytes or neurons. The potential significance of this to the understanding of human disease is discussed.
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PMID:Involvement of cytokines in normal CNS development and neurological diseases: recent progress and perspectives. 955 25

Nitric oxide produced by inducible nitric-oxide synthase (iNOS) in different cells including brain cells in response to proinflammatory cytokines plays an important role in the pathophysiology of stroke and other neurodegenerative diseases. The present study underlines the importance of protein phosphatase (PP) 1 and 2A in the regulation of the differential expression of iNOS in rat primary astrocytes and macrophages. Compounds (calyculin A, microcystin, okadaic acid, and cantharidin) that inhibit PP 1 and 2A were found to stimulate the lipopolysaccharide (LPS)- and cytokine-mediated expression of iNOS and production of NO in rat primary astrocytes and C6 glial cells. However, these inhibitors inhibited the LPS- and cytokine-mediated expression of iNOS and production of NO in rat resident macrophages and RAW 264.7 cells. Similarly, okadaic acid, an inhibitor of PP 1/2A, stimulated the iNOS promoter-derived chloramphenicol acetyltransferase activity in astrocytes and inhibited the iNOS promoter-derived chloramphenicol acetyltransferase activity in macrophages, indicating that okadaic acid also differentially regulates the transcription of the iNOS gene in astrocytes and macrophages. The observed stimulation of the expression of iNOS in astrocytes and the inhibition of the expression of iNOS in macrophages with the inhibition of PP 1/2A activity clearly delineate a novel role of PP 1/2A in the differential regulation of iNOS in rat astrocytes and macrophages. Because the activation of NF-kappaB is necessary for the induction of iNOS and the expression of tumor necrosis factor (TNF)-alpha also depends on the activation of NF-kappaB, we examined the effect of okadaic acid on the LPS-mediated activation of NF-kappaB and production of TNF-alpha in rat primary astrocytes and macrophages. Interestingly, in both cell types, okadaic acid stimulated the LPS-mediated DNA binding as well as transcriptional activity of NF-kappaB and production of TNF-alpha. This study suggests that the stimulation of iNOS expression in astrocytes by inhibitors of PP 1/2A is possibly due to the stimulation of NF-kappaB activation; however, activation of NF-kappaB is not sufficient for the induction of iNOS in macrophages and that apart from NF-kappaB some other signaling pathway(s) sensitive to PP 1 and/or PP 2A is/are possibly involved in the regulation of iNOS in macrophages. This differential induction of iNOS as compared with similar activation of NF-kappaB by inhibitors of PP 1/2A indicates the involvement of different intracellular signaling events for the induction of iNOS in two cell types of the same animal species.
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PMID:Inhibitors of protein phosphatase 1 and 2A differentially regulate the expression of inducible nitric-oxide synthase in rat astrocytes and macrophages. 957 70

We investigated the effects of N(omega)-monomethyl-L-arginine (L-NMMA) and fluid loading on tumor necrosis factor (TNF)-induced cardiovascular dysfunction in awake dogs. L-NMMA (40 mg x kg(-1) given intravenously over a period of 10 min, and followed by dosing at 40 mg x kg(-1) x h(-1) for 6 h) and TNF (20 or 45 microg x kg(-1) given intravenously for 20 min), given alone or in combination, significantly decreased stroke volume, cardiac index, oxygen delivery, and left-ventricular (LV) function plots over a period of 6 h. Of note was that the cardiac-depressant effects of TNF and L-NMMA given together were significantly less than additive. Thus, the combination was beneficial (or significantly less harmful to cardiac performance than expected), possibly because L-NMMA augmented cardiac preload as shown by significant increases in both pulmonary capillary wedge pressure (PCWP) and central venous pressure (CVP). Fluid challenges at 6 h (Ringer's solution at 80 ml x kg(-1) given over a period of 30 min) also significantly increased PCWP and CVP, and abolished the beneficial preload effect of L-NMMA on cardiac performance. Thus, after fluid loading, the cardiac-depressant effects of TNF and L-NMMA given together became equal to the sum of those produced by TNF and L-NMMA given separately. Although L-NMMA significantly decreased serum nitrite/nitrate levels, TNF did not increase these end products of nitric oxide (NO) production relative to controls. Therefore, after preload abnormalities were eliminated with fluid loading, L-NMMA had no beneficial effect on TNF-induced cardiac depression, and TNF did not increase end products of NO production. These findings are not consistent with NO being the mechanism of TNF-induced acute cardiac depression.
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PMID:Effects of L-NMMA and fluid loading on TNF-induced cardiovascular dysfunction in dogs. 960 14

