Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Dextromethorphan (DM), a dextrorotatory nonopioid antitussive, binds to specific high-affinity sites in the central nervous system. These sites are distinct from the opioid and other known neurotransmitter receptor sites. Antitussives such as carbetapentane and caramiphen also bind to DM sites with a nanomolar affinity. 2. The anticonvulsant drugs phenytoin and ropizine produce an allosteric enhancement of the binding of [3H]DM to guinea pig brain. DM, carbetapentane, and caramiphen also are efficacious anticonvulsant agents in the rat maximal electroshock seizures test, and DM enhances the anticonvulsant effects of phenytoin (PHT). 3. These results suggest that drugs that bind to the DM sites could be used alone as anticonvulsants or in combination with PHT to lower its effective dose and reduce its side effects. 4. The investigation of the DM binding sites may help to open new approaches for the treatment of convulsive disorders and to explain further some of the molecular mechanisms of neutronal excitability.
Cell Mol Neurobiol 1988 Jun
PMID:Dextromethorphan binding sites in the guinea pig brain. 304 91

The effectiveness and side effects of a carbamazepine monotherapy were evaluated in 40 children and adolescents (22 boys and 18 girls with an age distribution between 1 and 16 years) over a period of 6 years. In addition the attempt has been made, to find correlations between sex, age of seizure onset, aetiology of the disease, types of seizures, and EEG-abnormalities on the one hand, and the clinical response to the drug on the other. Selection criteria were, that the patients were under continuous follow-up, that they suffered from partial or/and secondarily generalized seizures and that Tegretol was the first and only drug at the beginning of the examination. The treatment with the Carbamazepine-monotherapy was successful in 63% of the patients, 37% remained resistant to the treatment. Carbamazepine proved to be effective against partial seizures as well as secondarily generalized grand-mal-seizures. The therapeutic range of the serum carbamazepine levels during monotherapy varied between 15-35 mu Mol/l. 40 patients entered, 38 completed the study. In two cases the drug had to be stopped owing to allergic skin rash due to the drug. No other serious side effects were observed in any of the remaining 38 patients. The most frequent laboratory changes were an increase of Gamma-GT and leucopenia. All the cases who became seizure-free (Responder) were compared with the remaining cases with unfavourable treatment results (Nonresponder) in order to find out whether there are significant differences between the two groups, as far as sex, age ... etc. (see above) are concerned.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Carbamazepine (Tegretol) monotherapy in epilepsies with partial and/or secondary generalized seizures in childhood and adolescence]. 309 70

The inhibitory action of a number of clinically effective anticonvulsants on neurotoxin-activated sodium channels in cultured neuroblastoma cells and rat brain synaptosomes has been examined. Diphenylhydantoin (KI = 35 microM) and carbamazepine (KI = 41 microM) inhibited batrachotoxin-activated 22Na+ influx in N18 cells. Similarly, batrachotoxin-activated 22Na+ influx in rat brain synaptosomes was also inhibited by diphenylhydantoin (KI = 38 microM) and carbamazepine (KI = 22 microM). Comparison of KI values with mean brain levels of these drugs achieved during prevention of electroshock seizures indicates that diphenylhydantoin and carbamazepine occupy 35% and 50%, respectively, of their receptor sites associated with sodium channels at mean therapeutic concentrations. Diazepam (KI = 51 to 63 microM) and phenobarbital (KI = 1.2 to 1.3 mM) inhibited batrachotoxin-activated 22Na+ flux in N18 cells and synaptosomes at concentrations in excess of mean therapeutic central nervous system levels. Carbamazepine, like diphenylhydantoin, acts as a competitive inhibitor of sodium channel activation by the full agonist batrachotoxin, but produces mixed inhibition of veratridine-activated channels. This finding is consistent with the conclusion that both carbamazepine and diphenylhydantoin act as allosteric inhibitors of neurotoxin-activated sodium channels. The dose-response relationships for carbamazepine and diphenylhydantoin inhibition of 22Na+ flux in N18 cells are shifted 1.5-fold to higher concentrations when 22Na+ flux measurements are made in the presence of physiological concentrations of sodium and calcium ions. These results suggest that anticonvulsant inhibition of neurotoxin-activated 22Na+ flux in our standard ion flux media, containing low concentrations of Na+ and no Ca2+, is likely to reflect an effect of these agents expected in vivo. The results of this study provide further evidence to support the hypothesis that diphenylhydantoin and carbamazepine, both of which possess similar therapeutic profiles in the treatment of grand mal and partial seizures, may exert their pharmacological effects by occupancy of receptor sites associated with the activation of voltage-sensitive sodium channels in the central nervous system.
Mol Pharmacol 1984 Mar
PMID:Inhibition of voltage-sensitive sodium channels in neuroblastoma cells and synaptosomes by the anticonvulsant drugs diphenylhydantoin and carbamazepine. 632 45

