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)

The involvement of GABA(B) receptors in the behavioural and epileptic electrocortical discharges occurring in chemical kindling induced by repeated treatments with a subconvulsant dose of pentylenetetrazole (25 mg/kg i.p.) has been investigated in CD1 mice. Behavioural and electrocorticographic epileptic seizures following kindling induced by pentylenetetrazole (25 mg/kg i.p.) were attenuated or completely antagonized in a dose-dependent manner by the GABA(B) receptor agonist R-baclofen (2 and 6 mg/kg) whilst the GABA(B) receptor antagonist 3-amino-propyl-diethoxy-methyl-phosphinic acid (CGP 35348, 25, 50 or 100 mg/kg) and 3-[1-(S)-(3, 4-dichloro-phenyl-ethyl]amino-2-(S)-hydroxy-propyl-benzyl-phosphinic acid (CGP 55845A, 10 or 20 mg/kg) produced a more rapid development of kindling and an increase in behavioural and electrocorticographic epileptic changes. In addition, all GABA(B) receptor antagonists were able to induce an increase in Fos and Jun protein expression in pentylenetetrazole (25 mg/kg i.p.) treated mice whilst the GABA(B) receptor agonist R-baclofen (2 or 6 mg/kg) attenuated the expression of Fos and Jun protein, at cortical and limbic structures. In order to study the persistence of changes induced by pentylenetetrazole kindling, different groups of mice were rechallenged with a kindling stimulus 15 or 30 days after withdrawal from the last injection of vehicle+pentylenetetrazole, R-baclofen+pentylenetetrazole or GABA(B) receptor antagonists+pentylenetetrazole. The groups receiving GABA(B) receptor antagonists+pentylenetetrazole showed a higher incidence of seizures following the kindling stimulus than mice receiving vehicle+pentylenetetrazole whilst animals treated with R-baclofen were protected from the kindling stimulus. The different effects observed following repeated treatment with the GABA(B) receptor agonist and antagonist used revealed that GABA(B) receptors are able to affect the development of the epileptic kindling state induced by pentylenetetrazole.
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PMID:Effects of compounds acting on GABA(B) receptors in the pentylenetetrazole kindling model of epilepsy in mice. 1096 58

Enhancement of GABAergic inhibition is central to the treatment of epilepsy. The role of the GABA(B) receptor, however, is poorly understood. The current study investigates the effects of r-baclofen (a GABA(B) receptor agonist) on spontaneous and evoked electrophysiological activity in the dentate gyrus of normal and epileptic rats in vivo. Administration of kainic acid (KA), which causes similar pathology to that seen in human temporal lobe epilepsy, was used to prepare chronically epileptic rats. Bursts of spontaneous high-amplitude field potentials (spiking) were observed in isoflurane-anaesthetised control and KA-treated rats in vivo; however, this activity was significantly more frequent in KA-treated rats (223+/-26.1 spikes min(-1)) than in control rats (124+/-17.4 spikes min(-1)). Feedback inhibition, measured using paired-pulsed stimulation, was also greater in KA-treated rats; 50% inhibition of the second response was observed at 43.05+/-4.46 ms in KA-treated animals, as opposed to 26.27+/-2.39 ms in control animals. r-Baclofen (10 mg kg(-1) i.v.) abolished spontaneous spiking and also reduced feedback inhibition in both control and KA-treated rats. These effects of r-baclofen may be due to inhibition of GABA release, through activation of pre-synaptic GABA(B) receptors on terminals of interneurones in the inhibitory feedback pathway. These results suggest a link between feedback inhibition and spontaneous spiking, and provide support for the hypothesis that mechanisms of synchronisation may give rise to seizure activity in human temporal lobe epilepsy.
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PMID:The effects of GABA(B) receptor activation on spontaneous and evoked activity in the dentate gyrus of kainic acid-treated rats. 1111 98