It is clear that inflammatory processes contribute to neurodegenerative disease, stroke, closed head injury, encephalitis, and other CNS disorders. These inflammatory processes are marked by local increases in cytokines, in particular tumor necrosis factor-alpha (TNF-alpha). It is important to control such CNS inflammation in order to preserve neural function. The neuroimmunomodulatory peptide alpha-melanocyte-stimulating hormone (alpha-MSH) has been shown to modulate peripheral inflammation by acting on melanocortin receptors in host cells (macrophages, neutrophils) to inhibit production of such proinflammatory agents. Our results indicate that alpha-MSH likewise acts directly within the brain to modulate local inflammation. To determine if microglia are involved in anti-inflammatory responses to alpha-MSH within the brain, murine cells were tested; they produced TNF-alpha and nitric oxide in response to challenge, and production of both was reduced by alpha-MSH. In tests on human astrocytes, both alpha-MSH (1-13) and alpha-MSH (11-13) reduced TNF-alpha. Ischemia/reperfusion in the posterior circulation in dogs causes inflammatory reactions and disturbance of function, estimated from decreases in auditory-evoked potentials. These deficits were reduced by administering alpha-MSH systemically during reperfusion, moreso when the peptide was given during both ischemia and reperfusion. The results indicate that, much as for inflammation in the periphery, alpha-MSH modulates brain inflammatory responses mediated by proinflammatory agents.
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PMID:Peptide modulation of inflammatory processes within the brain. 973 Jun 84

We describe the case of a seriously burned infant who suffered from a deep burn covering approximately 30% of his total body surface area. Because invasive hemodynamic monitoring is usually not suggested in infants, hemodynamic profile can be misunderstood. We tested a new echo-Doppler device to determine hemodynamic variation using a small esophageal probe specifically designed for newborns and infants. The aortic flowmeter was connected with satellite devices to obtain the hemodynamic profile, including aortic blood flow (ABF), preejection period, left ventricular ejection time, mean arterial pressure, heart rate, calculated stroke volume, calculated total systemic vascular resistance (TSVR), and end-tidal CO2 pressure. The positioning of the probe was easily obtained at each time. The hemodynamic management initially exhibited a hypovolemic status followed by a hyperdynamic profile, as suggested by a gradually increased ABF, which seemed similar to the variations currently reported in adult burn patients. Concurrent with hemodynamic determinations, plasma samples were drawn to measure interleukin-6 (IL-6), interleukin-1beta(IL-1beta), and tumor necrosis factor-alpha(TNF-alpha)levels. A consistent peak of IL-6 occurred simultaneously with the drop in TSVR. In contrast, no marked modifications were observed with IL-1beta and TNF-alpha. The same circulating cytokines moved alike in burned adults; IL-6 could partly explain the mechanisms of hemodynamic variation through the systemic inflammatory response syndrome. On the other hand, the echo-Doppler device could provide valuable noninvasive findings, allowing early improvement in resuscitation during the acute phase of critically burned infants and children.
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PMID:Early hemodynamic variations assessed by an echo-Doppler aortic blood flow device in a severely burned infant: correlation with the circulating cytokines. 973 54

