Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0085584 (encephalopathy)
18,178 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To elucidate the potential role of inducible nitric oxide synthase (iNOS) and neuronal constitutive nitric oxide synthase (cNOS) in the pathogenesis of virus-induced encephalopathy, the activities of both NOS isoforms were determined in the brains of rats infected with Borna disease virus (BDV) or rabies virus. iNOS activity strongly increased, whereas neuronal cNOS activity significantly decreased in a time-dependent manner after either BDV or rabies virus infection. Choline acetyltransferase activity in the brain remained unchanged during both virus infections, suggesting that the decrease in cNOS activity does not reflect a generalized neuronal loss. Immunohistochemistry and Northern blot analyses indicate that the decrease in neuronal cNOS activity is due to a decrease in cNOS protein and mRNA synthesis. These results suggest that both an excessive generation of NO by activated macrophages or microglia, as well as a decrease of NO production in neurons may contribute to the neuropathogenesis of neurotropic virus infections.
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PMID:Effect of neurotropic virus infection on neuronal and inducible nitric oxide synthase activity in rat brain. 922 48

Mechanisms underlying human immunodeficiency virus-1 encephalopathy are not completely known; however, recent studies suggest that the viral protein gp41 may be neurotoxic via activation of inducible nitric oxide synthase (iNOS) in glial cells. In the present study, we investigated the NO-generating activity of primary human fetal astrocytes in response to gp41 and the relationship to microglial cell production of interleukin-1 (IL-1). Gp41 failed to trigger iNOS mRNA expression in highly enriched (>99%) astrocyte or microglial cell cultures. However, gp41-treated microglia released a factor(s) that triggered iNOS mRNA expression and NO production in astrocytes. Because IL-1 receptor antagonist protein blocked gp41-induced NO production, a pivotal role was suggested for microglial cell IL-1 production in astrocyte iNOS expression. Also, gp41 induced IL-1beta mRNA expression and IL-1 production in microglial cell but not astrocyte cultures. Using specific inhibitors, we found that gp41-induced IL-1beta production in microglia was mediated via a signaling pathway involving protein-tyrosine kinase. These data support the hypothesis that gp41 induces astrocyte NO production indirectly by triggering upregulation of microglial cell IL-1 expression.
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PMID:Gp-41-mediated astrocyte inducible nitric oxide synthase mRNA expression: involvement of interleukin-1beta production by microglia. 1041 75

Kynurenine 3-mono-oxygenase, one of the key enzymes of the "kynurenine pathway", catalyses the formation of 3-hydroxykynurenine and may direct the neo-synthesis of quinolinic and kynurenic acids. While 3-hydroxykynurenine and quinolinic acid have neurotoxic properties, kynurenic acid antagonizes excitotoxic neuronal death. Here we report that the expression and activity of kynurenine 3-mono-oxygenase significantly increased in the spinal cord of rats with experimental allergic encephalopathy, an experimental model of multiple sclerosis. As a consequence of this increase, the spinal cord content of 3-hydroxykynurenine and quinolinic acid reached neurotoxic levels. We also report that systemic administration of Ro 61-8048, a selective kynurenine 3-mono-oxygenase inhibitor, reduced the increase of both 3-hydroxykynurenine and quinolinic acid, and caused accumulation of kynurenic acid. In the brain and spinal cord of the controls, kynurenine 3-mono-oxygenase immunoreactivity was located in granules (probably mitochondria) present in the cytoplasm of both neurons and astroglial cells. In the spinal cord of rats with experimental allergic encephalopathy, however, cells with a very intense kynurenine 3-mono-oxygenase immunoreactivity, also able to express class II major histocompatibility complex and inducible nitric oxide synthase, were found in perivascular, subependymal and subpial locations. These cells (most probably macrophages) were responsible for the large increase in 3-hydroxykynurenine and quinolinic acid found in the spinal cords of affected animals. The results show that cells of the immune system are responsible for the increased formation of 3-hydroxykynurenine and quinolinic acid, two neurotoxic metabolites that accumulate in the central nervous system of rats with experimental allergic encephalomyelitis. They also demonstrate that selective kynurenine 3-mono-oxygenase inhibitors reduce the neo-synthesis of these toxins.
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PMID:Kynurenine 3-mono-oxygenase activity and neurotoxic kynurenine metabolites increase in the spinal cord of rats with experimental allergic encephalomyelitis. 1122 5

The pathogenesis of influenza encephalopathy or encephalitis is poorly understood. This review summarizes our recent studies of the roles played by inflammatory cytokines, inducible nitric oxide synthase (iNOS), adhesion molecules and mini-plasmin in influenza encephalitis. After the intranasal infection of newborn mice with the non-neurotropic strain of influenza A virus (IAV) Aichi/2/68/H3N2, encephalitis and severe brain edema were observed within 3-5 days. IAV-RNA and abnormalities in the blood-brain barrier permeability were detected in association with an increase in the mRNA expressions of endothelin-1, iNOS, and tumor necrosis factor-alpha. Furthermore, the accumulation in the brain capillaries of mini-plasmin, which proteolytically induces the viral envelope fusion activity and allows the virus to enter the cells, changes the brain from non-susceptible to susceptible to non-neurotropic IAV multiplication. The accumulation of mini-plasmin was markedly greater in newborn mice with an impaired mitochondrial fatty acid metabolism. These inflammatory mediators and the accumulation of mini-plasmin in the brain may play an important role in the onset and progression of LAV encephalitis.
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PMID:Pathologic mechanisms of influenza encephalitis with an abnormal expression of inflammatory cytokines and accumulation of mini-plasmin. 1263 May 63

