Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Block of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate) and kainate currents by GYKI 52466 [1-(4-aminophenyl)-4-methyl-7,8- methylenedioxy-5H-2,3-benzodiazepine], a noncompetitive non-N-methyl-D-aspartate (AMPA/kainate) receptor antagonist, and two 3-N-substituted 3,4-reduced GYKI 52466 analogs was assessed in whole cell voltage-clamp recordings from cultured rat hippocampal neurons. In addition, the activity of the analogs was determined in the maximal electroshock seizure test and for protection against kainate-induced seizures in mice. The analogs of GYKI 52466 tested were the 3-N-methylcarbamyl [GYKI 53655; 1-(4-aminophenyl)-3-methylcarbamyl-4- methyl-3,4-dihydro-7,8-methylenedioxy-5H-2,3-benzodiazepine] and the 3-N-acetyl [GYKI 53405; 1-(4-aminophenyl)-3-acetyl-4-methyl-3,4-dihydro-7,8-methylenedioxy-5H-2, 3- benzodiazepine]. GYKI 53655 produced a concentration-dependent inhibition of AMPA- and kainate-induced currents with IC50 values of 1.1 and 1.5 microM, respectively; the corresponding values for GYKI 53405 were 3.8 and 5.0 microM. As blockers of AMPA currents, the analogs were 8- and 2.3-fold, respectively, more potent than the parent GYKI 52466. Kinetic analyses indicated increased association rates for the two 3-N-substituted analogs (2.5-2.6 x 10(5) M-1 sec-1) compared with GYKI 52466 (1.6 x 10(5) M-1 sec-1). The dissociation rates of GYKI 52466, GYKI 53405 and GYKI 53655 were inversely correlated with increasing blocking potency (2.9, 1.7 and 0.6 sec-1, respectively). Thus, the increased affinity of the 3-N-substituted analogs relates to their increased binding and decreased unbinding rates.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Non-N-methyl-D-aspartate receptor antagonism by 3-N-substituted 2,3-benzodiazepines: relationship to anticonvulsant activity. 752 24

Changes in gene expression after kindled seizures were examined using microdissection of discrete brain areas and Northern and slot blot analyses. Experimental animals were kindled with either of two protocols: (1) a paradigm in which 50 Hz/10 s stimulus trains were delivered every 30 min through hippocampal electrodes (12 stimulations every other day for 4 days) and (2) a traditional approach in which 50 Hz/10 s stimulus trains were given to the hippocampus three times daily for 16 days. Rats were sacrificed 24 h or 30 days after the last kindled seizure. We first examined the possibility that kindling may affect transcription of mRNA for neurotransmitter receptors. We found significant decreases (22-58%) in AMPA/kainate activated glutamate receptor mRNAs (GluR1, -2, -3 mRNAs) in hippocampus, amygdala/entorhinal cortex and in frontoparietal cortex 24 h but not 30 days after rapidly kindled seizures. However, changes in GABA receptor alpha 1, alpha 2, alpha 4 or beta 1 mRNAs were not observed in any brain region 30 days after traditional kindling or 24 h after rapidly kindled seizures. In addition, we tested whether changes in the expression of proenkephalin could be detected after kindling. We found significant increases (1.7-10 fold) in proenkephalin mRNA in the frontoparietal cortex, hippocampus and in the amygdala/entorhinal cortex 24 h but not 30 days after rapidly kindled seizures. Our findings suggest that changes in glutamate receptor and proenkephalin gene expression are robust, acute sequelae to kindled seizures and may be involved in kindling.
 ...
PMID:Changes in glutamate receptor and proenkephalin gene expression after kindled seizures. 752 14

The anticonvulsant activities of a noncompetitive (GYKI 52466) and a competitive (NBQX) AMPA/kainate antagonist were compared in the maximal electroshock (MES) seizure test and various chemoconvulsant models. Both antagonists were protective in the MES and pentylenetetrazol tests. GYKI 52466 was also protective against seizures and lethality induced by 4-aminopyridine, kainate and AMPA, but not by NMDA, whereas NBQX was ineffective in these chemoconvulsant tests. Both GYKI 52466 and NBQX produced motor impairment at doses similar to those that were protective in the MES test. Under some circumstances, noncompetitive AMPA/kainate antagonists could offer advantages over competitive antagonists in seizure therapy. However, neurological toxicity is an obstacle to the potential clinical use of both classes of agents.
 ...
PMID:Anticonvulsant activity of AMPA/kainate antagonists: comparison of GYKI 52466 and NBOX in maximal electroshock and chemoconvulsant seizure models. 769 50

