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

As illustrated in Figure 1, a disturbance of the intracellular Ca2+ homeostasis is thought to be a common pathogenic factor for the generation of secondary nerve cell damage that develops after brain trauma or stroke or during the course of neurodegenerative diseases. A neuronal Ca2+ overload which may result from an excessive glutamate-evoked membrane depolarization and consecutive Ca2+ influx as well as from an activation of metabotropic receptors and consecutive intracellular Ca2+ mobilization is known to have direct toxic effects on the cytoskeleton and the cell metabolism of neurons. In addition, a Ca(2+)-dependent activation of glial cells along with the loss of physiologically required mature astrocyte functions and with the acquisition of potentially neurotoxic microglial properties, has more recently been recognized as an additive pathogenic factor. This may provide an effective target for pharmacological interference. Specifically, the reinforcement of an endogenous homeostatic regulator, which obtained its sophisticated know-how during evolution, may provide a neuroprotective therapy which can handle the complexity of the pathological process with a minor risk of pharmacological side effects. Adenosine is such an ancient molecular signal that acts on both neurons and glial cells. In neurons, adenosine activates K+ and Cl- conductances, which limits synaptically evoked depolarization, thus counteracting the Ca2+ influx through voltage-dependent and NMDA receptor-operated ion channels. This A1 receptor-mediated effect seems to be the major action by which adenosine adds directly to the protection of neurons against Ca(2+)-dependent damage. In glial cells, the prevalent effect of adenosine is its regulatory influence on the Ca2+ and cAMP-dependent molecular signaling that determines the cellular proliferation rate, the differentiation state and related functions. When mimicking the activation of metabotropic glutamate receptors in cultures of immature rat astrocytes, which largely resemble pathologically activated astrocytes, a transient Ca2+ mobilization was initiated by adenosine. This A1 receptor-mediated Ca2+ signal caused a prolonged potentiation of the A2 receptor-mediated intracellular cAMP rise. An experimentally sustained enhancement of the cAMP signaling initiated the differentiation of cultured astrocytes and the new expression of K+ and Cl- channels which are required for the physiological astrocyte function to maintain the extracellular ion homeostasis. Evidence is accumulating that a strengthening of the cAMP signaling, which can be achieved by adenosine agonists and also by the pharmacon propentofylline (an adenosine uptake blocker and phosphodiesterase inhibitor), stimulates the mRNA production of neurotrophic factors in astrocytes. In cultured microglial cells, several days' treatment with adenosine agonists or propentofylline markedly inhibited their proliferation rate, the in vitro spontaneously occurring transformation into macrophages and their particularly high formation of free oxygen radicals. Adenosine agonists also depressed the release of the potentially toxic cytokine TNF alpha and induced programmed cell death in immunologically activated microglial cells. We conclude that a pharmacological reinforcement of the endogenous cell modulator adenosine may provide neuroprotection by counteracting neuronal Ca2+ overload, by depressing potentially neurotoxic microglial functions and by regaining physiologically required properties of differentiated astrocytes. Further information about the influence of adenosine on the molecular signaling and on ischemic brain damage is given in Refs. 37 and 38, and about the implicated possible relevance for the treatment of stroke in Ref. 39.
 ...
PMID:Protective mechanisms of adenosine in neurons and glial cells. 936 70

Proinflammatory cytokines play an eminent role in pathophysiology of infection and inflammation. Their actual clinical importance is, however, uncertain. In this study, we tested the hypothesis that inflammatory cytokines could be useful in detection of infections in high-risk patients. We prospectively studied the diagnostic value of determination of concentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and the 55- and 75-kd soluble TNF receptors (sTNFR-p55 and sTNFR-p75) in detection of nosocomial infections in 52 patients with acute ischemic stroke, as an exemplary high-risk group, and compared these findings to those of conventional inflammatory indicators of inflammation (C-reactive protein and leukocyte count). After 1 week of hospitalization, 27% of the patients had minor or moderately severe nosocomial infections. This subpopulation exhibited significantly increased concentrations of IL-6 and sTNFR-p55 but not of IL-1beta, TNF-alpha, or sTNFR-p75. As expected, levels of C-reactive protein and leukocytes were increased in infected patients. The sensitivity and specificity for detection of nosocomial infections at day 7 of hospitalization was highest for IL-6, followed by C-reactive protein and the leukocyte count. The data suggest that the proinflammatory cytokine IL-6, in addition to its considerable pathophysiologic importance in systemic inflammation, may be valuable in detection of infections in high-risk patients.
 ...
PMID:Proinflammatory cytokines: indicators of infection in high-risk patients. 939 Jun 42