The cell membrane-disordering potencies of sodium valproate, the sodium salts of other short-chain fatty acids, and ethanol were compared using fluorescence polarization with the probe 1,6-diphenyl-1,3,5-hexatriene. Valproate was about 7 times more potent in fluidizing synaptosomal plasma membranes than ethanol, a prototypic disordering agent. The disordering potency of the straight-chain fatty acids pentanoate through octanoate increased by a factor of 2.2 with each additional methylene group. The sedative potencies of the drugs were assessed by determining the brain concentration at which Swiss Webster mice lost the ability to balance on a stationary wooden dowel. Relative anticonvulsant potency was measured by determining the ED50 for protection against pentylenetetrazol-induced seizures and then determining the brain levels of drug that were actually achieved at the time of seizure protection. The ability of the fatty acids and ethanol to disorder membranes in vitro correlated closely with their ability to cause sedation and protect mice against pentylenetetrazol-induced seizures. These data suggest that valproic acid might exert some of its effects by disordering brain cell membranes--the proposed mechanism of action of ethanol and the general anesthetics.
Mol Pharmacol 1984 Jul
PMID:Membrane-disordering potency and anticonvulsant action of valproic acid and other short-chain fatty acids. 643 Dec 62

Derivatives of gamma-butyrolactone (GBL) substituted on the alpha- and/or gamma-positions were synthesized and tested for their effects on behavior in mice, on the electroencephalographs and blood pressure of paralyzed-ventilated guinea pigs, and on electrical activity of incubated hippocampal slices. Several compounds, including alpha-ethyl-alpha-methyl GBL (alpha-EMGBL), alpha, alpha-dimethyl GBL, alpha, gamma-diethyl-alpha, gamma-dimethyl GBL, and gamma-ethyl-gamma-methyl GBL, prevented seizures induced by pentylenetetrazol, beta-ethyl-beta-methyl-gamma-butyrolactone (beta-EMGBL), picrotoxin, or all three compounds in mice and guinea pigs but had no effect on seizures induced by maximal electroshock or bicuculline. Neither gamma-hydroxybutyrate (GHB) nor alpha-isopropylidine GBL had any anticonvulsant activity. The anticonvulsant alpha-substituted compounds had a potent hypotensive effect and antagonized the hypertensive effect of beta-EMGBL, alpha-EMGBL was tested in incubated hippocampal slices and was found to depress basal activity and antagonize excitation induced by beta-EMGBL. These results demonstrate that alpha-alkyl-substituted GBL and, to a lesser extent, gamma-substituted derivatives are anticonvulsant agents and that their effects are strikingly different from those of GHB or beta-alkyl-substituted GBLs, which are epileptogenic. Possibly beta- and alpha-substituted GBLs act at the same site as agonists and antagonists, respectively.
Mol Pharmacol 1982 Sep
PMID:Anticonvulsant properties of alpha, gamma, and alpha, gamma-substituted gamma-butyrolactones. 714 36