A growing body of evidence, primarily from animal models of cerebral ischemia and preliminary human studies, indicates that inflammatory mechanisms contribute to secondary neuronal injury after acute cerebral ischemia. Ischemia followed by reperfusion rapidly leads to the expression of inflammatory cytokines, particularly tumor necrosis factor-alpha and interleukin-1beta, which stimulate a complex cascade of events involving local endothelial cells, neurons, astrocytes, and perivascular cells. A secondary response includes the release of other cytokines, an increase in components of the coagulation system, an upregulation of cell adhesion molecule expression, and changes in the expression of components of the immune response. The net effect of these events is transformation of the local endothelium to a prothrombotic/proinflammatory state and induction of leukocyte migration to the site of injury. A number of studies have shown that leukocyte migration occurs within hours of reperfusion. Leukocytes accumulate in the injured region, where they cause tissue injury by several mechanisms, including occlusion of microvasculature, generation of oxygen free radicals, release of cytotoxic enzymes, alteration of vasomotor reactivity, and increase in cytokine and chemoattractant release. Monoclonal antibodies against leukocyte adhesion molecules have been shown to reduce infarct volume in animal models of ischemia-reperfusion. However, this treatment failed to show benefit in the Enlimomab Acute Stroke Trial. A number of factors may complicate the use of antibody directed adhesion molecule blockade in acute stroke and will be discussed in this article. Overall, an increased understanding of inflammatory and immunologic mechanisms still offers great potential for reducing acute stroke injury.
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PMID:The role of inflammation after acute stroke: utility of pursuing anti-adhesion molecule therapy. 974 39

Focal cerebral ischemia elicits a strong inflammatory response involving early recruitment of granulocytes and delayed infiltration of ischemic areas and the boundary zones by T cells and macrophages. Infiltration of hematogenous leukocytes is facilitated by an upregulation of the cellular adhesion molecules P-selectin, intercellular adhesion molecule-1 and vascular adhesion molecule-1 on endothelial cells. Blocking of the leukocyte/endothelial cell adhesion process significantly reduces stroke volume after transient, but not permanent middle cerebral artery occlusion. In the infarct region microglia are activated within hours and within days transform into phagocytes. Astrocytes upregulate intermediate filaments, synthesize neurotrophins and form glial scars. Local microglia and infiltrating macrophages demarcate infarcts and rapidly remove debris. Remote from the lesion no cellular infiltration occurs, but astroglia and microglia are transiently activated. Astrocytic activation is induced by spreading depression. In focal ischemia neurons die acutely by necrosis and in a delayed fashion by programmed cell death, apoptosis. Proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1 beta are upregulated within hours in ischemic brain lesions. Either directly or via induction of neurotoxic mediators such as nitric oxide, cytokines may contribute to infarct progression in the post-ischemic period. On the other hand, inflammation is tightly linked with rapid removal of debris and repair processes. At present it is unclear whether detrimental effects of inflammation outweigh neuroprotective mechanisms or vice versa. In global ischemia inflammatory responses are limited, but micro- and astroglia are also strongly activated. Glial responses significantly differ between brain regions with selective neuronal death and neighbouring areas that are more resistent to ischemic damage.
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PMID:Inflammation and glial responses in ischemic brain lesions. 976 Jun 99