To find general principles in the cellular mechanisms of epileptogenesis, one must analyze experimental epilepsy models and determine what exists in common between them. We consider here afterdischarges in hippocampal slices induced using either (1) GABAA blockade (e.g. with bicuculline), (2) a bathing solution lacking Mg2+ ions (low Mg-induced epilepsy), or (3) 4-aminopyridine (4AP). By 'afterdischarge' we mean an event that lasts hundreds of milliseconds or more, involving the synchronous firing of all the neurons in a population, shaped into a long initial burst and a series of one or more secondary bursts, and terminating in a prolonged afterhyperpolarization (AHP). We propose that the following features exists in common between these three experimental epilepsies: (1) recurrent excitatory synaptic connections; (2) sustained dendritic synaptic excitation, mediated by either AMPA or NMDA receptors, or both; (3) an intrinsic cellular response to sustained excitation, consisting of rhythmical dendritic bursts, primarily mediated by Ca spikes. In conclusion, if the picture outlined here proves correct, then the stereotypic appearance of epileptic afterdischarges--consisting of synchronized population bursts in series, whatever the network alteration leading to seizures--does indeed reflect a common set of mechanisms. The mechanisms cannot, apparently, be formulated in simple terms of this receptor or that receptor. Rather, we suggest, the recurrent excitatory synapses are able, under diverse circumstances, collectively to produce sustained dendritic conductances in neuronal populations. Pyramidal neurons, by virtue of their normal intrinsic membrane properties, respond to such sustained conductances with rhythmical bursts. The recurrent synapses, in a dual role, serve to maintain the synchrony of these bursts, and so shape the activity into a synchronized oscillation.
 ...
PMID:Are there unifying principles underlying the generation of epileptic afterdischarges in vitro? 780 Aug 28

Potential alterations in glutamate-utilizing excitatory circuits in resected human epileptogenic frontal and temporal neocortex were investigated by using immunocytochemical methods to visualize receptor subunits which comprise the AMPA/kainate (GluR2/3) and kainate (GluR5/6/7) receptor subtypes. Examination of the patterns of immunostaining in regions of neocortex that were identified as spiking and non-spiking based on intraoperative electrocorticography revealed dramatic, microzonal decreases in immunoreactivity for the receptor subunits examined. The patches of decreased immunostaining for GluR2/3 and for GluR5/6/7 were often coincident with respect to each other. However, such abnormal regions were not necessarily correlated with any particular electrocorticographically defined regions nor any overtly abnormal cytoarchitectural features in adjacent Nissl-stained sections. Moreover in many but not all cases, the focal regions of decreased receptor subunit immunoreactivity coincided with small patches of decreased parvalbumin immunoreactivity a calcium-binding protein which labels a subpopulation of powerful inhibitory GABAergic interneurons. These results indicate that in the human epileptogenic neocortex there may be alterations in particular excitatory and/or inhibitory synaptic systems at small, multiple neocortical foci, and that these alterations are found mostly in the same regions. We suggest that these alterations may contribute to the initiation and/or propagation of seizure activity.
 ...
PMID:Microzonal decreases in the immunostaining for non-NMDA ionotropic excitatory amino acid receptor subunits GluR 2/3 and GluR 5/6/7 in the human epileptogenic neocortex. 782 Jun 13

Intrahippocampal injection of the endogenous excitotoxin quinolinic acid (QUIN) induces seizures together with local, delayed neurodegeneration in specific cell layers. In situ hybridization histochemistry was used to study the spatio-temporal pattern of expression of neurotrophins (NTFs) after this treatment. As in other excitatory paradigms, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) mRNA levels increased dramatically and transiently in dentate gyrus after the administration of 120 nmol of QUIN to the left hippocampus. BDNF, but not NGF, mRNA also increased in the hippocampal pyramidal cell layer, mainly in the CA1 field. Neurotrophin-3 (NT3) mRNA levels decreased in dentate gyrus, practically disappeared around 12 h after the insult and returned to basal levels four days later. A very different pattern of expression of NTFs was found locally: (a) upregulation of NGF and BDNF mRNAs expression was prevented in a spherical region of 1-2 mm diameter around the injection site, (b) a delayed increase in NT3 mRNA levels, beginning at 12 h and lasting for at least 4 days after the administration of QUIN, was found in the same region, in cell layers showing neurodegeneration. Pretreatment with the non-competitive NMDA antagonist MK-801 (2 mg/kg, 30 min before the insult), partially blocked the increase in both BDNF and NGF mRNAs, as well as the decrease in NT3, in the contralateral hippocampus. However, this treatment did not prevent the QUIN-induced local downregulation of NGF and BDNF. Treatment with the AMPA/kainate antagonist NBQX (30 mg/kg, 15 and 5 min before, and 10 min after the insult) did not influence the effect of QUIN upon NGF or BDNF mRNA levels, although it partially prevented the hippocampal contralateral decrease in NT3 mRNA. In conclusion, the present study strongly supports previous work concerning different regulation of BDNF/NGF respect to NT3 in seizure inducing paradigms. Moreover, the different and to some extent opposite regulation of NTFs in the hippocampal region contiguous to the injection site, respect to the remaining hippocampus, suggests a differential regulation of NTFs in QUIN-induced neurodegenerative and seizural processes. Finally, our pharmacological data, (i) show that the upregulation of NGF and BDNF mRNAs, indirectly induced by QUIN, is not mediated by AMPA receptors, and (ii) suggest other effects for QUIN, apart from the stimulation of NMDA receptors.
 ...
PMID:Differential regulation of the expression of nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 mRNAs in adult rat brain after intrahippocampal injection of quinolinic acid. 785 71

