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)

DMCM (methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate) is a very potent convulsant with high affinity for specific benzodiazepine binding sites. A number of compounds were compared for their ability to prevent seizures induced by DMCM and pentylenetetrazol. DMCM seizures were antagonized by benzodiazepine (BZ) receptor antagonists, such as Ro 15-1788, CGS 8216 and several beta-carboline-3-carboxylates, which all fail to inhibit pentylenetetrazol seizures. The benzodiazepines diazepam, clonazepam and lorazepam as well as valproate, ethosuximid, phenobarbital, primidone, diphenylhydantoin and carbamazepine antagonized both DMCM and pentylenetetrazol. Muscimol and gamma-vinyl-GABA did not inhibit DMCM seizures whereas THIP showed a weak and selective effect against DMCM. Valproate showed a relatively potent (60 mg/kg i.p.) and competitive antagonism of short duration. Baclofen antagonized DMCM at 3 mg/kg. Valproate and baclofen were at least 5 times more potent against DMCM-induced than against pentylenetetrazol-induced seizures. DMCM most probably induces the seizures by selective impairment of the functions mediated by the GABA/BZ receptor-chloride channel complex (inverse agonism) and therefore differs from GABA receptor blockers.
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PMID:DMCM: a potent convulsive benzodiazepine receptor ligand. 631 96

We studied the binding of [35S]t-butylbicyclophosphorothionate to the GABAA receptor-mediated chloride channel in the CA1 area and fascia dentata of control and Schaffer collateral kindled rats, by means of semi-quantitative autoradiography. The [35S]t-butylbicyclophosphorothionate binding was determined at three stages during kindling acquisition: (i) after six afterdischarges, (ii) after 14 afterdischarges and (iii) after the induction of fully kindled seizures. Furthermore, the binding was studied at the long-term stage, 28 days after the last generalized tonic-clonic seizure [Racine R. J. (1972) Electroenceph. clin. Neurophysiol. 32, 281-294]. The binding was investigated at three [35S]t-butylbicyclophosphorothionate concentrations, 4, 47.5 (KD value) and 180 nM (Bmax value). A significant decrease in [35S]t-butylbicyclophosphorothionate binding in the CA1 area (-6 to -20%) and hilar formation (-17 to -37%), in one or more of the three [35S]t-butylbicyclophosphorothionate concentrations tested at the six and 14 afterdischarges and fully kindled stages was observed, but no significant changes at the long-term kindling stage were found. In contrast, the granular and molecular layers of the fascia dentata presented a significant increase in [35S]t-butylbicyclophosphorothionate binding (+15 to +38%) at the 14 afterdischarges, fully kindled and long-term kindled stages.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Autoradiographic analysis of [35S]t-butylbicyclophosphorothionate binding in kindled rat hippocampus shows different changes in CA1 area and fascia dentata. 764 19

We investigated the effects of 1-amino-5-bromouracil on the benzodiazepine-gamma-aminobutyric acid (GABA)A receptor complex to elucidate its central action. 1-Amino-5-bromouracil neither displaced nor enhanced [3H]muscimol, [35S]t-butylbicyclophosphorothionate (TBPS), or [3H]dehydroepiandrosterone sulfate binding to the rat brain synaptosomal membranes. The anesthesia induced by 1-amino-5-bromouracil was potentiated by diazepam, pentobarbital, and muscimol, and was antagonized by picrotoxin but not by bicuculline. 1-Amino-5-bromouracil protected mice from picrotoxin-induced seizure and slightly ameliorated TBPS-induced seizure, but did not antagonize bicuculline-induced seizure. Diazepam antagonized both the bicuculline- and the picrotoxin-induced seizure, and pentobarbital antagonized the picrotoxin- and the TBPS-induced seizure. Our in vivo studies suggest that part of the central action of 1-amino-5-bromouracil is concerned with the benzodiazepine-GABAA receptor complex including the chloride channel.
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PMID:Effects of 1-amino-5-bromouracil on the benzodiazepine-GABAA receptor complex. 769

