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:C0036572 (seizures)
80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenosine monophosphate, inosine monophosphate, inosine, adenosine, guanosine, adenine, guanine, hypoxanthine, xanthine and uric acid were determined in cerebrospinal fluid (CSF) of 15 children after complex febrile seizures (CFS) and in 27 after simple febrile seizures (SFS), and compared with those in a control group of 63 children. There was no statistically significant difference between the groups for any of these metabolites, suggesting that CFS and SFS neither significantly disturb the metabolism of nucleotides, nucleosides or bases nor significantly deplete neuron adenosine triphosphate levels.
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PMID:Cerebrospinal fluid purine metabolites after complex febrile convulsions. 881 95

Gel retardation electrophoresis revealed that binding of a radiolabeled double stranded oligonucleotide probe for the nuclear transcription factor activator protein-1 (AP1) was markedly potentiated 2 h after the intraperitoneal injection of kainic acid (KA) at a dose range of 10-40 mg/kg in a dose-dependent manner in the murine hippocampus. The potentiation was seen in a manner independent of the crisis of convulsive seizures following the administration of KA at different doses. At the highest dose employed, the systemic KA significantly potentiated the AP1 binding in most central discrete structures examined except the cerebellum. In contrast, KA significantly potentiated binding of a radiolabeled probe for cyclic AMP response element binding protein (CREB) in a dose-dependent fashion in the hippocampus, without altering that in other parts of murine brain. No significant alteration was detected in binding of a probe for c-Myc in any brain regions examined 2 h after the administration of KA at different doses. However, immunoblotting analysis demonstrated that KA was ineffective in altering endogenous levels of both CREB and CREB phosphorylated at serine133 in the hippocampus and cerebellum. These results suggest that in vivo systemic KA signals may be selectively transduced to nuclear AP1 in the hippocampus through a mechanism different from phosphorylation of CREB at serine133 in murine brain.
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PMID:Particular nuclear transcription factors responsive to systemic administration of kainic acid in murine brain. 888 88

Nuclear extracts of mouse brain contained binding of radiolabeled oligonucleotide probes for particular transcription factors with leucine-zipper motifs including activator protein-1 (AP1), cyclic AMP response element binding protein (CREB) and c-Myc. An acute intraperitoneal injection of pentylenetetrazole (PTZ) at a convulsive dose significantly potentiated binding of the probe for AP1 in the cerebral cortex, hippocampus, striatum, hypothalamus and midbrain, without affecting that in the medulla-pons and cerebellum, 2 h after the administration. However, PTZ failed to affect binding of the probe for CREB under the similar experimental conditions. In contrast, PTZ induced a slight but statistically significant decrease in binding of the AP1 probe in the cerebellum, without altering that in the hippocampus, 14 h after the injection. On the other hand, repeated administration of PTZ at a subconvulsive dose led to spontaneous kindling seizures in animals, with a concomitant decrease in binding of the AP1 probe in both the hippocampus and cerebellum. In contrast to these animals with acquired spontaneous seizures, however, binding of the AP1 probe was significantly higher in three different telencephalic structures of inherently spontaneous epileptic El mice than that in the parent ddY mice, with binding of probes for CREB and c-Myc being unchanged. These results suggest that different molecular mechanisms may underlie the expression of being unchanged. These results suggest that different molecular mechanisms may underlie the expression of AP1 in discrete brain structures of mice with acquired and inherent spontaneous seizures.
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PMID:Binding of double stranded oligonucleotide probes for particular transcription factors with leucine-zipper motifs in discrete brain structures of mice with acquired and inherent spontaneous seizures. 888 92

