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)

Experiments were performed to examine the roles of gamma-aminobutyric acid(B) (GABA(B)) and gamma-hydroxybutyric acid (GHB) receptors in long-term potentiation (LTP) of the hippocampal CA1 region in vivo and in the genesis of the spike and wave discharges (SWDs) associated with absence seizures. When tetanic stimulation was delivered to the CA3 region, stable LTP was observed in the CA1 region in saline-treated mice. In mice treated with 5 mg/kg baclofen, the population spike amplitude was significantly potentiated by tetanic stimulation and the degree of potentiation was the same as that induced in saline controls. However, this potentiation decayed to the baseline level about 90 min after stimulation. The decay was reversed by pretreatment with 200 mg/kg P-[3-aminopropyl]-P-diethoxymethylphosphinic acid (CGP 35348), a selective GABA(B) receptor antagonist. In mice treated with 50 mg/kg gamma-butyrolactone (GBL), a prodrug of GHB, stable LTP was observed 90 min after tetanic stimulation and was greater than that in saline controls. GBL-induced potentiation of LTP was antagonized by 50 mg/kg NCS 382, a putative GHB receptor antagonist. Administration of baclofen (20 mg/kg) or GBL (70 mg/kg) induced absence-like seizures associated with 3-6 Hz SWDs, and CGP 35348 suppressed both baclofen- and GBL-induced SWDs. NCS 382 also attenuated SWDs induced by GBL and baclofen. These results suggest that baclofen and GHB have different effects on LTP in the CA1 region of the hippocampus in vivo, although they have a common mode of action on the thalamocortical functions related to the pathogenesis of absence seizures.
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PMID:Roles of gamma-aminobutyric acidB (GABA B) and gamma-hydroxybutyric acid receptors in hippocampal long-term potentiation and pathogenesis of absence seizures. 935 66

Although a wide variety of drugs are available for treatment of epilepsy, many patients with epilepsy still experience uncontrolled seizures. In addition, there is a need for new drugs that can halt epileptogenesis after brain injury. Mechanisms that underlie seizure processes constitute potential target areas for the development of new antiepileptic drugs (AEDs). An understanding of the underlying mechanisms of interictal spike discharge and seizure spread is critical for the development of AEDs for treatment of partial seizures. Suppression of specific forms of voltage-dependent calcium currents and inhibition of GABA(B) receptor-mediated inhibition are two key target areas for new AEDs to treat primary generalized seizures. As researchers gain more understanding of the cellular, molecular, and genetic mechanisms underlying seizure propagation, we should be better able to develop therapeutic agents designed to suppress seizure-provoking mechanisms and to enhance the brain's natural protective mechanisms.
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PMID:Basic mechanisms of epilepsy: targets for therapeutic intervention. 957 39

The characterized nuclear cyclic AMP responsive element (CRE)- and activator protein 1 (AP-1) DNA-binding activities in various brain regions of lethargic (lh/lh) mice, a genetic model of absence seizures. Gel-shift assays showed that nuclear CRE- and AP-1 DNA-binding activities in the thalamus and cerebral cortex, but not in other regions such as the hippocampus and cerebellum of lethargic mice were significantly higher than those of non-epileptic control mice. Furthermore, CRE- and AP-1 DNA-binding activities in lethargic mice, but not control mice, were inhibited by the specific GABA(B) receptor antagonist CGP 46831, at a dose which suppressed seizure behavior and spike and wave discharges. These results suggest that enhanced nuclear CRE- and AP-1 DNA-binding activities in the thalamocortical region are related to generation and/or propagation of absence seizures in lethargic mice.
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PMID:Characterization of absence seizure-dependent cyclic AMP responsive element-and activator protein 1 DNA-binding activities in lethargic (lh/lh) mice. 1007 71

Thalamocortical circuits are recognized as the main elements involved in the genesis of synchronized oscillations typical of certain generalized seizures. We addressed the capability of thalamic disinhibition to generate synchronized oscillations in neocortex. Microdialysis was used to infuse GABA(A) and GABA(B) receptor antagonists directly into the thalamus of anesthetized rats while recording cortical field potentials from 16 sites aligned perpendicular to the cortical surface, using 100 microm spaced linear array silicon probes. The results demonstrate that block of thalamic GABA(A) receptors induces continuous 3 Hz discharges in neocortex and that thalamic GABA(B) receptors mediate this activity. Also, during thalamic disinhibition sporadic long-lasting discharges at 12 Hz occur that do not depend on GABA(B) receptors. Current source density analysis of these activities revealed that the dynamics of sinks and sources for the 3 and 12 Hz discharges was quite distinct, in a way that suggests a different active involvement of the neocortex. The results indicate that intrathalamic inhibitory processes play an essential role in the generation of neocortical synchronized oscillatory activity that may be related to certain forms of generalized seizures.
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PMID:Neocortical synchronized oscillations induced by thalamic disinhibition in vivo. 1047 20