Stargazer mutant mice inherit a recessive neuronal excitability phenotype featuring frequent non-convulsive spike-wave seizures that arise from synchronous bursting in neocortical, thalamic and hippocampal networks. Immunocytochemistry reveals that granule cells in the mutant dentate gyrus aberrantly express neuropeptide Y (NPY) at multiple ages following the developmental onset of seizures. The ectopic NPY is selectively concentrated in the mossy fibers, co-localizing with the releasable dense core vesicle pool. The NPY content of native NPY+local circuit neurons is also elevated in the mutant CNS. There is no concurrent elevation of hippocampal 72 kDa heat shock protein (HSP72), glial fibrillary acidic protein (GFAP) or NADPH-diaphorase, three markers that are induced during cellular injury, and no evidence of granule cell loss. Since mossy fiber NPY expression appears after the developmental onset of spike-wave discharges and can be induced in wild type granule cells by electrical stimulation, the altered peptide phenotype is likely to reflect transynaptic gene induction triggered by synchronous bursting. These results link a specific pattern of repetitive synaptic input with selective molecular plasticity in dentate granule cells that may contribute to dynamic modifications in hippocampal network excitability.
Brain Res Mol Brain Res 1995 Jul
PMID:Aberrant expression of neuropeptide Y in hippocampal mossy fibers in the absence of local cell injury following the onset of spike-wave synchronization. 747 19

To investigate the molecular changes underlying kindling epileptogenesis in the rat hippocampus, the expression levels of the genes encoding for 13 different gamma-aminobutyric acid type-A receptor (GABAAR) subunits were measured in hippocampal principal neurons using in situ hybridization techniques and semi-quantitative analysis of the autoradiograms. Schaffer collateral-commissural pathway kindled rats were investigated at three different stages of kindling acquisition, at 24 h after the last seizure and at long-term (28 days) after termination of kindling stimulations. Changes were distinct for the different subunits in the three analyzed regions (CA1, CA3, fascia dentata) and also different for the various kindling stages. In all hippocampal areas at the early phases of kindling epileptogenesis, before the appearance of generalized seizures, an increase was found of those transcripts that constituted the majority of the expressed variants in control animals (alpha 1, alpha 2, alpha 4, beta 1, beta 2, beta 3, gamma 2/gamma 2L mRNA). In these stages, the increased levels of different variants in the granular neurons of the fascia dentata were more pronounced when compared to the pattern of changes in pyramidal cells of CA1 and CA3. In fully kindled animals, the expression levels of several subunits returned to control levels, whereas beta 3 and gamma 2/gamma 2L mRNA expression was still significantly enhanced in all areas. At long-term, few changes were encountered. The long-splice variant of gamma 2 was decreased within pyramidal and granular neurons while the total level of gamma 2 mRNA was not different from controls. The increased GABAAR subunit expression in the fascia dentata may underly the reported increased GABAAR ligand binding and the increased GABA mediated inhibition. However, the decreased GABAAR binding and the attenuation of GABAergic inhibition in CA1, could not be explained by a decrement of receptor subunit expression.
Brain Res Mol Brain Res 1995 Jul
PMID:Expression of GABAA receptor subunit mRNAs in hippocampal pyramidal and granular neurons in the kindling model of epileptogenesis: an in situ hybridization study. 747 32

Previous work has shown that c-Fos and several Fos-like proteins or Fras (Fos-related antigens) are induced acutely in brain in response to a wide variety of stimuli. In contrast, several stimuli induce apparently distinct Fos-like proteins, termed chronic Fras, after chronic administration. We show that delta FosB, a truncated splice variant of FosB, responds like the other acute Fras: it is induced rapidly and transiently in cerebral cortex after acute electroconvulsive seizure (ECS) and in striatum after acute cocaine but does not accumulate after chronic ECS or cocaine treatment. Although the chronic Fras are immunochemically related to delta FosB, they can be distinguished from delta FosB based on their temporal properties in that they are induced after chronic ECS and cocaine treatments only. Moreover, the chronic Fras and delta FosB can be distinguished by their migration patterns on one- and two-dimensional gel electrophoresis. The chronic Fras, therefore, appear to be novel FosB-related proteins. We also provide evidence that the chronic Fras heterodimerize primarily with Jun-D and Jun-B, as opposed to c-Jun. The possibility that AP-1 complexes containing the chronic Fras function as negative regulators of AP-1 mediated transcription is discussed.
Mol Pharmacol 1995 Nov
PMID:Regulation of delta FosB and FosB-like proteins by electroconvulsive seizure and cocaine treatments. 747 19