The neuropathological correlates of encephalopathy and autonomic dysfunction in septic shock are unclear. We performed post mortem analysis of 5 brain areas susceptible to ischemia and 5 autonomic nuclei (AN) in 23 patients who had died in our intensive care unit (ICU) from septic shock and 8 dying from non-septic shock as well as 5 controls who had died suddenly from extracranial injury. Proinflammatory cytokine (IL1-beta and TNF-alpha) and inducible nitric oxide synthase (iNOS) expression was assessed by immunocytochemistry. Abnormalities in septic shock were: hemorrhages (26%), hypercoagulability syndrome (9%), micro-abscesses (9%), multifocal necrotizing leukoencephalopathy (9%) and ischemia (100%). The incidence of cerebral hemorrhage or hypercoagulability syndrome was not related to clotting disturbances. The intensity of ischemia within susceptible areas was the same in both ICU groups, but more pronounced in the autonomic centers of septic patients (P < 0.0001). Neuronal apoptosis assessed using anti-caspase 3 immunocytochemistry and in situ end labeling was more pronounced in the autonomic nuclei of septic patients. (P < 0.0001). TNF-alpha expression did not differ between groups but vascular iNOS expression assessed by immunocytochemistry was higher in sepsis (P<0.0001) and correlated with autonomic center neuronal apoptosis (P < 0.02). We conclude that septic shock is associated with diffuse cerebral damage and specific autonomic neuronal apoptosis which may be due to circulating factors particularly iNOS.
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PMID:The neuropathology of septic shock. 1499 34

Neonatal hypoxic-ischaemic (HI) brain injury resulting in encephalopathy is a leading cause of morbidity and mortality with no effective treatment. Here we show that caffeic acid phenethyl ester (CAPE), an active component of propolis, administered either before or after an HI insult, significantly prevents HI-induced neonatal rat brain damage in the cortex, hippocampus and thalamus. In addition to blocking HI-induced caspase 3 activation, CAPE also inhibits HI-mediated expression of inducible nitric oxide synthase and caspase 1 in vivo and potently blocks nitric oxide-induced neurotoxicity in vitro. Furthermore, CAPE directly inhibits Ca2+-induced cytochrome c release from isolated brain mitochondria. Thus, CAPE induces neuroprotection against HI-induced neuronal death, possibly by blocking HI-induced inflammation and/or directly inhibiting the HI-induced neuronal death pathway. CAPE may therefore be a novel effective therapy for preventing neonatal HI injury.
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PMID:Caffeic acid phenethyl ester prevents neonatal hypoxic-ischaemic brain injury. 1546 48

To analyze whether exposure to oxygen-glucose deprivation (OGD) of immature rat brain slices might reproduce the main pathophysiologic events leading to neuronal death in neonatal hypoxic-ischemic encephalopathy (NHIE), 500 microm-thick brain slices were obtained from 7-day-old Wistar rats, and incubated in oxygenated physiological solution. In OGD group, oxygen and glucose were removed from the medium for 10-30 min (n = 25); then, slices were re-incubated in normal medium. In control group the medium composition remained unchanged (CG, n = 30). Medium samples were obtained every 30 min for 3 h. To analyze neuronal damage, slices were stained with Nissl and CA1 area of hippocampus and cortex were observed under microscopy. In addition, neuronal death was quantified as LDH released to the medium determined by spectrophotometry. Additionally, medium glutamate (Glu) levels were determined by HPLC and those of TNFalpha by ELISA, whereas inducible nitric oxide synthase expression was determined by Western blot performed on slices homogenate. Optimal OGD time was established in 20 min. After OGD, a significant decrease in the number of neurones in hippocampus and cortex was observed. LDH release was maximal at 30 min, when it was five-fold greater than in CG. Furthermore, medium Glu concentrations were 200 times greater than CG levels at the end of OGD period. A linear relationship between Glu and LDH release was demonstrated. Finally, 3 h after OGD a significant induction of iNOS as well as an increase in TNFalpha release were observed. In conclusion, OGD appears as a feasible and reproducible in vitro model, leading to a neuronal damage, which is physiopathologically similar to that found in NHIE.
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PMID:Immature rat brain slices exposed to oxygen-glucose deprivation as an in vitro model of neonatal hypoxic-ischemic encephalopathy. 1592 37