Receptor autoradiography with the high affinity antagonist radioligand [3H]CGP62349 and in situ hybridization with radiolabelled oligonucleotides were used to investigate GABA(B) receptor protein expression, and GABA(B(1)) mRNA splice variant (GABA(B(1a)) and GABA(B(1b)) levels, in brain sections from rats 4 h following a single electroshock-induced generalized seizure. Densitometric analysis indicated that GABA(B(1a)) mRNA levels were not significantly altered by an acute electroshock seizure, but that GABA(B(1b)) mRNA levels were significantly increased throughout the brain. GABA(B) receptor expression at this time point was unaffected by the seizure. The observed up-regulation of GABA(B(1b)) mRNA levels may imply increased importance of this splice variant in the regulation of further seizure activity.
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PMID:GABA(B(1)) splice variant mRNAs are differentially affected by electroshock induced seizure in rats. 1111 97

The contribution of GABAergic mechanisms in thalamic relay nuclei to spike and wave discharges (SWDs) during spontaneous seizures was assessed using the WAG/Rij strain of rats, an established genetic model of absence epilepsy, in combination with single-unit recordings and microiontophoretic techniques in the ventrobasal thalamic complex in vivo. Spontaneous SWDs occurring on the electroencephalogram at 5-9 Hz were associated with burst firing in thalamocortical neurons, which was phase-locked with the spike component. Microiontophoretic application of the GABA(A) receptor antagonist bicuculline significantly increased the magnitude of SWD-related firing in all tested cells. Application of the GABA(B) receptor antagonist CGP 55845A exerted a statistically insignificant modulatory effect on neuronal activity during spontaneous SWDs but significantly attenuated the bicuculline-evoked aggravation of SWD-related firing. The data indicate that, in thalamocortical neurons, (1) GABA(A) receptor-mediated events are recruited with each SWD, (2) SWD-related activity can be evoked with no significant contribution of GABA(B) receptors, and (3) blockade of GABA(A) receptors potentiates SWD-related activity, presumably through an indirect effect mediated through GABA(B) receptors. These results vote against a predominant or even exclusive contribution of GABA(B) receptors to spontaneous SWDs in thalamic relay nuclei in the WAG/Rij strain, but rather point to a critical role of GABA(A) receptor activation. This conclusion is in support of the view that the two subtypes of GABA receptors play a differential role in fast (5-10 Hz) and slow (3 Hz) spike-wave paroxysms observed during absence seizures.
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PMID:Contribution of GABA(A) and GABA(B) receptors to thalamic neuronal activity during spontaneous absence seizures in rats. 1116 Apr 9

Of three recently cloned T-type voltage-gated calcium channels, alpha(1g) is most likely responsible for burst firing in thalamic relay cells. These neurons burst during various thalamocortical oscillations including absence seizures. In this issue of Neuron, Kim et al. inactivated alpha(1g), and resultant mice were deficient in relay cell bursting and resistant to GABA(B) receptor-dependent absence seizures, suggesting roles for alpha(1g) and relay cell bursting in absences.
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PMID:It takes T to tango. 1149 49

T-type Ca(2+) currents have been proposed to be involved in the genesis of spike-and-wave discharges, a sign of absence seizures, but direct evidence in vivo to support this hypothesis has been lacking. To address this question, we generated a null mutation of the alpha(1G) subunit of T-type Ca(2+) channels. The thalamocortical relay neurons of the alpha(1G)-deficient mice lacked the burst mode firing of action potentials, whereas they showed the normal pattern of tonic mode firing. The alpha(1G)-deficient thalamus was specifically resistant to the generation of spike-and-wave discharges in response to GABA(B) receptor activation. Thus, the modulation of the intrinsic firing pattern mediated by alpha(1G) T-type Ca(2+) channels plays a critical role in the genesis of absence seizures in the thalamocortical pathway.
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PMID:Lack of the burst firing of thalamocortical relay neurons and resistance to absence seizures in mice lacking alpha(1G) T-type Ca(2+) channels. 1149 42

GABA(B) receptors play an important role in the excitability of neuronal networks and can influence seizure activity. Here we demonstrate for the first time that kindling, an animal model for human temporal lobe epilepsy, leads to both early and delayed changes of GABA(B) receptor immunoreactivity in hippocampal and cortical areas. We propose that the altered GABA(B) receptor levels might be a compensatory mechanism to reduce excitability induced by recurrent kindled seizures, or alternatively, may promote the development of kindled epilepsy.
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PMID:Changes in GABA(B) receptor immunoreactivity after recurrent seizures in rats. 1171 Dec 21

