Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We describe efficient methods for using functional proteomics analysis to study signal transduction pathways in murine fibroblast L929 cells following stimulation with tumor necrosis factor (TNF)-alpha. After stimulation with TNF-alpha, cellular proteins of L929 cells were extracted with a lysis buffer containing 0.3% sodium dodecyl sulfate (SDS) for 10-30 min time intervals, and were separated by two-dimensional (2-D) electrophoresis followed by immunoblot analysis with anti-phosphotyrosine antibody and alkaline phosphatase-anti IgG antibody conjugate. To improve detection sensitivity by immunoblot analysis we used a chemifluorescent substrate for alkaline phosphatase. One hundred protein spots were detected in the TNF-alpha stimulated L929 cell extract by immunoblot analysis. The use of chemifluorescence allowed us to quantitate immunoblotted spots with fluoroscanner so that we were able to detect time-dependent changes of a number of immunoblotted spots. Protein spots on a silver-stained 2-D gel corresponding to those detected by immunoblot analysis were subjected to in-gel trypsin digestion- matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF)-mass spectrometry analysis, respectively. Twenty-one proteins detected by immunoblot analysis were identified by MS-Fit database search analysis. Among them, the proteins that show time-dependent changes in staining intensity include vimentin, tubulin beta-chain, eukaryotic translation initiation factor 1A, chromatin assembly factor 1 (P48 subunit), probable protein disulfide isomerase P5, and several other proteins. Vimentin and tubulin beta-chain have been reported to be phosphorylated at tyrosine residues and involved in the signal transduction pathway induced by TNF-alpha. However, the other proteins have no previously known function in the signal transduction pathway. Thus, the methods used in this study seem to be suitable for the identification of time-dependent changes in many proteins that are involved in signal transduction. Usefulness of the method for comprehensive analysis of the proteins involved in signal transduction pathway and the limitations of the method are discussed.
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PMID:Matrix assisted laser desorption/ionization-time of flight-mass spectrometry analysis of proteins detected by anti-phosphotyrosine antibody on two-dimensional-gels of fibrolast cell lysates after tumor necrosis factor-alpha stimulation. 1087 Sep 74

We have previously reported increased concentrations of interleukin (1L)-6 in CSF from patients with tonic-clonic seizures, where increased cytokine production most likely is a consequence of neuronal epileptic activity associated with seizures. The biological effects of IL-6 are mediated by other cytokines, which are studied here in addition to IL-6. The purpose of this study was to analyze levels of soluble cytokines from plasma and CSF from patients with newly developed tonic-clonic seizures. The concentrations of IL-6, IL-1 receptor antagonist (IL-1RA), IL-1beta, tumor necrosis factor (TNFalpha) and nerve growth factor (NGF) were measured from plasma and CSF from 22 patients with newly developed tonic-clonic seizures within 24 h from the seizure and 18 controls. The mean concentrations of IL-6 were significantly increased in CSF (P<0.001) and plasma (P<0.01) after tonic-clonic seizures, there was some indication of increased concentrations of IL-1RA and no significant change in NGF, IL-1beta or TNFalpha. Our study shows that cytokine network is activated in patients after recent tonic-clonic seizures. We provide evidence of intrathecal production of IL-6 associated with electrical seizure activity.
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PMID:Interleukin-6 and interleukin-1 receptor antagonist in cerebrospinal fluid from patients with recent tonic-clonic seizures. 1096 11