Sphingolipids and their metabolic products are now known to have second-messenger functions in a variety of cellular signaling pathways. Lactosylceramide (LacCer), a glycosphingolipid (GSL) present in vascular cells such as endothelial cells, smooth muscle cells, macrophages, neutrophils, platelets, and monocytes, contributes to atherosclerosis. Large amounts of LacCer accumulate in fatty streaks, intimal plaque, and calcified intimal plaque, along with oxidized low density lipoproteins (Ox-LDLs), growth factors, and proinflammatory cytokines. A possible role for LacCer in vascular cell biology was suggested when this GSL was found to stimulate the proliferation in vitro of aortic smooth muscle cells (ASMCs). A further link of LacCer in atherosclerosis was uncovered by the finding that Ox-LDLs stimulated specifically the biosynthesis of LacCer. Ox-LDL-stimulated endogenous synthesis of LacCer by activation of UDP-Gal:GlcCer,beta1-4galtransferase (GalT-2) is an early step in this signaling pathway. In turn, LacCer serves as a lipid second messenger that orchestrates a signal transduction pathway, ultimately leading to cell proliferation. This signaling pathway includes LacCer-mediated activation of NADPH oxidase that produces superoxide. Such superoxide molecules stimulate the GTP loading of p21(ras). Subsequently, the kinase cascade (Raf-1, Mek2, and p44MAPK [mitogen-activated protein kinase]) is activated. The phosphorylated form of p44MAPK translocates from the cytoplasm to the nucleus and engages in c-fos expression, proliferating cell nuclear antigen (PCNA) such as cyclin activation, and cell proliferation takes place. Interestingly, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), an inhibitor of GalT-2, can abrogate the Ox-LDL-mediated activation of GalT-2, the signal kinase cascade noted above, as well as cell proliferation. Additional studies have revealed that LacCer mediates the tumor necrosis factor-alpha (TNF-alpha)-induced nuclear factor-kappaB expression and intercellular adhesion molecule (ICAM-1) expression in vascular endothelial cells via the redox-dependent transcriptional pathway. LacCer also stimulates the expression of CD11/CD8, or Mac-1, on the surface of human neutrophils. Collectively, this phenomenon may contribute to the adhesion of neutrophils or monocytes to the endothelial cell surface and thus initiate the process of atherosclerosis. In addition, the LacCer-mediated proliferation of ASMCs may contribute to the progression of atherosclerosis. On the other hand, programmed cell death (apoptosis) by proinflammatory cytokines such as TNF-alpha, interleukin-1, and high concentrations of Ox-LDL occur via activation of a cell membrane-associated neutral sphingomyelinase (N-SMase). N-SMase hydrolyzes sphingomyelin into ceramide and phosphocholine. In turn, ceramide or a homologue serves as an important stress-signaling molecule. Interestingly, an antibody against N-SMase can abrogate Ox-LDL- and TNF-alpha-induced apoptosis and therefore may be useful for in vivo studies of apoptosis in experimental animals. Because plaque stability is an integral aspect of atherosclerosis management, activation of N-SMase and subsequent apoptosis may be vital events in the onset of plaque rupture, stroke, or heart failure. Interestingly, in human liver cells, N-SMase action mediates the TNF-alpha-induced maturation of the sterol regulatory-element binding protein. Moreover, a cell-permeable ceramide can reconstitute the phenomenon above in a sterol-independent fashion. Such findings may provide new avenues for therapy for patients with atherosclerosis. The findings described here indicate an important role for sphingolipids in vascular biology and provide an exciting opportunity for further research in vascular disease and atherosclerosis.
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PMID:Sphingolipids in atherosclerosis and vascular biology. 976 22

Cocaine abuse has been associated with vasculitis and stroke, and is suspected to influence the progression of AIDS dementia. Cocaine may enhance HIV-1 neuroinvasion by actions directed at the blood-brain barrier. HIV-1 appears to penetrate the human brain microvascular endothelial cell barrier by a paracellular route breached by tumor necrosis factor-alpha (TNF-alpha). Cocaine's effects on the blood-brain barrier were investigated using human brain microvascular endothelial cells and peripheral blood monocytes. Cocaine (10(-5) M and 10(-6) M) increased molecular permeability of the barrier and viral invasion by the macrophage-tropic HIV-1(JR-FL) into the brain chamber. Cocaine also augmented apoptosis of brain endothelial cells and monocytes, increased secretion of four chemokines (interleukin-8, interferon-inducible protein-10, macrophage inflammatory protein-1alpha, and monocyte chemoattractant protein-1) and the cytokine, TNF-alpha, by human monocytes. TNF-alpha enhanced invasion of the brain compartment by macrophage-tropic, lymphotropic, and bitropic HIV-1 strains. These data indicate that HIV-1 neuroinvasion can be increased by (a) cocaine's direct effects on brain microvascular endothelial cells and (b) paracrine effects of cocaine-induced pro-inflammatory cytokines and chemokines on the blood-brain barrier.
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PMID:Cocaine opens the blood-brain barrier to HIV-1 invasion. 1006 3

Semax is the first domestic nootropic drug of an unexhausted type from the group of neuropeptides. In experimental studies it showed angioprotective, antihypoxic and neurotrophic activity in the doses 100-150 micrograms/kg. A combined clinical-electrophysiologic study revealed its high efficiency in acute ischemic stroke. A clinical trial was performed of immunobiochemical mechanisms of neuroprotective properties of Semax in acute period of ischemic stroke. A retrospective comparative clinicoimmunobiochemical analysis provided objective data on the molecular level on activating influence of Semax on antiinflammatory postischemic reactions in the brain. Shifting neuromediatory balance toward a prevalence of the antiinflammatory agents (interleukin-10, tumor necrosis factor-alpha) over the factors maintaining the inflammation (interleukin-8, C-reactive protein).
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PMID:[Investigation of mechanisms of neuro-protective effect of semax in acute period of ischemic stroke]. 1035 12


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