Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The influence of kainic acid (KA)-induced limbic seizure activity on the expression of mRNA for nerve growth factor (NGF) in adult rat brain was studied using in situ hybridization and S1 nuclease protection techniques with RNA probes complementary to murine and rat NGF mRNA. Within hippocampus, intracerebroventricular injection of 0.5 microgram KA caused a dramatic bilateral increase in hybridization of the 35S-labeled cRNA within stratum granulosum. This increase was first evident 1 h post-KA, appeared maximal at approximately 20-fold control levels at 2-3 h post-injection, and declined to control levels by 48 h post-injection. During the period of maximal hybridization, all but the deepest cells within stratum granulosum appeared to be autoradiographically labeled. Hybridization of the NGF cRNA probe was also increased within superficial layers of piriform and entorhinal cortex and, to much lesser extent, within scattered neurons of layers II and III of neocortex in KA-treated rats. In olfactory cortical areas, hybridization was maximally elevated 15.5-24.5 h after KA injection. In contrast to these effects, KA treatment did not consistently influence the density of hybridization, or number of neurons labeled, within the dentate gyrus hilus or the hippocampus proper (CA1-CA3). In agreement with the in situ hybridization results, S1 nuclease protection assay detected KA-induced increases in hybridization within pooled dentate gyrus/CA1 samples, but not hippocampal CA3 samples. These data support the conclusion that seizure activity stimulates a transient increase in NGF expression by select populations of forebrain neurons and indicates that experimental seizure paradigms might be further exploited for analyses of the mechanisms of NGF regulation and processing in the adult brain.
Brain Res Mol Brain Res 1991 Jan
PMID:Kainic acid-induced seizures stimulate increased expression of nerve growth factor mRNA in rat hippocampus. 170 74

In order to determine whether calcium binding protein (calbindin-D28k or CaBP) and glutamate decarboxylase (GAD) may be involved in the process underlying the generation of seizure activity, changes in CaBP protein and mRNA and in GAD mRNA were examined in the kindling model of epilepsy. Following amygdaloid (AK) and commissure (CK) kindling significant decreases in the concentration of CaBP of 20% and 30%, respectively, were specifically observed in the hippocampal formation. However, using a cDNA specific to mammalian CaBP, Northern analysis of poly(A+) RNA and slot blot analysis of total RNA revealed no changes in the levels of CaBP mRNA in hippocampus, subcortical area (including amygdala, substantia nigra and striatum) or cerebellum of rats sacrificed 30 min, 1 h, 6 h or 24 h after the last kindled seizure. Similarly when these blots were reprobed with a cDNA specific to mammalian GAD, no changes in GAD gene expression were observed. However, fos gene expression was markedly enhanced at 1 h after seizure. We also tested whether changes in CaBP or GAD mRNA could be detected at any of the various stages of the kindling process. Slot blot analysis of cortex, subcortical structures and hippocampus revealed no changes in CaBP or GAD mRNA during the course of commissure kindling. In situ hybridization studies with GAD and CaBP 35S-labeled antisense probes also indicated no obvious changes upon visual analysis of autoradiographs. However, when silver grains were counted, significant changes in GAD mRNA in individual cells in hippocampus and substantia nigra were noted after kindling induced epilepsy. Our results indicate that, unlike fos gene expression, prominent alterations in GAD and CaBP mRNA in gross brain regions (as measured by slot blot and Northern blot analyses) are not observed in the kindling process. However, our in situ hybridization studies suggest that changes in GAD mRNA in individual cells may be involved in the process underlying kindling induced seizure activity.
Brain Res Mol Brain Res 1991 Feb
PMID:Calcium binding protein (calbindin-D28k) and glutamate decarboxylase gene expression after kindling induced seizures. 170 39

A common feature of demyelinating diseases such as multiple sclerosis in humans and experimental autoimmune encephalomyelitis in rodents is the marked elevation in the expression of the major histocompatibility complex (MHC) antigens in the involved sites. By specific targeting of a syngeneic MHC class I gene to oligodendrocytes, we have generated transgenic mice which not only exhibit severe involuntary tremors and develop tonic seizures but also show extensive demyelination in both the brain and the spinal cord. The fact that demyelination in these mice occurs in the absence of immune infiltration dismisses an autoimmune involvement but suggests that the MHC class I antigens play a direct role in inducing disease. Our findings lend support to the possibility that demyelinating diseases are induced by infectious agents such as viruses which can either directly activate MHC gene expression in oligodendroglia or indirectly activate expression through the release by reactive T cells of gamma interferon in the brain.
Mol Cell Biol 1991 Nov
PMID:Transgenic mouse model for central nervous system demyelination. 171 29