During severe sepsis several immunological defence mechanisms initiate a cascade of inflammatory events leading to multi-organ failure including septic encephalopathy and ultimately death. To assess the reaction and participation of parenchymal brain cells during endotoxaemia, the present study evaluates micro- and astroglial activation, expression of the inducible nitric oxide synthase (iNOS) pro- and antiapoptotic protein levels Bax and Bcl-2, and apoptosis. Male Wistar rats received 10 mg/kg lipopolysaccharide (LPS) or vehicle intraperitoneally and were sacrificed for brain collection at 4, 8 or 24 h after induction of experimental sepsis. One group of animals received 10 mg/kg of the NOS inhibitor N-monomethyl-L-arginine (L-NMMA) intraperitoneally 1 day before and during the experiment. Immunohistochemical evaluation revealed a sepsis-induced, time-dependent increase in the immunoreactivity of iNOS, glial fibrillary acidic protein (GFAP) and activated microglia (ED-1), paralleled by a time-dependent increase of apoptotic brain cells marked by terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL), an increase of Bax-positive cells and a decrease of Bcl-2-positive cells. Evaluation of different brain regions revealed that the hippocampus is the most vulnerable region during experimental sepsis. iNOS-inhibition with L-NMMA significantly reduced the number of apoptotic cells in hippocampus, midbrain and cerebellum. In addition, it reduced the increase of the proapoptotic protein Bax in all examined brain regions and reduced the decrease of Bcl-2-positive cells in the hippocampus. We therefore conclude, that peripheral inflammation leads to a profound glial activation, the generation of nitric oxide and changes of Bax and Bcl-2 protein regulation critical for apoptosis.
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PMID:Systemic inflammation induces apoptosis with variable vulnerability of different brain regions. 1612 4

In this study, we demonstrate that mice deficient in TNFR1 (TNFR1(-/-)) were resistant to LPS-induced encephalopathy. Systemic administration of lipopolysaccharide (LPS) induces a widespread inflammatory response similar to that observed in sepsis. Following LPS administration TNFR1(-/-) mice had less caspase-dependent apoptosis in brain cells and fewer neutrophils infiltrating the brain (p<0.039), compared to control C57Bl6 (TNFR1(+/+)) mice. TNFR1-dependent increase in aquaporin (AQP)-4 mRNA and protein expression was observed with a concomitant increase in water content, in brain (18% increase in C57Bl6 mice treated with LPS versus those treated with saline), similar to cerebral edema observed in sepsis. Furthermore, absence of TNFR1 partially but significantly reduced the activation of astrocytes, as shown by immunofluorescence and markedly inhibited iNOS mRNA expression (p<0.01). Septic encephalopathy is a devastating complication of sepsis. Although, considerable work has been done to identify the mechanism causing the pathological alterations in this setting, the culprit still remains an enigma. Our results demonstrate for the first time that endotoxemia leads to inflammation in brain, with alteration in blood-brain barrier, up-regulation of AQP4 and associated edema, neutrophil infiltration, astrocytosis, as well as apoptotic cellular death, all of which appear to be mediated by TNF-alpha signaling through TNFR1.
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PMID:TNF is a key mediator of septic encephalopathy acting through its receptor, TNF receptor-1. 1788 56

Encephalopathy and brain edema are serious complications of acute liver failure (ALF). The precise pathophysiologic mechanisms responsible have not been fully elucidated but it has been suggested that oxidative/nitrosative stress is involved. In the present study we evaluated the role of oxidative/nitrosative stress in the pathogenesis of hepatic encephalopathy and brain edema in rats with ALF resulting from hepatic devascularization. We also studied the effect of hypothermia, a treatment previously shown to delay the progression of encephalopathy and the onset of brain edema, on ALF-induced oxidative stress. ALF rats were sacrificed at precoma and coma stages of encephalopathy along with their appropriate sham-operated controls. Hypothermic ALF rats were sacrificed in parallel with normothermic comatose ALF rats. Nitric oxide production in plasma and brain was assessed indirectly by measuring the level of its stable end products, nitrite/nitrate (NOx), using the Griess reagent. Expression of nitric oxide synthase (NOS) isoforms and heme oxygenase-1 (HO-1) were measured using real-time quantitative PCR, Western blot analysis and immunohistochemistry. Increased nitrite/nitrate levels were observed in the plasma and frontal cortex in ALF rats at coma stage of encephalopathy compared to sham-operated controls. Increased expression of HO-1 protein and mRNA was observed in the frontal cortex of ALF rats at both precoma and coma stages of encephalopathy. Significant increases in expression of endothelial and inducible NOS mRNA isoforms also occurred at precoma and coma stages of encephalopathy. Expression of the neuronal nitric oxide synthase isoform (nNOS) was not altered by ALF. Hypothermia normalized nitrite/nitrate levels in brain and significantly attenuated HO-1, eNOS and iNOS expression. These results suggest that, oxidative/nitrosative stress participates in the pathogenesis of brain edema and its complications in ALF and that the beneficial effect of hypothermia depends in part on its ability to inhibit oxidative/nitrosative stress-related mechanisms.
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PMID:Hypothermia attenuates oxidative/nitrosative stress, encephalopathy and brain edema in acute (ischemic) liver failure. 1942 16


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