Cellular volume and potassium contents were determined in rat astrocytes from primary culture following suspension in isoosmotic (269 mOsm) and hypoosmotic (136 mOsm) phosphate-buffered saline (PBS) containing various potassium concentrations. Within 1 min of suspension in hypoosmotic PBS, cells swelled to 135% of their volume in isoosmotic PBS. This initial swelling was not altered by varying the potassium concentration of the hypoosmotic PBS. After suspension in hypoosmotic PBS containing 3.2 mM potassium, a regulatory volume decrease (RVD) was observed. Higher concentrations of potassium in hypoosmotic PBS inhibited RVD following osmotic swelling. Cells swollen in hypoosmotic PBS containing 50 mM potassium continued to swell for 7 min, reaching a volume of 141% of their initial isoosmotic volume. After 7 min, these cells demonstrated a subsequent decrease in volume. The swelling observed between 1-7 min after suspension in hypoosmotic PBS containing 50 mM potassium was not affected by 10 microM gadolinium, 1 mM quinine, 1 mM DIDS (4,4'-diisothiocyanato-2,2'-stilbenedisulfonic acid), 1 mM SITS (4-acetamido-4'-isothiocyanato-2,2'-stilbenedisulfonic acid), 1 mM furosemide, or 100 microM bumetanide. Normal RVD was obtained in hypoosmotic PBS containing 50 mM potassium, if chloride was replaced with gluconate (but not nitrate) to reduce the extracellular K.Cl product to that of hypoosmotic PBS containing 3.2 mM potassium. The volume decrease seen between 7-30 min after exposure to hypoosmotic PBS containing 50 mM potassium was blocked by 1 mM DIDS, 1 mM SITS, or 1 mM furosemide. Cellular potassium content was elevated by approximately 60% after 7 min exposure to isoosmotic or hypoosmotic PBS containing 50 mM potassium. In hypoosmotic PBS, this increase in cellular potassium was reduced with replacement of chloride by gluconate, but not by nitrate. The results indicate that astrocytes swollen in PBS containing elevated potassium concentrations continue to swell, in part, by accumulation of potassium plus chloride mediated by an approach to Donnan equilibrium. Cotransport carriers or stretch-activated channels do not play a role in the enhanced swelling observed in hypoosmotic PBS containing 50 mM potassium. We suggest that a voltage-sensitive chloride channel mediates this continuation of cell swelling. This mechanism may be important in the persistent swelling of astrocytes observed in pathologic conditions such as trauma and seizures where extracellular potassium is elevated, or when other factors are present which may cause astroglial depolarization.
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PMID:Hypoosmotic volume regulation of astrocytes in elevated extracellular potassium. 774 27

The neurosteroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha, 5 alpha-THP) acts as a potent allosteric modulator and a direct activator of the GABA-chloride channel complex. This neurosteroid has also been found to protect against seizures that arise from blockade of the GABA-chloride channel complex. Because 3 alpha,5 alpha-THP protects against excitotoxin-induced seizure activity and because seizure activity has been found to be associated with aberrant hippocampal nerve cell growth, the rapid effect of the neurosteroid 3 alpha,5 alpha-THP upon nerve cell growth was investigated using videomicroscopy of hippocampal neurons in culture. Within 40 min of exposure 3 alpha,5 alpha-THP induced a significant decrease in the area and length of neurites. A concomitant decrement in the number and length of filopodia decorating neuritic extensions also occurred within the 40 min of 3 alpha,5 alpha-THP exposure. Both rapid and slow retrograde movement of intracellular organelles was observed in 3 alpha,5 alpha-THP-treated neurons. 3 alpha,5 alpha-THP-induced regression of neuritic extensions occurred only in nerve cells that had not yet established contact with other nerve or glial cells in culture. Established structural connections between neurons or glia did not erode during 3 alpha,5 alpha-THP exposure. Neither the inactive stereoisomer 3 beta-hydroxy-5 beta-pregnan-20-one nor progesterone had a significant effect upon any of the morphological parameters assessed. In approximately 25% of the cells in which 3 alpha,5 alpha-THP had induced regression, subsequent exposure to 17 beta-estradiol induced profuse filopodial growth within 60 sec of exposure. In cultures similar in age to those used in the morphological studies, 3 alpha,5 alpha-THP induced a significant increase in 36Cl- uptake within 10 sec. The magnitude of 36Cl- uptake was comparable to that induced by exposure to 100 microM GABA. In older, more mature cultures in which the nerve cells had established structural connections, 3 alpha,5 alpha-THP protected cells from picrotoxin-induced nerve cell death. These results demonstrate that 3 alpha,5 alpha-THP can induce regression of neuronal morphology within a relatively rapid time frame. 3 alpha,5 alpha-THP induction of 36Cl- uptake within 10 sec suggests that activation of neurosteroid-regulated chloride channels is an initial step in the biochemical mechanism underlying the retraction induced by this progesterone metabolite steroid. In select instances, 17 beta-estradiol induced an extremely rapid reversal of the filopodial regression produced by 3 alpha,5 alpha-THP.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The neurosteroid 3 alpha-hydroxy-5 alpha-pregnan-20-one induces cytoarchitectural regression in cultured fetal hippocampal neurons. 791 Feb 1

This autoradiographic study examines regional GABAA receptors in lidocaine-kindled rats. [35S]t-Butylbicyclophosphorothionate (TBPS), which binds in or near the chloride channel, was used to radiolabel GABAA complexes. Male Sprague-Dawley rats were injected daily with lidocaine (65mg/kg, i.p.). Seizure activity was evaluated using the Racine Scale (Racine, 1972). The animals displayed a gradual increase in the indices and by day 20 greater than 50% were in stage 4 or 5. Regression of behavior was seen in half of the experimental group and this subgroup was considered 'compensated'. Autoradiographs were analyzed using a computer-based image analysis system. Several regions within the kindled group display a decrease in TBPS binding, including the subiculum, posterior lateral thalamic nuclei, the lateral hippocampus CA1, and the lateral hippocampus CA3. Conversely, within the compensated group these regions display normal or heightened TBPS binding. The data support the theory that alterations in the GABAA receptors are involved in the kindling model of epilepsy.
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PMID:Alterations in t-butylbicyclophosphorothionate binding in the brains of lidocaine-kindled rats. 819 42

To further study the putative gamma-butyrolactone site of the GABAA/chloride channel complex, constrained derivatives of convulsant and anticonvulsant alpha,alpha-disubstituted gamma-butyrolactones (alpha-spirocyclopropyl- and alpha-spirocyclopentyl-gamma-butyrolactones) were synthesized and evaluated biologically. Most of the spirocyclopropyl agents were anticonvulsants when tested against pentylenetetrazole-induced seizures in mice. These agents effectively displaced 35[S]-tert-butylbicyclophosphorothionate (35[S]-TBPS), a ligand for the picrotoxin binding site of the GABAA/chloride channel, from rat neuronal membranes and affected the GABA-mediated current in hippocampal neurons. The monomethyl-substituted spirocyclopropyl agent with a methyl group cis to the carbonyl (15) potentiates GABA-induced current whereas the trans derivative (16) blocks the current. The only anticonvulsant in the spirocyclopentyl series was the unsubstituted spirocyclopentyl compound 2. All the other substituted spirocyclopentyl targets were inactive in vivo at the highest dose tested except for convulsant 9, which has a trans 2,5-dimethyl-substituted cyclopentyl ring. All the spirocyclopentyl derivatives displaced 35[S]-TBPS from rat neuronal membranes very effectively, and they also all potentiated GABA-induced chloride current except for convulsant 9 which blocked the current. From the data obtained in this investigation, it appears that when the volume occupied above and below the lactone ring is as large as that occupied by spirocyclopentyl agent 9, convulsant activity is observed. Groups with less volume in these areas either are inactive in the behavioral test or have anticonvulsant activity. When bound to the GABAA/chloride channel, the larger molecules may stabilize the closed state of the channel whereas the smaller molecules may stabilize the open state.
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PMID:Alpha-spirocyclopentyl- and alpha-spirocyclopropyl-gamma-butyrolactones: conformationally constrained derivatives of anticonvulsant and convulsant alpha,alpha-disubstituted gamma-butyrolactones. 829 15