Late effects after radiotherapy for brain tumors can be severe and tend to limit the efficacy of this treatment modality. The mechanisms governing the development of late radiation-induced lesions in the brain are not clear, but they are preceded by cycles of molecular and cellular events including production of cytokines, one of which is tumor necrosis factor (TNF)-alpha. There is literature to support possible roles for TNF-alpha as a contributor to edema, gliosis, and demyelination in the brain, all of which are histopathologically associated with radiation-induced brain damage. We have examined the role of TNF-alpha signaling in the response to brain irradiation using TNFRp55- or TNFRp75-deficient and control mice. Mice lacking TNFRp75 exhibited increased early radiation-induced apoptosis in putative stem cell regions of the brain. At 1 month, they had decreased proliferative responses in the same regions, and by 3 months they were demonstrating dose-dependent seizures and other severe neurological abnormalities that were not seen in control or TNFRp55-/- mice. Seizure activity correlated with the onset of extensive demyelination, and by 6 months, levels of myelin basic protein in irradiated TNFRp75-/- mice were approximately 40% of those seen in the other two strains; the animals were moribund and had to be euthanized. These observations indicate that radiation-induced TNF-alpha, acting through TNFRp75, protects against the development of late complications of brain irradiation.
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PMID:The role of tumor necrosis factor signaling pathways in the response of murine brain to irradiation. 1175 9

The systemic symptoms associated with influenza infection are mainly attributable to cytokines. To elucidate whether the high incidence of creatine kinase elevation and febrile seizures in influenza infection could be related to cytokines, we examined the serum levels of creatine kinase and cytokines (interferon-alpha, interleukin-6, and tumor necrosis factor-alpha) in patients with influenza and other febrile illness. Among those in the influenza group, 12 of 43 patients demonstrated elevated levels of creatine kinase (more than 200 IU/L), whereas in the control group two of 14 patients demonstrated elevated creatine kinase levels. When age was limited to under 7 years, seven of 32 patients (21.9%) in the influenza group had febrile seizures, whereas one of seven patients (14.3%) had a seizure in the control group. The influenza group demonstrated significantly high levels of interferon-alpha and interleukin-6. There was no correlation between cytokine levels and duration of fever or serum creatine kinase levels. The number of patients with high levels of interferon-alpha (>400 pg/mL) was significantly larger in the febrile seizure group than in the control group (six of seven patients in the febrile seizure group, 16 of 36 in the control group; P < 0.05). The present findings suggest the possible contribution of interferon-alpha in the pathogenesis of febrile seizures.
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PMID:Possible contribution of interferon-alpha to febrile seizures in influenza. 1243 68

Proinflammatory cytokines (such as interleukin-1beta, tumor necrosis factor-alpha) and nitric oxide are known to have both direct and indirect modulating effects on neurons and neurotoxic neurotransmitters released during excitation or inflammation. We measured interleukin-1beta, tumor necrosis factor-alpha, and nitrite levels in the peripheral blood and cerebrospinal fluid of children with febrile seizures and compared our results with those of children with febrile illnesses without seizures. Twenty-nine children with febrile seizure and 15 controls were studied. The mean concentrations of interleukin-1beta and nitrite were significantly increased in the cerebrospinal fluid (P < .01) of the children with febrile seizure. There were no significant changes in serum interleukin-1beta, tumor necrosis factor-alpha, nitrite, and cerebrospinal fluid tumor necrosis factor-alpha levels. Our data support the hypothesis that increased production of interleukin-1beta in the central nervous system or increased diffusion of interleukin-1beta through the blood-brain barrier is involved in the pathogenesis of febrile seizures.
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PMID:Interleukin-1beta, tumor necrosis factor-alpha, and nitrite levels in febrile seizures. 1254 29

