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)

Synaptosomal-associated protein of 25 kDa (SNAP-25) is thought to play a key role in vesicle exocytosis and in the control of transmitter release. However, the precise mechanisms of action as well as the regulation of SNAP-25 remain unclear. Here we show by immunoprecipitation that activation of protein kinase C (PKC) by phorbol esters results in an increase in SNAP-25 phosphorylation. In addition, immunochemical analysis of two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels shows that SNAP-25 focuses as three or four distinct spots in the expected range of molecular weight and isoelectric point. Changing the phosphorylation level of the protein by incubating the slices in the presence of either a PKC agonist (phorbol 12,13-dibutyrate) or antagonist (chelerythrine) modified the distribution of SNAP-25 among these spots. Phorbol 12,13-dibutyrate increased the intensity of the spots with higher molecular weight and lower isoelectric point, whereas chelerythrine produced the opposite effect. This effect was specific for regulators of PKC, as agonists of other kinases did not produce similar changes. Induction of long-term potentiation, a property involved in learning mechanisms, and production of seizures with a GABA(A) receptor antagonist also increased the intensity of the spots with higher molecular weight and lower isoelectric point. This effect was prevented by the PKC inhibitor chelerythrine. We conclude that SNAP-25 can be phosphorylated in situ by PKC in an activity-dependent manner.
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PMID:Activity-dependent phosphorylation of SNAP-25 in hippocampal organotypic cultures. 1009 80

1. Several derivatives and analogues of the general anaesthetic 2,6-diisopropylphenol (propofol) have been recently synthesised with the aim of exploring the structure-activity relationships. 2. In the present study, the effects of one such compound, 4-iodo-2,6-diisopropylphenol (4-I-Pro), on gamma-aminobutyric acid type A (GABA(A)) receptors in vitro were compared with its in vivo effects in rodents. Human GABA(A) receptors were expressed in Xenopus oocytes, and the actions of 4-I-Pro on receptor function were compared with those of propofol by two-electrode voltage-clamp recording. 3. Similar to propofol, 4-I-Pro directly activated Cl- currents in the absence of GABA at all combinations of receptor subunits tested. However, the efficacy of 4-I-Pro in inducing direct activation of alpha1beta2gamma2S receptors was markedly less than that of propofol. 4. Similarly to propofol, 4-I-Pro potentiated in a concentration-dependent manner GABA-evoked Cl- currents measured at different GABA(A) receptor constructs. 5. As expected, intraperitoneal injection of propofol induced sedation, ataxia, and loss of the righting reflex in rats. In contrast, administration of 4-I-Pro failed to produce any of these behavioural effects. 6. Administration of 4-I-Pro to rats reduced in a dose-dependent manner the incidence of tonic-clonic seizures induced by pentylenetetrazol and induced an anticonflict effect as measured in the Vogel test. 7. Microdialysis revealed that, like propofol, administration of 4-I-Pro reduced acetylcholine release in the hippocampus of freely moving rats. 8. These results demonstrate that para-substitution of the phenol ring of propofol with iodine yields a compound that exhibits anticonvulsant and anticonflict effects, but is devoid of sedative-hypnotic and anaesthetic properties. Thus, 4-I-Pro possesses pharmacological characteristics more similar to anxiolytic and anticonvulsant drugs than to general anaesthetics.
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PMID:Characterization of the electrophysiological and pharmacological effects of 4-iodo-2,6-diisopropylphenol, a propofol analogue devoid of sedative-anaesthetic properties. 1021 39

Clinical research into the etiology of ethanol withdrawal seizures has shown an increase in the number and severity of seizures with increasing numbers of withdrawal episodes. The aim of the present study was to determine the effects of multiple ethanol withdrawals on the seizure sensitivity to the GABA(A) receptor inverse agonist Ro15-4513. In this study, three groups of laboratory rats received varying amounts of either continuous or intermittent ethanol exposure. A fourth group (Naive) received no ethanol exposure. Eight hours following the last withdrawal from chronic ethanol exposure, animals were tested for sensitivity to Ro15-4513-induced motor convulsions. Seizure sensitivity was significantly increased in all ethanol-treated groups compared to ethanol-naive controls, which did not exhibit any convulsive responses to this dose of Ro15-4513. Furthermore, rats exposed to multiple ethanol withdrawals exhibited significantly higher sensitivity to drug-induced seizures than did animals experiencing only a single ethanol withdrawal. Although the specific mechanism of this enhanced convulsant effect of Ro15-4513 following multiple ethanol withdrawals remains to be determined, these results suggest an involvement of GABA(A)-benzodiazepine receptors in this multiple withdrawal phenomenon.
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PMID:Increased Ro15-4513-induced seizures following multiple ethanol withdrawals. 1034 May 28