In this paper we describe the synthesis of a series of alpha-substituted analogues of the potent and selective group II metabotropic glutamate receptor (mGluR) agonist (1S,1'S,2'S)-carboxycyclopropylglycine (2, L-CCG 1). Incorporation of a substitutent on the amino acid carbon converted the agonist 2 into an antagonist. All of the compounds were prepared and tested as a series of four isomers, i.e., two racemic diastereomers. On the basis of the improvement in affinity realized for the alpha-phenylethyl analogue 3, in this paper we explored the effects of substitution on the aromatic ring as a strategy to increase the affinity to these compounds for group II mGluRs. Affinity for group II mGluRs was measured using [3H]glutamic acid (Glu) binding in rat forebrain membranes. Antagonist activity was confirmed for these compounds by measuring their ability to antagonize (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid-induced inhibition of forskolin stimulated cyclic-AMP in RGT cells transfected with human mGluR2 and mGluR3. Meta substitution on the aromatic ring of 3 with a variety of substituents, both electron donating (e.g., methyl, hydroxy, amino, methoxy, phenyl, phenoxy) and electron withdrawing (e.g., fluorine, chlorine, bromine, carboxy, trifluoromethyl) gave from 1.5- to 4.5-fold increases in affinity. Substitution with p-fluorine, as in 97 (IC50 = 0.022 +/- 0.002), was the exception. Here, a greater increase in affinity was realized than for either the ortho- or meta-substituted analogues; 97 was the most potent compound resulting from monosubstitution of the aromatic. At best, only modest increases in affinity were realized for certain compounds bearing either two chlorines or two fluorines, and two methoxy groups gave no improvement in affinity (all examined in a variety of substitution patterns). Three amino acids, 4, 5, and 104, were resolved into their four constituent isomers, and affinity and functional activity for group II mGluRs was found to reside solely in the S,S,S-isomers of each, consistent with 1. With an IC50 = 2.9 +/- 0.6 nM, the resolved xanthylmethyl compound 168 was the most potent compound from this SAR. Amino acid 168 demonstrated high plasma levels following intraperitoneal (i.p.) administration and readily penetrated into the brain. This compound, however, had only limited (approximately 5%) oral bioavailability. Systemic administration of 168 protected mice from limbic seizures produced by the mGluR agonist 3,5-dihydroxyphenylglycine, with an ED50 = 31 mg/kg (i.p., 60 min preinjection). Thus, 168 represents a valuable tool to study the role of group II mGluRs in disease.
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PMID:2-substituted (2SR)-2-amino-2-((1SR,2SR)-2-carboxycycloprop-1-yl)glycines as potent and selective antagonists of group II metabotropic glutamate receptors. 2. Effects of aromatic substitution, pharmacological characterization, and bioavailability. 946 67

Absence seizures are characterised by a well-defined disturbance of thalamocortical function, and there is no spread to other systems. In this study, we continue our examination of the mechanisms underlying the increased nuclear cyclic AMP responsive element (CRE)- and activator protein 1 (AP-1) DNA-binding activities in a gamma-butyrolactone (GBL)-induced mouse model of absence seizure. The administration of GBL increased CRE- and AP-1 DNA-binding activities in the cerebral cortex and thalamus, but not in other regions such as the hippocampus, cerebellum or pons + medulla oblongata, at doses which induced absence seizures. Not only the absence-seizure behavior but also the increased CRE- and AP-1 DNA-binding activities in the thalamocortical regions were reversibly inhibited by ethosuximide, a typical anti-absence drug, and the GABAB antagonists CGP 35348 and CGP 46381. A gel-supershift assay revealed that the GBL-induced CRE-binding activity was supershifted by an anti-CRE-binding protein (CREB) antibody, and that AP-1 DNA-binding activity was blocked by anti-c-Jun and anti-c-Fos antibodies. These results suggest that increased CRE- and AP-1 DNA-binding activities in the cerebral cortex and thalamus are related to the pathogenesis of generalized absence seizures and that these increases in DNA-binding activity are related to ethosuximide- and GABAB antagonist-sensitive abnormal neuronal activity in the thalamocortical circuit.
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PMID:Pharmacological profiles of absence seizure-induced increases in CRE- and AP-1 DNA-binding activities in gamma-butyrolactone-treated mice. 986 26

The characterized nuclear cyclic AMP responsive element (CRE)- and activator protein 1 (AP-1) DNA-binding activities in various brain regions of lethargic (lh/lh) mice, a genetic model of absence seizures. Gel-shift assays showed that nuclear CRE- and AP-1 DNA-binding activities in the thalamus and cerebral cortex, but not in other regions such as the hippocampus and cerebellum of lethargic mice were significantly higher than those of non-epileptic control mice. Furthermore, CRE- and AP-1 DNA-binding activities in lethargic mice, but not control mice, were inhibited by the specific GABA(B) receptor antagonist CGP 46831, at a dose which suppressed seizure behavior and spike and wave discharges. These results suggest that enhanced nuclear CRE- and AP-1 DNA-binding activities in the thalamocortical region are related to generation and/or propagation of absence seizures in lethargic mice.
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PMID:Characterization of absence seizure-dependent cyclic AMP responsive element-and activator protein 1 DNA-binding activities in lethargic (lh/lh) mice. 1007 71

The mammalian brain has a high degree of plasticity, with dentate granule cell neurogenesis and glial proliferation stimulated by an enriched environment combining both complex inanimate and social stimulation. Moreover, rodents exposed to an enriched environment both before and after a cerebral insult show improved cognitive performance. One of the most robust associations of environmental enrichment is improved learning and memory in the Morris water maze, a spatial task that mainly involves the hippocampus. Furthermore, clinical evidence showing an association between higher educational attainment and reduced risk of Alzheimer and Parkinson-related dementia indicates that a stimulating environment has positive effects on cerebral health that may provide some resilience to cerebral insults. Here we show that in addition to its effects on neurogenesis, an enriched environment reduces spontaneous apoptotic cell death in the rat hippocampus by 45%. Moreover, these environmental conditions protect against kainate-induced seizures and excitotoxic injury. The enriched environment induces expression of glial-derived neurotrophic factor and brain-derived neurotrophic factor and increases phosphorylation of the transcription factor cyclic-AMP response element binding protein, indicating that the influence of the environment on spontaneous apoptosis and cerebral resistance to insults may be mediated through transcription factor activation and induction of growth factor expression.
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PMID:Environmental enrichment inhibits spontaneous apoptosis, prevents seizures and is neuroprotective. 1020 38