Loreclezole is an anticonvulsant and anxiolytic compound which has been reported to potentiate GABA via a novel allosteric site on the beta-subunit of the receptor. We have now studied in rats both the in vivo and in vitro pharmacology of the compound. The dose of loreclezole required to increase by 50% the dose of intravenous pentylenetetrazol eliciting a seizure was comparable to that of barbiturates and chlormethiazole (in mg/kg): diazepam, 1.3; pentobarbitone, 16; chlormethiazole, 22; loreclezole, 25; pentobarbitone, 36. Loreclezole dose-dependently decreased locomotion (dose to decrease locomotion by 50% (in mg/kg): chlormethiazole, 9; pentobarbitone, 16; loreclezole, 25). Loreclezole, chlormethiazole and pentobarbitone all failed to displace [3H]muscimol and [3H]flunitrazepam binding from a rat cortical membrane preparation. All three compounds fully displaced [35S]TBPS binding (IC50 values: loreclezole, 4.34 +/- 0.68 microM; pentobarbitone, 37.39 +/- 3.24 microM; chlormethiazole, 82.10 +/- 8.52 microM). Addition of bicuculline (10 microM) produced a major rightward shift in the loreclezole and pentobarbitone displacement curves, increasing IC50 values for [35S]TBPS binding by 25 times (loreclezole), 6 times (pentobarbitone) and 2.7 times (chlormethiazole), suggesting a greater involvement of GABA in the interaction of loreclezole with the chloride channel than in the case of chlormethiazole. Anticonvulsant activity of the compounds did not appear to relate to [35S]TBPS binding activity. Other binding data suggested that although the evidence of others indicates that loreclezole interacts with a specific allosteric site on the beta-subunit, it nevertheless also alters the binding characteristics of other modulatory sites.
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PMID:A behavioural and neurochemical study in rats of the pharmacology of loreclezole, a novel allosteric modulator of the GABAA receptor. 901 39