The levels of prostaglandin F1 (6-keto-PGF1 alpha), thromboxane B2 (11-dehydro-TxB2), and peptidoleukotriene C4 (LTC4) were measured (acetylcholinesterase immunoassay) in the frontal cortex (FC) and the striatum (SA) of the rat brain to study the possible role of eicosanoids in seizures induced by hyperbaric oxygen (HBO). The rats were exposed to (1) hyperbaric oxygen (HBO, 6 ATA O2) up to the first seizure (2) compressed air (6 ATA air, i.e., approximately equal to 1.25 ATA O2) or (3) atmospheric pressure (1 ATA air, i.e., 0.21 ATA O2); there was no seizure in groups 2 and 3. Transition from 6 ATA to atmospheric pressure was obtained in 15 min; the rats were then decapitated and their heads frozen in liquid nitrogen before extraction and analysis of prostanoids. Whatever the conditions, cortical levels of 6-keto-PGF1 alpha and 11-dehydro-Tx B2 are higher than striatal levels; considering the same area, 11-dehydro-Tx B2 and LTC4 concentrations were not significantly different whatever the condition, but there is a trend for lower 6-keto-PGF1 alpha levels in FC after HBO seizure. Biochemical mechanisms are discussed. Eicosanoids do not seem to play a major role in HBO seizures, although some modifications of their metabolism may take place.
Mol Chem Neuropathol 1991 Aug
PMID:The influence of one hyperbaric oxygen-induced seizure on brain eicosanoid content. 177 30

Interleukin-1 (IL-1), a cytokine involved in the acute phase reaction to injury and infection, has multiple effects in the central nervous system, including induction of fever and sleep and the release of several neuropeptides. We evaluated effects of IL-1 beta on inhibitory postsynaptic function at the gamma-aminobutyric acidA (GABAA) receptor. IL-1 (100 pg/ml to 10 ng/ml) augmented GABAA receptor function in cortical synaptic preparations. This effect of IL-1 was largely prevented by incubation with a specific IL-1 receptor antagonist. The related cytokines interleukin-6 and tumor necrosis factor did not augment GABA-dependent chloride transport. Similar enhancement of GABAA receptor function was observed in tissue prepared from mice previously injected intraperitoneally with IL-1 (1 microgram). Electrophysiological studies in cultured primary cortical neurons demonstrated that IL-1 enhanced the GABA-mediated increase in chloride permeability, whereas IL-1 alone produced no alterations in resting conductance. Behavioral studies indicated that IL-1 is similarly active in vivo; mice treated with IL-1 showed a decrease in open-field activity and an increase in the threshold for pentylenetetrazol-induced seizures. The interaction of IL-1 with GABAA receptors might account for the somnogenic and motor-depressant effects of this cytokine.
Mol Pharmacol 1991 Feb
PMID:Interleukin-1 augments gamma-aminobutyric acidA receptor function in brain. 184 88

The effects of systemic kainic acid (KA) administration on hippocampal levels of prodynorphin and proenkephalin mRNA, as well as opioid peptides derived from these precursors, were evaluated. A single subcutaneous injection of KA induced a range of seizure states, from mild wet dog shakes to generalized motor seizures. Northern blot analysis of hippocampal mRNA revealed an increase in both prodynorphin and proenkephalin mRNA levels which corresponded to the intensity of the convulsions. Conversely, hippocampal levels of immunoreactive dynorphin A (1-8) and [Met]5-enkephalin were decreased as a function of seizure frequency and intensity. The time course of KA-induced alterations in prodynorphin and proenkephalin mRNA and peptide levels was also investigated. Hippocampal prodynorphin mRNA levels rose at a dramatic rate. At 3 h following KA administration, mRNA levels were maximally elevated approximately 13-fold. The levels decreased over a 48 h period, eventually reaching control values. In contrast, proenkephalin mRNA levels increased more slowly. At 24 h, a maximal 24-fold increase was observed. At 72 h after injection, proenkephalin mRNA levels were still slightly elevated. In the same experiment, immunoreactive enkephalin peptide levels, although somewhat decreased at 3-12 h, began to increase between 12 and 24 h after injection, and were still rising at 72 h. In marked contrast, immunoreactive dynorphin peptide levels ranged from 40% to 80% of control values at all times tested.(ABSTRACT TRUNCATED AT 250 WORDS)
Brain Res Mol Brain Res 1991 Jan
PMID:Systemic administration of kainic acid differentially regulates the levels of prodynorphin and proenkephalin mRNA and peptides in the rat hippocampus. 185 80

The regulatory effect of the perforant path on opioid gene expression in the entorhinal cortex-hippocampal region was investigated. The left perforant path was electrically stimulated at the angular bundle under conditions which elicit wet dog shakes but no motor seizures in rats. Animals were given either an acute stimulation composed of several consecutive stimulation trials, or daily stimulations with a single trial every day for 6 days. Rats were then sacrificed at 24 h or 6 days after the last trial. The amounts of prodynorphin mRNA (DYN mRNA) and proenkephalin A mRNA (EK mRNA) in the hippocampus and entorhinal cortex were measured by RNA blot analysis. Dynorphin A(1-8) and [Met5]enkephalin immunoreactivities were determined by radioimmunoassay. A decrease in DYN mRNA level of approximately 50-80% was found on both sides of the hippocampus 24 h after both acute and daily stimulation. Hippocampal dynorphin A(1-8) immunoreactivity was also reduced at 24 h, and persisted for at least 6 days. In contrast, bilateral increases in EK mRNA level were observed in the hippocampus (54-101%) and entorhinal cortex (97-165%) 24 h after the acute stimulation. Also, [Met5]enkephalin immunoreactivity in the hippocampus tended to be increased at this time. These results indicate that activation of the perforant path inhibits the gene expression of prodynorphin, but enhances that of proenkephalin in the entorhinal cortex-hippocampal region.
Brain Res Mol Brain Res 1990 Apr
PMID:Perforant path stimulation differentially alters prodynorphin mRNA and proenkephalin mRNA levels in the entorhinal cortex-hippocampal region. 197 Aug 44