Pregnenolone sulfate (PS) is an endogenous neurosteroid known to antagonize GABA(A) receptor-mediated inhibitory responses and potentiate NMDA receptor-mediated excitatory responses in vitro. To assess the actions of the steroid as a modulator of seizure susceptibility in vivo, PS (30-300 nmol) was administered intracerebroventricularly in mice. At doses of 50 to 150 nmol, PS elicited seizures characterized by head jerks, rearing and falling, severe forelimb and hindlimb clonus, opisthotonos and explosive running. The seizures increased in severity and frequency with time and eventually progressed to status epilepticus, tonic hindlimb extension and death. The doses producing convulsions in 50% (CD(50)) and 97% (CD(97)) of animals were 92 and 205 nmol, respectively. A subconvulsant dose of PS (50 nmol) significantly increased the convulsant potencies of systemically administered pentylenetetrazol (30-50 mg/kg) and NMDA (50-100 mg/kg). Systemically administered PS at doses as high as 100 mg/kg failed to induce seizures or alter the convulsant potencies of pentylenetetrazol and NMDA. Protection against PS (205 nmol)-induced seizures and lethality was conferred by the GABA(A) receptor positive allosteric modulators clonazepam and allopregnanolone, and by the NMDA receptor antagonists dizocilpine and (R)-CPP. The overall pharmacological profile suggests that the convulsant actions of PS are mediated predominantly via its effects on GABA(A) receptors, and also possibly by effects on NMDA receptors.
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PMID:Convulsant actions of the neurosteroid pregnenolone sulfate in mice. 1041 90

The purpose of this study was to investigate whether GABA(A) receptors in the dorsal striatum regulate basal or stimulant-induced behaviors. Correspondingly, the question of possible GABA(A) receptor control of neuropeptide mRNA expression in nigrostriatal neurons was addressed. The GABA(A) receptor antagonist, bicuculline, was unilaterally or bilaterally microinjected into the dorsal striatum of rats in a series of 3 studies. In the first study, unilateral administration of 10-50 ng/microliter of bicuculline did not alter behavior. However, 250 ng/microliter bicuculline produced motor dyskinesias and/or seizures. In the second study, 100 ng/microliter bicuculline administered unilaterally prior to saline or amphetamine treatment, produced mild twitching in 61% of rats but did not affect amphetamine (2.5 mg/kg, i.p.)-induced behavioral activity, specifically rearing and sniffing. In the third study, 75 ng/microliter of bicuculline was administered unilaterally or bilaterally into the striatum in two separate experiments. Administration of bicuculline either unilaterally or bilaterally produced mild transient twitching of the forelimbs but did not affect behaviors induced by the selective D(1) receptor agonist SKF-82958 (0.5 mg/kg, s.c.). Three hours after unilateral bicuculline administration, the brains were removed and processed for quantitative in situ hybridization. Bicuculline did not significantly affect the basal or SKF-82958-induced increase in preprodynorphin or substance P mRNA expression in striatonigral neurons on the side of injection. These data suggest that blockade of GABA(A) receptors in the dorsal striatum does not affect dopamine agonist-stimulated behaviors or neuropeptide mRNA expression in striatonigral neurons in the rat striatum.
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PMID:The role of dorsal striatal GABA(A) receptors in dopamine agonist-induced behavior and neuropeptide gene expression. 1041 9

The critical, fundamental mechanisms that determine the emergence of status epilepticus from a single seizure and the prolonged duration of status epilepticus are uncertain. However, several general concepts of the pathophysiology of status epilepticus have emerged: (a) the hippocampus is consistently activated during status epilepticus; (b) loss of GABA-mediated inhibitory synaptic transmission in the hippocampus is critical for emergence of status epilepticus; and, finally (c) glutamatergic excitatory synaptic transmission is important in sustaining status epilepticus. This review focuses on the alteration of GABAergic inhibition in the hippocampus that occurs during the prolonged seizures of status epilepticus. If reduction in GABAergic inhibition leads to development of status epilepticus, enhancement of GABAergic inhibition would be expected to interrupt status epilepticus. Benzodiazepines and barbiturates are both used in the treatment of status epilepticus and both drugs enhance GABA(A) receptor-mediated inhibition. However, patients often become refractory to benzodiazepines when seizures are prolonged, and barbiturates are often then used for these refractory cases of status epilepticus. Recent evidence suggests the presence of multiple GABA(A) receptor isoforms in the hippocampus with different sensitivity to benzodiazepines but similar sensitivity to barbiturates, thus explaining why the two drug classes might have different clinical effects. In addition, rapid functional plasticity of GABA(A) receptors has been demonstrated to occur during status epilepticus in rats. During status epilepticus, there was a substantial reduction of diazepam potency for termination of the seizures. The loss of sensitivity of the animals to diazepam during status epilepticus was accompanied by an alteration in the functional properties of hippocampal dentate granule cell GABA(A) receptors. Dentate granule cell GABA(A) receptor currents from rats undergoing status epilepticus had reduced sensitivity to diazepam and zinc but normal sensitivity to GABA and pentobarbital. Therefore, the prolonged seizures of status epilepticus rapidly altered the functional properties of hippocampal dentate granule cell GABA(A) receptors, possibly explaining why benzodiazepines and barbiturates may not be equally effective during treatment of the prolonged seizures of status epilepticus. A comprehensive understanding of the cellular and molecular events leading to the development, maintenance, and cytotoxicity of status epilepticus should permit development of more effective treatment strategies and reduction in the mortality and morbidity of status epilepticus.
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PMID:Acute cellular alterations in the hippocampus after status epilepticus. 1042 57