Secondary ischemic brain injury has been shown to develop as a consequence of inflammation and vasogenic brain edema. In this study we show that inflammatory cytokines and simulated in vitro ischemia stimulate the surface expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and endothelial-leukocyte adhesion molecule-1 (E-selectin) in human cerebromicrovascular endothelial cells (HCEC) in culture. The levels of all three adhesion molecules were dramatically (3 to 10-fold) up-regulated by 4-24 hour exposure to the inflammatory cytokines. IL-1 beta (10-200 u/ml) or TNF alpha (50 200 u/ml), and by a 4 hour exposure to "simulated" in vitro ischemia, as determined by immunocytochemistry and ELISA. Following 24 hours of subsequent reperfusion, the expression of ICAM-1 and VCAM-1 was maintained at ischemia-induced levels, whereas E-selectin was no longer detectable. Both the cytokine- and ischemia-induced up-regulation of adhesion molecules were completely abolished by the transcriptional inhibitor, actinomycin D (10 micrograms/ml), and inhibited by the cycloxygenase (COX) inhibitor, indomethacin (300 microM). These findings implicate HCEC in the processes of leukocyte adhesion and recruitment in the brain during stroke in vivo.
 ...
PMID:Increase in surface expression of ICAM-1, VCAM-1 and E-selectin in human cerebromicrovascular endothelial cells subjected to ischemia-like insults. 941 64

The role of tumor necrosis factor-alpha (TNF alpha) in brain injury is controversial. We studied the effect of anti-TNF-alpha antibody in a rat model of reversible middle cerebral artery occlusion. During focal ischemia and early reperfusion, TNF-alpha was rapidly and transiently released into circulation. Pretreatment with intravenous anti-TNF-alpha antibody reduced cortical (71%, P < 0.015) and subcortical (58%, P < 0.007) injury, enhanced the cerebral blood flow during reperfusion, and improved the neurologic outcome. This further supports the contention that TNF-alpha is a deleterious cytokine in stroke, whereas circulating antibody against TNF-alpha may protect brain from reperfusion injury.
 ...
PMID:Circulating antibody against tumor necrosis factor-alpha protects rat brain from reperfusion injury. 942 5

Myocardial dysfunction due to sepsis is common in patients with multiple organ dysfunction syndrome and is believed to be produced by inflammatory mediators. Some of these mediators may be eliminated by continuous hemofiltration, which is a standard procedure in an ICU for renal replacement therapy. This study was designed to directly compare the effects of ultrafiltrates from patients with sepsis (UFs) with ultrafiltrates from healthy volunteers (UFh) in well-characterized cardiomyocyte culture systems. Isovolemic hemofiltration (filtration rate: 2 L/h, polyamide membrane) was performed during 12 hours in 5 patients with severe sepsis (Elebute Score >20) and simultaneously reduced left ventricular contractility (left ventricular stroke work index [LVSWI] <30 g m/m2) and in 5 healthy volunteers. Inflammatory mediator concentrations (interleukin [IL]-1beta, IL-6, IL-8, tumor necrosis factor [TNF] alpha, C3a, and C5a) were measured in plasma and ultrafiltrate samples taken shortly after the beginning of the hemofiltration procedure. Cell culture experiments were done comparing UFs with UFh by using spontaneously beating or electrically driven neonatal rat cardiomyocyte cultures. UFs contained significantly higher amounts of IL-1, IL-8, and C3a when compared to UFh. Simultaneously, UFs induced a decrease in the contraction frequency of electrically-stimulated cardiomyocytes, whereas UFh had no effect. The cardiotoxic effect could be reversed by the addition of a high concentration (2.4 mM) of Ca++. Hemofiltration did not alter parameters of cardiac performance during 12 hours in patients with sepsis. UFs induced significant cardiotoxic effects in rat cardiomyocytes, whereas UFh showed no cardiotoxicity. Contact of blood with the hemofiltration membrane did not induce activation of cardiotoxic mediators. Significantly higher filtration rates may be required to improve left ventricular contractility in patients with sepsis by hemofiltration.
 ...
PMID:Hemofiltrate from patients with severe sepsis and depressed left ventricular contractility contains cardiotoxic compounds. 1048 94