Childhood absence epilepsy (CAE) is an idiopathic generalised epilepsy (IGE) characterised by onset of typical absence seizures in otherwise normal children of school age. A genetic component to aetiology is well established but the mechanism of inheritance and the genes involved are unknown. Available evidence suggests that mutations in genes encoding GABA receptors or brain expressed voltage-dependent calcium channels (VDCCs) may underlie CAE. The aim of this work was to test this hypothesis by linkage analysis using microsatellite loci spanning theses genes in 33 nuclear families each with two or more individuals with CAE. Seventeen VDCC subunit genes, ten GABA(A)R subunit genes, two GABA(B) receptor genes and the ECA1 locus on 8q24 were investigated using 35 microsatellite loci. Assuming locus homogeneity, all loci gave statistically significant negative LOD scores, excluding these genes as major loci in the majority of these families. Positive HLOD scores assuming locus heterogeneity were observed for CACNG3 on chromosome 16p12-p13.1 and the GABRA5, GABRB3, GABRG3 cluster on chromosome 15q11-q13. Association studies are required to determine whether these loci are the site of susceptibility alleles in a subset of patients with CAE.
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PMID:Linkage analysis between childhood absence epilepsy and genes encoding GABAA and GABAB receptors, voltage-dependent calcium channels, and the ECA1 region on chromosome 8q. 1190 35

The present study investigated the effect of the GABA(B) receptor antagonist, SCH 50911 [(2S)(+)-5,5-dimethyl-2-morpholineacetic acid], on the occurrence of seizures in ethanol-dependent rats undergoing ethanol withdrawal syndrome. The acute administration of nonconvulsive doses of SCH 50911 (0, 100, 170 and 300 mg/kg, i.p.) resulted in a dramatic facilitation of spontaneous seizure occurrence. This finding, together with the reported ability of the GABA(B) receptor agonist, baclofen, to suppress seizures associated to ethanol withdrawal syndrome, suggests that the GABA(B) receptor may be part of the neural substrate underlying the hyperexcitability of ethanol withdrawal syndrome.
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PMID:Proconvulsive effect of the GABA(B) receptor antagonist, SCH 50911, in rats undergoing ethanol withdrawal syndrome. 1207 84

The study was designed to examine the effect of butorphanol, a classical opioid on convulsive behaviour using maximal electroshock (MES) test. An attempt was also made to investigate the role of possible receptor mechanisms involved. MES seizures were induced in mice via transauricular electrodes (60 mA, 0.2 s). Seizure severity was assessed by the duration of tonic hindlimb extensor phase and mortality due to convulsions. Intraperitoneal administration of butorphanol produced a dose-dependent (0.25-2 mg/kg) protection against hindlimb extensor phase. The anticonvulsant effect of butorphanol was antagonized by all the three opioid receptor antagonists (i.e., naloxone [mu], MR2266 [kappa], and naltrindole [delta], respectively). Coadministration of gamma-aminobutyric acid (GABA)-ergic drugs (diazepam, GABA, muscimol, and baclofen) and N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK801), with butorphanol augmented the anticonvulsant action of the latter drug. In contrast, flumazenil, a central benzodiazepine (BZD) receptor antagonist, reversed the facilitatory effect of diazepam on the anti-MES effect of butorphanol. Similarly, delta-aminovaleric acid (DAVA), a GABA(B) receptor antagonist, antagonized the facilitatory effect of baclofen, a GABA(B) agonist on anti-MES action of butorphanol. These BZD-GABAergic antagonists, flumazenil or DAVA, per se also counteracted the anti-MES effect of butorphanol given alone. These data exemplify the benefits of using the MES test, which is sensitive to opioidergic compounds and distinguished convulsive behavioural changes associated with GABAergic and NMDAergic effects. Taken together, the results implicate a role for multitude of neurotransmitter systems, i.e., opioid (mu, kappa, delta), NMDA channel, BZD-GABA(A) chloride channel complex, and GABA(B) receptors in the anti-MES action of butorphanol.
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PMID:Possible mechanism involved in the anticonvulsant action of butorphanol in mice. 1247 53


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