Status epilepticus (SE) is associated with both acute and permanent pathological sequellae. One common long term consequence of SE is the subsequent development of a chronic epileptic condition, with seizures frequently originating from and involving the limbic system. Following SE, many studies have demonstrated selective loss of neurons within the hilar region of the dentate gyrus, CA1 and CA3 pyramidal neurons. Selective loss of distinct subpopulations of interneurons throughout the hippocampus is also frequently evident, although interneurons as a whole are selectively spared relative to principal cells. Accompanying this loss of neurons are circuit rearrangements, the most widely studied being the sprouting of dentate granule cell (DGC) axons back onto the inner molecular layer of the dentate gyrus, termed mossy fiber sprouting. Less studied are the receptor properties of the surviving neurons within the epileptic hippocampus following SE. DGCs in epileptic animals exhibit marked alterations in the functional and pharmacological properties of gamma-aminobutyric acid (GABA) receptors. DGCs have a significantly elevated density of GABA(A) receptors in chronically epileptic animals. In addition, the pharmacological properties of GABA(A) receptors in post-SE epileptic animals are quite different compared to controls. In particular, GABA(A) receptors in DGCs from epileptic animals show an enhanced sensitivity to blockade by zinc, and a markedly altered sensitivity to modulation by benzodiazepines. These pharmacological differences may be due to a decreased expression of alpha1 subunits of the GABA(A) receptor relative to other alpha subunits in DGCs of post-SE epileptic animals. These GABA(A) receptor alterations precede the onset of spontaneous seizures in post-SE DGCs, and so are temporally positioned to contribute to the process of epileptogenesis in the limbic system. The presence of zinc sensitive GABA receptors combined with the presence of zinc-containing "sprouted" mossy fiber terminals innervating the proximal dendrites of DGCs in the post-SE epileptic hippocampus prompted the development of the hypothesis that repetitive activation of the DG in the epileptic brain could result in the release of zine. This zinc in turn may diffuse to and block "epileptic" zinc-sensitive GABA(A) receptors in DGCs, leading to a catastrophic failure of inhibition and concomitant enhanced seizure propensity in the post-SE epileptic limbic system.
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PMID:Chronic epileptogenic cellular alterations in the limbic system after status epilepticus. 1042 58

The present experiments compared the central BZ-omega binding characteristics and pharmacological profiles of two synthetic flavonoids (6-bromoflavone and 6-bromo-3'-nitroflavone) with those of the benzodiazepine (BZ) diazepam. In vitro experiments showed that while diazepam displaced [3H]flumazenil binding to the GABA(A) receptor in membranes from rat cerebellum and spinal cord, two brain areas enriched in the BZ-omega1 and BZ-omega2 receptor subtypes, with nearly equivalent half maximally effective concentrations, 6-bromo-3'-nitroflavone was somewhat more potent in displacing [3H]flumazenil binding to membranes from rat cerebellum (IC50 = 31 nM) than from spinal cord (IC50 = 120 nM), indicating selectivity for the BZ-omega1 receptor subtype. 6-Bromoflavone displayed weak (IC50 = 970 nM) affinity for the BZ-omega1 and no affinity for the BZ-omega2 (IC50 > 1000 nM) receptor subtypes. Diazepam, but not the synthetic flavonoids increased the latency to clonic seizures produced by isoniazid, thereby indicating that neither 6-bromoflavone nor 6-bromo-3'-nitroflavone display detectable intrinsic activity at GABA(A) receptors in vivo. Results from two conflict tests in rats showed that 6-bromoflavone (3-10 mg/kg) and 6-bromo-3'-nitroflavone (0.3-1 mg/kg) elicited anxiolytic-like activity in the punished drinking test, while both drugs were inactive in the punished lever pressing test. The positive effects displayed by the synthetic flavonoids in the punished drinking procedure were smaller than that of diazepam and were not antagonized by the BZ receptor antagonist flumazenil. In two models of exploratory activity, 6-bromoflavone (3-30 mg/kg) and 6-bromo-3'-nitroflavone (0.3-1 mg/kg) produced anxiolytic-like effects in the rat elevated plus-maze test, whereas both compounds failed to modify the behavior of mice in the light/dark test over a wide dose-range. The effects in the elevated plus-maze were antagonized by flumazenil. In the mouse defense test battery, where mice were confronted with a natural threat (a rat), 6-bromoflavone and 6-bromo-3'-nitroflavone failed to decrease flight reactions after the rat was introduced into the test area and risk assessment behavior displayed when subjects were constrained in a straight alley, and only weakly affected risk assessment of mice chased by the rat and defensive biting upon forced contact with the threat stimulus. In a drug discrimination experiment 6-bromoflavone and 6-bromo-3'-nitroflavone up to 30 and 3 mg/kg, respectively, did not substitute for the BZ chlordiazepoxide. Taken together, these results failed to demonstrate that the synthetic flavonoids 6-bromoflavone and 6-bromo-3'-nitroflavone possess anxiolytic-like properties similar or superior to that of diazepam, as was suggested previously. Furthermore, they question the contribution of BZ-omega receptors to the behavioral effects of 6-bromoflavone and 6-bromo-3'-nitroflavone.
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PMID:Pharmacological studies on synthetic flavonoids: comparison with diazepam. 1042 15