The quinolone antibacterials enoxacin and norfloxacin (2.5 mg/kg, i.v.) provoked clonic convulsions in mice treated concomitantly with biphenylacetic acid (BPAA, 100 mg/kg, i.p.), a major metabolite of the nonsteroidal anti-inflammatory drug fenbufen. Gel-shift assays showed that enoxacin-induced convulsions resulted in increases in nuclear activator protein 1 (AP-1) DNA- and cyclic AMP responsive element (CRE)-binding activities in the cerebral cortex and hippocampus, but not in other regions, such as the cerebellum and thalamus. In contrast, ofloxacin and levofloxacin, at the same doses, in the presence of BPAA did not evoke convulsions or increase these DNA-binding activities. Administration of these quinolones and BPAA alone elicited neither convulsions nor increases in these DNA-binding activities. These results suggest that the increased nuclear AP-1 DNA- and CRE-binding activities in the cerebral cortex and hippocampus induced by quinolones with BPAA correlated with seizure activities and that these brain regions play pivotal roles in quinolone-induced convulsions.
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PMID:Characterization of quinolone antibacterial-induced convulsions and increases in nuclear AP-1 DNA- and CRE-binding activities in mouse brain. 1034 Mar 9

Convulsive seizures caused by many different stimuli have been shown to induce activator protein-1 (AP-1) transcription factors in the brain, particularly in the hippocampus. Previous results from our laboratory demonstrated that thalamic and cerebral cortical AP-1 DNA- and cyclic AMP responsive element (CRE)- binding activities in the absence seizure model mice were significantly higher than those in nonepileptic control mice. In order to characterize further a correlation between convulsive seizures and inducible transcription factors, we investigated convulsive seizure-dependent increases in AP-1 DNA- and CRE-binding activities in various brain regions of the mice. Administration of pentylentetrazole and kainic acid provoked clonic and limbic type seizures, respectively, and increased AP-1 DNA- and CRE- binding activities in the cerebral cortex and hippocampus but not in other regions. Maximal electric shock (MES) induced tonic convulsions and increased hippocampal and cerebral cortical AP-1 DNA- and CRE- binding activities. Sodium phenobarbital (50 mg/kg, i.p.), an anticonvulsant, suppressed both convulsions and increases in these DNA-binding activities induced by MES. In contrast, ethosuximide, an antiabsence drug, did not affect MES-induced convulsions or increases in these DNA-binding activities. These data suggest that convulsive seizures increase not only AP-1 DNA-binding but also CRE-binding activities in the cerebral cortex and hippocampus. These data combined with our previous results also suggest that regional differences in increases in CRE- and AP-1 DNA-binding activities between convulsive seizures and absence seizures are attributable to differences in the regions and pathways which are responsible for the genesis and spreading seizure activities in the central nervous system.
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PMID:[Cyclic AMP responsive element- and activator protein 1 DNA-binding activities in epilepsy model mice]. 1043 3

The therapeutic mechanism of the action of lithium in the treatment of bipolar affective disorder is not known, in spite of a burgeoning number of biochemical studies linking lithium to signal transduction processes. This article reviews a decade of studies examining the behavioural manifestations of manipulating inositol, cyclic adenosine monophosphate (cAMP) and G proteins in rats. Inositol, forskolin, dibutyryl cAMP and pertussis toxin all interacted with lithium when rearing behavior was measured. Lithium potentiated the increase in locomotion induced by injections of cholera toxin into the nucleus accumbens, consistent with the hypothesis that it inactivates inhibitory G proteins. More specific interactions were found between lithium and inositol following cholinergic and serotonergic stimulation. Inositol, but not forskolin, attenuated lithium-pilocarpine seizures and the enhancement of the serotonin syndrome; however, inositol had no effect on lithium-induced attenuation of wet dog shakes following an injection of 5-hydroxytryptophan. Behavioural evidence supports biochemical findings suggesting that lithium's interactions with the phoshphatidyl inositol and cyclic AMP signal transduction systems may be relevant to its therapeutic effects in bipolar disorder. Further research on more specific behaviours may elucidate the relevant pharmacological mechanisms underlying the therapeutic effect of lithium.
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PMID:Interactions of lithium and drugs that affect signal transduction on behaviour in rats. 1052 45


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