Two relatively well characterised kinase signalling pathways are those involving MAPK/ERK and p38/SAPK2, that are known to be activated in vitro by various factors known to increase following stroke, such as glutamate, IL-1 and TNF. The present study was designed to investigate the activation and cellular distribution of phosphorylated-ERK1/2, -p38 and the transcription factor CREB following focal cerebral ischaemia using phosphospecific antibodies. Up to 24 h following transient MCAO (90 min) and 6 h following permanent MCAO, phospho-ERK1/2 staining was markedly increased within the cytoplasm of neuronal perikarya in 'penumbral-like' regions. In contrast, phospho-p38 immunostaining was markedly increased in cells with astrocyte-like morphology in both 'core' and 'penumbral-like' regions. Phospho-p38 staining was also detected in some neurones within 'penumbral-like' regions up to 24 h following transient MCAO. CREB activation was confined to neurones in 'penumbral-like' regions. Increased phospho-p38 immunoreactivity was detected in astrocyte-like cells present in the subcortical white matter ipsilateral to the occluded MCAO, while phospho-CREB and -ERK1/2 staining was localised to cells with the morphological appearance of oligodendrocytes. This study demonstrates phosphorylation, indicative of activation, of both the MAPK and p38 pathways following transient and permanent MCAO. However, each pathway shows a distinct cellular and spatial distribution within ischaemic tissue. Together these data indicate that neuroprotection offered by agents directed towards the ERK1/2 pathway may act directly through protection of neurones and oligodendrocytes, while those directed towards the p38 pathway kinase signalling pathways may be indirectly via inhibition of cytokines and other mediators involved in the brains response to injury.
 ...
PMID:Differential activation of MAPK/ERK and p38/SAPK in neurones and glia following focal cerebral ischaemia in the rat. 1081 33

1. The effects of propentofylline (PPF, 25 mg kg(-1) body weight per day) on rat cerebral energy state and cytokine expression as well as on behaviour and histopathology were studied after acute and long-term permanent bilateral common carotid artery occlusion (BCCAO). 2. In the absence of PPF, acute ischaemia led to a decrease in energy-rich phosphates in parietotemporal cortex and hippocampus which correlated with an increase in AMP and adenosine concentrations measured by high-performance liquid chromatography technique. The concentrations of cortical cytokines TNF alpha and IL1 beta were increased 12 and 19 fold, respectively. 3. PPF had a neuroprotective action after 20 min of BCCAO, reducing the deleterious effect of acute ischaemia on rat brain energy state and microglial reaction. Simultaneously, PPF treatment increased cyclic-AMP 3 fold. 4. Three weeks of permanent BCCAO did not significantly disturb brain energy metabolism, microglial reaction or histopathology. However, a significant reduction of 30 -- 50% in rat memory capacities and a locomotor hyperactivity were obtained. 5. Continuous PPF-application, however, led to a marked increase in rat working memory and to reduced locomotor activity, which were returned nearly to control levels by 1 week after permanent BCCAO. In summary, PPF showed a clear neuroprotective effect on cerebral energy state and pro-inflammatory cytokines under conditions of acute global ischaemia. Continuous administration of PPF led to memory improvement during permanent BCCAO. 6. These results underscore the benefit of treatment with PPF in clinical practice, particularly during stroke, but also in cerebrovascular and neurodegenerative disorders.
 ...
PMID:Neuromodulatory effect of propentofylline on rat brain under acute and long-term hypoperfusion. 1132