Transgenic mice with glial fibrillary acidic protein (GFAP) promoter driven-astrocyte production of the cytokines interleukin-6 (IL-6) and tumor necrosis factor (TNF) were used to determine whether the pre-existing production of these cytokines in vivo might modulate the sensitivity of neurons to excitotoxic agents. Low doses of kainic acid (5 mg/kg) that produced little or no behavioral or electroencephalogram (EEG) alterations in wild type or glial fibrillary acidic protein (GFAP)-TNF animals induced severe tonic-clonic seizures and death in GFAP-IL6 transgenic mice of 2 or 6 months of age. GFAP-IL6 mice were also significantly more sensitive to N-methyl-D-aspartate (NMDA)- but not pilocarpine-induced seizures. Kainic acid uptake in the brain of the GFAP-IL6 mice was higher in the cerebellum but not in other regions. Kainic acid binding in the brain of GFAP-IL6 mice had a similar distribution and density as wild type controls. In the hippocampus of GFAP-IL6 mice that survived low dose kainic acid, there was no change in the extent of either neurodegeneration or astrocytosis. Immunostaining revealed degenerative changes in gamma aminobutyric acid (GABA)- and parvalbumin-positive neurons in the hippocampus of 2-month-old GFAP-IL6 mice which progressed to the loss of these cells at 6 months of age. Thus, GFAP-IL6 but not GFAP-TNF mice showed markedly enhanced sensitivity to glutamatergic- but not cholinergic-induced seizures and lethality. This may relate, in part, to a compromise of inhibitory interneuron function. Therefore, pre-existing IL-6 production and inflammation in the central nervous system (CNS) not only causes spontaneous neurodegeneration but also synergizes with other neurotoxic insults to induce more severe acute functional neurological impairment.
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PMID:Profound increase in sensitivity to glutamatergic- but not cholinergic agonist-induced seizures in transgenic mice with astrocyte production of IL-6. 1283 60

One group of male Wistar rats was kindled by electrical stimulation (ES) of the amygdala, one group was sham operated, while other rats were stimulated in the paleocortex of the cerebellum. The kindled generalized clonictonic seizures were followed by a net increase of the tumor necrosis factor-alpha (TNF-alpha) content both in the cerebral cortex (from 34.7 +/- 6.0 to 76.7 +/- 6.9 pg/mg of wet brain tissue) and cerebellum (from 106.6 +/- 17.7 to 193.8 +/- 29.8 pg/mg of wet tissue) in comparison with the data from sham-operated animals. This effect was observed 24 h after the induction of the last kindled seizures. ES of the cerebellum (100 Hz) was not followed by any changes in TNF-alpha content in the cortex and cerebellum. Moreover, kindling was not followed by any changes in thiol/disulfide system, but ES of the paleocerebellum induced an increase in free thiol groups in the cortical tissue. It can be concluded that the increase in TNF-alpha content is specific for the kindling process and that the antiepileptic effects of cerebellar ES might be realized via an intensification of antioxidative processes in the neural tissue.
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PMID:TNF-alpha in cerebral cortex and cerebellum is affected by amygdalar kindling but not by stimulation of cerebellum. 1286 21

The proinflammatory cytokines tumor necrosis factor (TNFalpha), interleukin-1 (IL-1alpha), and interleukin-6 (IL-6) have been associated with various models of hippocampal damage. To examine their role in initiation of an acute hippocampal injury response, 21-day-old male CD-1 mice received an acute intraperitoneal (i.p.) injection of trimethyltin hydroxide (TMT; 2.0 mg/kg) to produce necrosis of dentate granule neurons, astrocyte, and microglia reactivity. Tremors and intermittent seizures were evident at 24 hr. Intercellular adhesion molecule-1 (ICAM-1), glial fibrillary acidic protein (GFAP), anti-apoptotic TNFalpha-inducible early response gene (A-20), macrophage inflammatory protein (MIP)-1alpha, TNFalpha, IL-1alpha, IL-6, and caspase 3 mRNA levels were significantly elevated. Pretreatment with the antioxidant, ebselen, decreased ICAM-1, A-20, and TNFbeta elevations. Pentoxifylline blocked elevations in A-20 and decreased elevations in GFAP mRNA levels. Neither prevented histopathology or behavioral effects. Intracisternal injection of TNFalpha-neutralizing antibody significantly inhibited both behavioral effects and histopathology. RNase protection assays showed that TMT-induced elevations in mRNA levels for ICAM-1, A-20, GFAP, MIP-1alpha, IL-1alpha, TNFalpha, TNFbeta, and caspase 3 were blocked by anti-TNFalpha. These data demonstrate a significant role for TNFalpha in an acute neuro-injury in the absence of contribution from infiltrating cells. The cerebellum shows limited if any damage after TMT; however, in combination with the i.c.v. injection, elevations were seen in GFAP and in EB-22, a murine acute-phase response gene homologous to the alpha (1)-antichymotrypsin gene. Elevations were similar for artificial cerebral spinal fluid and anti-IL-1alpha, and significantly increased with anti-TNFalpha, anti-IL-6, or the combination of antibodies. Responses seen in the cerebellum suggest synergistic interactions between the baseline state of the cell and manipulations in the cytokine environment. Data suggests a role for TNFalpha in the pathogenesis of hippocampal injury induced by TMT.
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PMID:Differential modulation of hippocampal chemical-induced injury response by ebselen, pentoxifylline, and TNFalpha-, IL-1alpha-, and IL-6-neutralizing antibodies. 1289 37