We have cloned NGFI-C, a nerve growth factor-induced early-response gene which encodes a Cys2/His2 zinc finger protein. RNA blot analysis demonstrates that NGFI-C mRNA is induced within minutes of stimulation of PC12 cells by nerve growth factor and is similarly activated in brain after a Metrazol-induced seizure. The cDNA sequence predicts a protein that contains three zinc fingers which show striking homology to the DNA-binding regions of three previously reported zinc finger proteins, NGFI-A, Krox-20, and the Wilms' tumor gene product. NGFI-C binds to the previously described DNA-binding site of these three proteins, which is GCGGGGGCG. Cotransfection experiments revealed that NGFI-C strongly activates transcription from this site in mammalian cells. The isolation of another early-response gene that encodes a member of the G(C/G)G or GSG element-binding family should provide an opportunity to investigate the relative contributions of a family of transcription factors to the cell's response to changes in its environment.
Mol Cell Biol 1991 Aug
PMID:The early response gene NGFI-C encodes a zinc finger transcriptional activator and is a member of the GCGGGGGCG (GSG) element-binding protein family. 207 95

mRNA levels for the protooncogene c-fos, measured by Northern blot analysis, were greatly increased in brains of mice undergoing ethanol withdrawal seizures. This increase was transient (levels were increased at the time of the seizure and returned to normal by 24 hr or less after seizure) and was larger in hippocampus (40-fold) than in cerebral cortex (10-fold) or in cerebellum (6-fold). In mice that were fed ethanol chronically and withdrawn but that did not undergo overt withdrawal seizures, c-fos mRNA levels were not significantly increased. The findings with ethanol withdrawal seizures are similar in many respects to results of earlier studies with chemically induced seizures or kindling, which had led to the suggestion that c-fos expression may play a role in neuronal adaptation. The development of ethanol withdrawal seizures has been likened to kindling, and there is evidence indicating that ethanol withdrawal symptoms become more severe after repeated episodes of withdrawal. The present data support the hypothesis that this phenomenon may involve ethanol withdrawal seizure-induced increases in c-fos expression in various brain areas.
Mol Pharmacol 1990 Mar
PMID:Ethanol withdrawal seizures produce increased c-fos mRNA in mouse brain. 210 90

The convulsant and/or anticonvulsant activity of unsubstituted and mono-alkyl-substituted cyclopentanones and cyclohexanones were examined by testing the ability of these compounds to produce seizures or to inhibit seizures induced by pentylenetetrazol and maximal electroshock in CF-1 mice. In addition, these compounds were tested for their ability to bind to the picrotoxin receptor. The unsubstituted compounds, cyclopentanone and cyclohexanone, prevented both pentylnetetrazol- and maximal electroshock-induced seizures. Cyclopentanones and cyclohexanones with small (less than 3 carbon atoms) alkyl substituents in the 2-position were also anticonvulsant; all of these compounds, except 2-ethylcyclohexanone, blocked both pentylenetrazol- and maximal electroshock-induced seizures. 2-Ethylcyclohexanone was very effective against pentylenetetrazol seizures but did not prevent maximal electroshock seizures. Cyclohexanones with larger alkyl substituents in the 2-position, 2-propylcyclohexanone and 2-t-butylcyclohexanone, caused clonic seizures following injection into mice. Of the cyclopentanones and cyclohexanones with alkyl substitutions in the 3-position that were studied, one was an anticonvulsant (3-methylcyclopentanone), one was a mixed convulsant/anticonvulsant (3-ethylcyclohexanone), and the other two (3-ethylcyclopentanone and 3-t-butylcyclohexanone) were convulsants. Finally, two cyclohexanones with alkyl substituents in the 4-position were studied. Both 4-ethylcyclohexanone and 4-t-butylcyclohexanone produced convulsions when injected into mice. All the neuroactive cyclopentanones and cyclohexanones competitively displaced [35S]t-butylbicyclophosphorothionate, a ligand specific for the picrotoxin receptor, from rat brain membranes. The convulsant compounds were generally more potent than the anticonvulsants. The cyclohexanones were more potent than their corresponding cyclopentanones and the binding potency of both increased as the size of the alkyl substituent increased. These results suggest that cyclopentanone, cyclohexanone, and their alkyl-substituted derivatives act at the picrotoxin receptor to increase or decrease neuronal activity. Thus, they appear to have sites and mechanisms of action similar to those of the neuroactive gamma-butyrolactones and gamma-thiobutyrolactones.
Mol Pharmacol 1990 Jan
PMID:Convulsant and anticonvulsant cyclopentanones and cyclohexanones. 215 13


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