Stroke is the third most common cause of death in the Western world. The mechanisms of brain damage in the affected areas are largely unknown. Hence, rational treatment strategies are limited. Previous experimental evidence suggested that cerebral lesions were less prominent in CD95 (APO-1/Fas)-deficient (lpr) than in wild-type mice. Additional results strongly suggested that the CD95-ligand (CD95L) was a major cause of neuronal autocrine suicide in the penumbra. These data and the assumption that death-receptor systems might determine stroke-related damage in the brain prompted us to examine these systems in in vitro and in vivo models of ischemia. We showed that hybrids of TNF-deficient and gld mice were strongly resistant towards stroke-induced damage. To determine the mechanism of action of TNF and CD95L, we separately investigated their influence on primary ischemic death and secondary inflammatory injury. Inhibition of both TNF and CD95L in vitro prevented death of primary neurons induced by oxygen-glucose deprivation and reperfusion. The recruitment of inflammatory cells to the ischemic hemisphere was abrogated in the absence of both TNF and CD95L. Significantly, mice injected with a mixture of neutralizing anti-TNF and anti-CD95L antibodies 30 min after induction of stroke showed a marked decrease in both infarct volumes and mortality. Accordingly, the locomotor performance of these animals was not significantly impaired in comparison to sham-operated animals. These data reveal that inhibition of TNF and CD95L blocks stroke-related damage at two levels, the primary ischemic and the secondary inflammatory injury. These results offer new approaches in stroke treatment.
 ...
PMID:Therapeutic neutralization of CD95-ligand and TNF attenuates brain damage in stroke. 1146 9

Interleukin-1 (IL-1) is a key mediator in the cytokine network, controlling important functions in the immune system, during development, infection, inflammation, cell-differentiation, tissue remodelling, and even cell death. The agonistic isoforms of IL-1 (i.e., IL-1alpha and IL-1beta), the IL-1 receptor antagonists, the receptors and receptor-associated proteins, as well as the recently identified IL-18 and its receptor belong to the IL-1 family of proteins. Activation of the IL-1beta and IL-18 precursors is performed enzymatically by caspase-1, previously termed IL-1beta-converting enzyme (ICE). This molecule is the founding member of the caspase family of enzymes, which are involved in maturation of cytokines and in initiation and execution of apoptotic processes. It has been suggested that cytokines and apoptosis are involved in pathogenesis of cardiovascular diseases such as atherosclerosis, chronic heart failure, myocarditis, cardiomyopathy, or stroke. Since IL-1, like TNF, is a central mediator in the cytokine network, it may act as a potent activator of cardiovascular cells. We know that cells of the vessel wall and the heart can produce IL-1 and respond to this mediator by production of other cytokines or regulation of other cardiovascular cell functions. Thus, this report summarizes general information about the molecules of the IL-1 family of proteins, including the caspases, as well as data regarding these proteins in relation to the vessel wall and the heart and their role in cardiovascular disease in adults and children. The summarized information indicates a role of these molecules in regulation of local inflammatory responses during cardiovascular disease.
 ...
PMID:Interleukin-1 and related proteins in cardiovascular disease in adults and children. 1177 30

Fas, (APO-1/CD95), a transmembrane glycoprotein belonging to the tumor necrosis (TNF) receptor superfamily, transduces apoptotic death upon crosslinking by its cognate ligand (FasL). As upregulation of Fas/FasL expression occurs in neuropathological conditions (e.g., stroke, central nervous system [CNS] trauma and seizures) associated with oxidative damage, we questioned whether reactive oxygen species (ROS) can directly affect Fas and FasL expression in neuronal cells. Utilizing rat PC12 cells neuronally differentiated with nerve growth factor (NGF), we observed that concentrations of H(2)O(2) inducing apoptotic cell death rapidly trigger the expression of Fas mRNA and protein as well as FasL mRNA. Although NGF-addition to naive PC12 downregulated constitutive Fas and FasL transcription, the H(2)O(2)-induced Fas and FasL mRNA upregulation invariably occurred either in the presence or in the absence of NGF. Similarly, phorbol 1,2-myristate 1, 3-acetate (PMA), a potent protein kinase C (PKC) activator, did not modify Fas and FasL mRNA upregulation subsequent to H(2)O(2) exposure. On the contrary, forskolin and dibutyryl cAMP, which elevate intracellular cAMP by independent mechanisms, both counteracted H(2)O(2)-induced Fas, but not FasL, mRNA upregulation and increased constitutive expression of FasL mRNA. Altogether, our data show that oxidative stress is a major stimulus in eliciting Fas and FasL expression in NGF-differentiated PC12 cells. Moreover, we describe here for the first time the existence of cAMP-dependent mechanism(s) modulating Fas and FasL expression.
 ...
PMID:H(2)O(2) induces upregulation of Fas and Fas ligand expression in NGF-differentiated PC12 cells: modulation by cAMP. 1211 99


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