Effective treatments to improve survivability following exposure to the nerve agent soman have been established and are currently available. Unfortunately, electrographic brain seizures, neuroinflammation and brain cell death are still a potential problem even with treatment. In the present study we have characterized the time course of the central neuro-inflammatory gene response using quantitative real time-PCR (TaqMan). Male Sprague-Dawley rats were pre-treated with HI-6 (1-2-hydroxy-iminomethyl-1-pyridino-3-(4-carbamoyl-1-pyridino-2-oxapropane dichloride); 125 mg/kg, i.p.) and exposed 30 min later to 1.6 x LD(50) of soman (pinacolyl methyl-phosphonofluoridate, 180 microg/kg, s.c.) followed at 1 min by atropine methyl nitrate (4 mg/kg, i.m.). Initially, a significant and dramatic upregulation of tumor necrosis factor-alpha and vascular cell adhesion molecule-1 mRNA levels was measured 2 h post-exposure followed at 6 h by upregulation of interleukin-1beta, interleukin-6, E-selectin, and intercellular adhesion molecule-1 with eventual resolution by 24-48 h. In conclusion, an acute and transient upregulation of the inflammatory gene response is activated following soman exposure that may be involved in the soman-induced brain injury process.
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PMID:Central neuro-inflammatory gene response following soman exposure in the rat. 1295 Nov 90

Physiologically in the brain, cytokines such as tumor necrosis factor-alpha (TNalpha) are released by the immune system and can modulate neurological responses. Conversely, the central nervous system (CNS) is also able to modulate cytokine production. In the case of CNS disorders, cytokine release may be modified. Cerebral malaria (CM) is a complication of Plasmodium falciparum infection in humans and is characterized by a reversible encephalopathy with seizures and loss of consciousness. Central clinical signs are partly due to sequestration of parasitized red blood cells in the brain microvasculature due to interactions between parasite proteins and adhesion molecules. TNFalpha is produced and released by host cells following exposure to various malarial antigens. The increase of TNFalpha release is responsible for the overexpression of adhesion molecules. This article reviews the involvement of TNFalpha in cerebral malaria and the relation with all the processes involved in this pathology. It shows that (i). TNFalpha levels are increased in plasma and brain but with no clear correlation between TNFalpha levels and occurrence and severity of CM; (ii). TNFalpha is responsible for intercellular adhesion molecule-1 upregulation in CM, the relation being less clear for other adhesion molecules; (iii). TNFalpha receptors are upregulated in CM, with TNF receptor 2 (TNFR2) showing a higher upregulation than TNFR1 in vivo; (iv). in murine CM, low doses of TNFalpha seem to protect from CM, whereas excess TNFalpha induces CM and anti-TNFalpha therapies (antibodies, pentoxifylline) did not show any efficiency in protection from CM. Moreover, the involvement of lymphotoxin a, which shares with TNFalpha the same receptors with similar affinity, appears to be an interesting target for further investigation.
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PMID:Tumor necrosis factor alpha in the pathogenesis of cerebral malaria. 1450 53


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