The neurophysiological effects of 2 novel AMPA/kainate receptor antagonists, GYKI 52466 and LY 293558, on the high pressure neurological syndrome have been investigated in the rat and baboon (GYKI 52466) and rat (LY 293558). Rats were exposed to increasing ambient pressures of helium and oxygen at 3 ATA/min, on one occasion each. GYKI 52466 at 20 mumol/kg i.v. immediately before, followed by 70 mumol/kg/hr i.v. during compression delayed tremor by 85% and myoclonus by 30%, compared with control vehicle, and no side effects were observed. Seizure activity was not affected by any of the doses used. LY 293558 at 36 mumol/kg i.p. delayed tremor and myoclonus (44% and 12%), LY 293558 72 mumol/kg additionally delayed seizure activity (21%). Side effects, principally tranquilization at the higher dose, were also noted. Six baboons were exposed to a maximum pressure of 91 ATA at 0.3 ATA/min, in the same environment, on two occasions. One exposure was treated with an i.v. infusion of GYKI 52466 15.2 mumol/kg/hr, the other with the same volume of control vehicle. Limb and face tremor and myoclonus were delayed and the severity of signs reduced. No seizures were observed in the drug treated group before 91 ATA. EEG changes associated with exposure to pressure were not affected. It is concluded that antagonism at the AMPA/kainate receptor by GYKI 52466 and LY 293558 beneficially alters HPNS signs but in a manner which is dependent on both the drug and species being studied.
 ...
PMID:Protection from high pressure induced hyperexcitability by the AMPA/kainate receptor antagonists GYKI 52466 and LY 293558. 793 94

We tested the hypothesis that glutamate receptor antagonists increase the dose of lidocaine required to induce seizure activity. Sprague-Dawley rats were anesthetized with halothane in 40% O2/balance N2 and mechanically ventilated. After surgical preparation, halothane was discontinued. Normocapnia, normoxia, and normothermia were maintained. The electroencephalogram (EEG) and arterial blood pressure were monitored continuously. Rats were then randomized to one of six groups (control, one of three intravenous [i.v.] bolus doses of the competitive glutamate N-methyl-D-aspartate [NMDA] receptor antagonist CGS 19755, or one of two i.v. bolus and continuous infusion regimens of the competitive glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA] receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo-(F)quinoxalline [NBQX]). Thirty minutes after onset of CGS 19755 or NBQX administration (end-tidal halothane < 0.2%), rats received a continuous i.v. infusion of 1.5% lidocaine until EEG seizures occurred. The duration of the infusion (min) and total lidocaine dose (mg/kg) administered were recorded. CGS 19755 increased the lidocaine seizure threshold in a log-linear dose-dependent fashion (P < 10(-6)). The largest dose of CGS 19755 (112.5 mg/kg) increased the time to initial EEG seizure activity more than twofold (e.g., control = 12.6 +/- 2.6 min; CGS 19755 = 28.6 +/- 6.9 min). The effect of AMPA receptor antagonism was less obvious because treatment resulted in an EEG morphology dissimilar to that observed in the CGS 19755 or control groups. Our findings indicate that competitive NMDA receptor antagonists (e.g., CGS 19755) increase the dose of lidocaine required for seizures.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Glutamatergic antagonism: effects on lidocaine-induced seizures in the rat. 794 78

The expression level of the mRNAs encoding the Flip and Flop versions of the AMPA-selective glutamate receptor subunits A, B, C and D was studied using in situ hybridization in the hippocampus of rats kindled by Schaffer collateral/commissural fibre stimulation. The expression levels of the Flip variant of GluR-A, B and C mRNAs were bilaterally enhanced in the dentate granule neurons of fully kindled animals 24 h after the last seizure. These changes were already observed after the sixth kindling stimulation (preconvulsive-stage), but not after a single afterdischarge. Four weeks after the last seizure, when the animals were still hypersensitive to kindling stimulations, only GluR-A Flip expression was enhanced. These results suggest that kindling epileptogenesis is accompanied by an increased number and enhanced sensitivity of the expressed AMPA type glutamate receptors in the fascia dentata, leading to an enhanced excitatory synaptic transmission which may contribute to the process of kindling epileptogenesis.
 ...
PMID:Rat hippocampal kindling induces changes in the glutamate receptor mRNA expression patterns in dentate granule neurons. 795 92

We investigated the anticonvulsant and adverse effects of various dose combinations of the AMPA receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline) and the low-affinity, rapidly channel blocking NMDA receptor antagonist memantine in the kindling model of epilepsy. While memantine was ineffective when given alone, co-administration with NBQX markedly potentiated the increase in focal seizure threshold induced by NBQX alone. This synergistic (i.e. over-additive) interaction was seen at doses of both drugs which did not induce behavioural adverse effects. The data substantiate that combinations of AMPA and NMDA receptor antagonists provide a new strategy for the treatment of epileptic seizures.
 ...
PMID:Over-additive anticonvulsant effect of memantine and NBQX in kindled rats. 795 2


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>