Picrotoxin, an antagonist of GABA(A) receptor-mediated activity, elicited 320- to 475-ms synchronized bursts from the CA3 region of the guinea pig hippocampal slice. The addition of the selective group I metabotropic glutamate receptor (mGluR) agonist (S)-3, 5-dihydroxyphenylglycine (DHPG, 50 microM; 20- to 45-min application) gradually increased the burst duration to 1-4 s; this effect persisted 2-3 h after agonist removal. To determine whether the induction of this long-lasting effect required ongoing synchronized activity during mGluR activation, DHPG application in a second set of experiments took place in the presence of CNQX and (R, S)-CPP, antagonists of AMPA/kainate and NMDA receptors, respectively. In these experiments, synchronized bursting was silenced during the mGluR agonist application, yet after wash out of the DHPG and the ionotropic glutamate receptor (iGluR) blockers, epileptiform discharges 1-10 s in duration appeared and persisted at least 2 h after wash out of the mGluR agonist. The potentiated bursts were reversibly shortened by application of 500-1,000 microM (+)-alpha-methyl-4-carboxyphenylglycine (MCPG) or (S)-4-carboxyphenylglycine (4CPG), agents with group I mGluR antagonist activity. These data suggest that transient activation of group I mGluRs, even during silencing of synchronized epileptiform activity, may have an epileptogenic effect, converting brief interictal-length discharges into persistent seizure-length events. The induction process is iGluR independent, and the maintenance is largely mediated by the action of endogenous glutamate on group I mGluRs, suggesting that autopotentiation of the group I mGluR-mediated response may underlie the epileptogenesis seen here.
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PMID:Group I mGluR-mediated silent induction of long-lasting epileptiform discharges. 1044 1

Functional modulation of gamma-aminobutyric acid(A) (GABA(A)) receptors by Zn(2+), pentobarbital, neuroactive steroid alphaxalone, and flunitrazepam was studied in the cerebral cortex and cerebellum of rats undergoing status epilepticus induced by pilocarpine. Under control conditions, Zn(2+) dose-dependently inhibited muscimol-stimulated uptake of (36)Cl(-) in cortical and cerebellar membranes. However, Zn(2+) inhibition of stimulated (36)Cl(-) uptake was selectively decreased in the cortex (but not in the cerebellum) 1 to 2 h after the onset of status epilepticus. This loss of Zn(2+) response in the cortex appeared to be selective to Zn(2+) only, because pentobarbital-, alphaxalone-, or flunitrazepam enhancement of muscimol-stimulated (36)Cl(-) uptake did not change in this brain region either at 1 or 2 h after seizures. Because this loss of Zn(2+) response in the cortex was apparent only about 1 h after the onset of status epilepticus but not earlier, we tested whether status epilepticus was critical for the development of the loss of Zn(2+) response. We found that, in rats where status epilepticus was terminated by diazepam within 30 min after seizure onset, Zn(2+) response was preserved in the cortex. These findings suggest that continuous seizures of pilocarpine-induced status epilepticus caused a rapid and selective decrease in Zn(2+) inhibition of GABA(A) receptor function in the cortex. The possible relevance of such rapid seizure-induced GABA(A) receptor plasticity in the cerebral cortex is discussed.
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PMID:Zinc inhibition of gamma-aminobutyric acid(A) receptor function is decreased in the cerebral cortex during pilocarpine-induced status epilepticus. 1049 Sep 25


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