Calcium/calmodulin-dependent protein kinase type II (CamKII) is a ubiquitous brain enzyme implicated in a wide variety of neuronal processes. Understanding CamKII has become increasingly complicated with the recent identification of multiple gene transcripts coding for separate subunits. Previous studies have shown that mRNA for the alpha subunit of CamKII can be increased by reduction of afferent input. In this study we have examined the regulation of alpha CamKII mRNA following increased activity due to seizures. Using in situ hybridization with a cRNA probe against the rat alpha CamKII sequence we found reduced levels of hybridization following limbic seizures induced by lesions of the hilus of the dentate gyrus. Hybridization was most dramatically reduced in the granule cells of the dentate gyrus and the pyramidal cells of hippocampal region CA1. There were also significant reductions in hybridization in the superficial layers of neocortex and piriform cortex. In each of these region hybridization was decreased in the molecular layers which is consistent with the reported dendritic localization of alpha CamKII mRNA. All changes in mRNA content were transient, with maximal reductions at 24 h following lesion placement and a return to control levels by 96 h. These findings demonstrate the negative regulation of alpha CamKII mRNA by seizure activity and raise the possibility that synthesis of this kinase may be regulated by normal physiological activity.
Brain Res Mol Brain Res 1995 Sep
PMID:Decreased expression of the alpha subunit of Ca2+/ calmodulin-dependent protein kinase type II mRNA in the adult rat CNS following recurrent limbic seizures. 750 Aug 33

We have shown previously that the neurosteroid pregnenolone sulfate acts as a positive allosteric modulator at the N-methyl-D-aspartate (NMDA) receptor while inhibiting the kainate, the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), the glycine, and the gamma-aminobutyric acid (GABA) responses of chick spinal cord neurons. Here, we report that 3 alpha-hydroxy-5 beta-pregnan-20-one sulfate (5 beta 3 alpha S), a sulfated form of naturally occurring 5 beta 3 alpha, inhibits both the NMDA and the non-NMDA receptor-mediated responses as measured by whole cell voltage clamp recordings. 100 microM 5 beta 3 alpha S rapidly and reversibly inhibits the response to 30 microM NMDA by 66%, 50 microM kainate by 37%, and 25 microM AMPA by 29%. Application of 50 microM nonsulfated 5 beta 3 alpha does not produce any significant effect on the NMDA response, demonstrating that the sulfate moiety is important for the effect of 5 beta 3 alpha S on the NMDA response. The effect of 5 beta 3 alpha S on the NMDA response is concentration dependent, with an EC50 of 62 microM. 5 beta 3 alpha S reduces the maximum NMDA response with little effect on the NMDA EC50, indicating that antagonism of the NMDA response by 5 beta 3 alpha S is noncompetitive. The fact that 5 beta 3 alpha S inhibition of the NMDA response is neither agonist nor voltage dependent demonstrates that 5 beta 3 alpha S does not act as an open channel blocker. Furthermore, inhibition of the NMDA response by 5 beta 3 alpha S is not reduced by the addition of a maximal concentration (10 microM) of glycine, indicating that 5 beta 3 alpha S does not act via the glycine recognition site. The inhibitory action of 5 beta 3 alpha S on the NMDA and non-NMDA receptors may provide a basis for inhibiting glutamate receptor-induced seizures and excitotoxic cell death.
Mol Pharmacol 1994 Jul
PMID:3 alpha-Hydroxy-5 beta-pregnan-20-one sulfate: a negative modulator of the NMDA-induced current in cultured neurons. 752 Jan 24


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