Ganaxolone (CCD 1042) is a 3beta-methyl-substituted analog of the endogenous neuroactive steroid 3alpha-hydroxy-5alpha-pregnan-20-one. Ganaxolone inhibited binding of the gamma-aminobutyric acid (GABA)A receptor-chloride channel ligand t-[35S]butylbicyclophosphorothionate (IC50 of 80 nM) and enhanced binding of the benzodiazepine site ligand [3H]flunitrazepam (EC50 of 125 nM) and the GABA site ligand [3H]muscimol (EC50 of 86 nM), consistent with activity as a positive allosteric modulator of the GABA(A) receptor. Electrophysiological recordings showed that, whereas nanomolar concentrations of ganaxolone potentiated GABA-evoked chloride currents in Xenopus oocytes expressing the human GABA(A) receptor subunits alpha1beta1gamma2L, alpha2beta1gamma2L or alpha3beta1gamma2L, direct activation of chloride flux occurred to a limited extent only at micromolar concentrations. Ganaxolone was effective in nontoxic doses against clonic convulsions induced by s.c. pentylenetetrazol administration in mice and rats (ED50 values of 4.3 and 7.8 mg/kg i.p., respectively). Ganaxolone also exhibited potent anticonvulsant activity against seizures induced by s.c. bicuculline (ED50 of 4.6 mg/kg i.p.), i.p. TBPS (ED50 of 11.7 mg/kg i.p.) and i.p. aminophylline (ED50 of 11.5 mg/kg i.p.) in mice. Although ganaxolone effectively blocked tonic seizures induced by maximal electroshock in mice (ED50 of 29.7 mg/kg i.p.), it did so only at doses that produced ataxia on the Rotorod (TD50 of 33.4 mg/kg i.p.). Conversely, ganaxolone was a potent anticonvulsant against fully kindled stage 5 seizures induced by corneal kindling in rats (ED50 of 4.5 mg/kg i.p.), producing these effects at doses well below those that resulted in ataxia (TD50 of 14.2 mg/kg i.p.). The seizure threshold, as determined by an increase in the dose of i.v. infused pentylenetetrazol required to induce clonus, was also significantly elevated by nontoxic doses of ganaxolone in mice. In summary, these data indicate that ganaxolone is a high-affinity, stereoselective, positive allosteric modulator of the GABA(A) receptor complex that exhibits potent anticonvulsant activity across a range of animal procedures. The profile of anticonvulsant activity obtained for ganaxolone supports clinical evaluation of this drug as an antiepileptic therapy with potential utility in the treatment of generalized absence seizures as well as simple and complex partial seizures.
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PMID:Characterization of the anticonvulsant properties of ganaxolone (CCD 1042; 3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one), a selective, high-affinity, steroid modulator of the gamma-aminobutyric acid(A) receptor. 906 15

The GABA(A) receptor is a ligand gated chloride channel consisting of five membrane spanning proteins for which 13 different genes have been identified in the mammalian brain. The present review summarizes recent work from our laboratory on the characterization of the immunocytochemical distribution of these GABA(A) receptor subunits in the rat brain and changes in immunoreactivity and mRNA expression after kainic acid-induced status epilepticus. A heterogeneous distribution of immunoreactive GABA(A) receptor subunits was observed. The most abundant ones were: alpha1, alpha2, alpha4, alpha5, beta2, beta3, gamma2, and delta. Alpha1, beta2, and gamma2 were about equally distributed in all subfields of the hippocampus; alpha4- and delta-subunits were preferentially found in the dentate molecular layer and in CA1; alpha2 was localized to the dentate molecular layer and CA3; alpha5 was found in the dendritic areas of CA1 to CA3; and beta1 was preferentially seen in CA2. Alpha1, beta2, gamma2 and delta were highly concentrated in interneurons. Kainic acid-induced seizures caused acute and chronic changes in the expression of mRNAs and immunoreactive proteins. Acute changes included decreases in alpha2, alpha5, beta1, beta3, gamma2 and delta mRNA levels (by about 25-50%), accompanied by increases (by about 50%) in alpha1, alpha4, and beta2 messages in granule cells (after 6-12 h). Chronic changes, characterized by losses in mRNA and immunoreactive proteins in CA1 and CA3, are undoubtedly due to seizure-related cell damage. However, compensatory expression of alpha2 and beta3 subunits, especially in CA3b/c, was observed. Furthermore, increases in mRNAs and immunoreactive proteins were seen for alpha1, alpha2 alpha4, beta1, beta2, beta3 and gamma2 in granule cells and in the molecular layer of the dentate gyrus at 7-30 days after kainic acid injection. The changes in the expression of GABA(A) receptor subunits, observed in practically all hippocampal subfields, may reflect altered GABA-ergic transmission during development of the epileptic syndrome. Increased expression of GABA(A) receptor subunits in the dendritic field of granule cells and CA3 suggest that GABA-ergic inhibition may be augmented at these levels. However, the lasting preservation of alpha1-, beta2-, and gamma2-subunits in interneurons could provide a basis for augmented inhibition of GABA-ergic interneurons, leading to net disinhibition.
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PMID:Expression of GABA(A) receptor subunits in the hippocampus of the rat after kainic acid-induced seizures. 976 15


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