GABA(B) receptors are believed to be associated with the efferents of the nucleus reticularis thalami, which is implicated in the regulation of activity in the thalamocortical-corticothalamic circuit and plays a role in absence seizures. Yet, the distribution of GABA(B) receptors in the thalamus has only been studied in the rat, and there is no comparable information in primates. The potent GABA(B) receptor antagonist [3H]CGP 62349 was used to study the distribution and binding properties of the receptor in control monkeys and those with small ibotenic acid lesions in the anterodorsal segment of the nucleus reticularis thalami. Eight-micrometer-thick cryostat sections of the fresh frozen brains were incubated in the presence of varying concentrations of the ligand. Autoradiographs were analysed using a quantitative image analysis technique, and binding parameters were calculated for select thalamic nuclei as well as basal ganglia structures present in the same sections. The overall number of GABA(B) binding sites in the monkey thalamus and basal ganglia was several-fold higher than previously reported values for the rat. In the thalamus, the receptors were distributed rather uniformly and the binding densities and affinities were high (Bmax range of 245.5-437.9 fmol/ mg of tissue, Kd range of 0.136-0.604 nM). In the basal ganglia, the number of binding sites and the affinities were lower (Bmax range of 51.1-244.2 fmol/mg of tissue; K(d) range of 0.416-1.394 nM), and the differences between nuclei were more pronounced, with striatum and substantia nigra pars compacta displaying the highest binding densities. Seven days post-lesion, a 20-30% decrease in Bmax values (P < 0.05) was found in the nuclei receiving input from the lesioned nucleus reticularis thalami sector (the mediodorsal nucleus and densicellular and magnocellular parts of the ventral anterior nucleus) without changes in affinity. No significant changes were detected in any other structures. The results of the lesioning experiments suggest that a portion of thalamic GABA(B) receptors is in a presynaptic location on the nucleus reticularis thalami efferents. The overall distribution pattern in the thalamus also suggests a partial association of GABA(B) receptors with corticothalamic terminals presynaptically.
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PMID:Distribution and properties of GABA(B) antagonist [3H]CGP 62349 binding in the rhesus monkey thalamus and basal ganglia and the influence of lesions in the reticular thalamic nucleus. 1050 58

The present study examined synaptic potentials of neurons in inferior colliculus (IC) cortex slice and the roles of GABA and glutamate receptors in generating these potentials. Multipolar (82%) and elongated (18%) cells were observed with intracellular biocytin staining. Electrical stimulation of the IC commissure (CoIC) elicited only inhibitory postsynaptic potentials (IPSPs) (10% of cells), only excitatory postsynaptic potentials (EPSPs) (51%), or both (38%). IPSPs were elicited at lower thresholds and shorter latencies than EPSPs (mean: 1.6+/-1.2 ms) and IPSPs were observed in all neurons following membrane depolarization. Short-latency EPSPs were blocked by non-NMDA receptor antagonists, and longer-latency EPSPs were blocked by NMDA antagonists. CoIC stimulation evoked short-latency IPSPs (mean: 0.55+/-0.33 ms) in 48% of neurons, and the IPSPs persisted despite glutamate receptor blockade, which implies monosynaptic inhibitory input. A GABA(A) antagonist blocked IPSPs and paired pulse inhibition of EPSPs, suggesting GABA(A) receptor mediation. A GABA(B) antagonist reduced paired pulse inhibition of IPSPs, suggesting GABA(B) receptor modulation. Thus, GABA-mediated inhibition plays a critical role in shaping synaptic responses of IC cortex neurons. Normal GABAergic function in IC has been shown to be important in acoustic coding, and reduced efficacy of GABA function in IC neurons is critical in IC pathophysiology in presbycusis, tinnitus and audiogenic seizures.
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PMID:Synaptic response patterns of neurons in the cortex of rat inferior colliculus. 1054 30

Thalamocortical spike-and-wave discharges characterize the nonconvulsive absence seizures that occur spontaneously in genetic absence epilepsy rats from Strasbourg (GAERS), a selected strain of Wistar rats. GABA is crucial in the generation of absence seizures. The susceptibility to convulsions induced by threshold doses of various GABA receptor antagonists and inhibitors of GABA synthesis, kainic acid and strychnine, was compared in GAERS and in nonepileptic rats from a selected control strain (NE). The brain structures involved in the drug-elicited convulsive seizures were mapped by c-Fos immunohistochemistry. Injection of various antagonists of the GABA(A) receptor, bicuculline and picrotoxin, and inverse agonists of the benzodiazepine site (FG 7142 and DMCM) induced myoclonic spike-and-wave discharges followed by clonic or tonic-clonic seizures with high paroxysmal activity on the cortical EEG. The incidence of the convulsions was dose-dependent and was higher in GAERS than in NE rats. Mapping of c-Fos expression showed that the frontoparietal cortex was constantly involved in the convulsive seizures elicited by a threshold convulsant dose, whereas limbic participation was variable. In contrast, GAERS were less susceptible than NE rats to the tonic-clonic convulsions induced by the inhibitors of glutamate decarboxylase, isoniazide and 3-mercaptopropionic acid. The GABA(B) receptor antagonist CGP 56999 and kainic acid induced a similar incidence of seizures in GAERS and NE rats and predominantly activated the hippocampus. No difference in the tonic seizures elicited by strychnine could be evidenced between the strains. These results suggest that an abnormal cortical GABAergic activity may underlie absence seizures in GAERS.
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PMID:Selective susceptibility to inhibitors of GABA synthesis and antagonists of GABA(A) receptor in rats with genetic absence epilepsy. 1068 90

Gamma-hydroxybutyric acid (GHB) has the ability to induce absence seizures. The precise way in which GHB causes seizures remains unclear, but GABA(B)- and/or GHB-mediated presynaptic mechanisms within thalamocortical circuitry may play a role. In the present study, we determined the basal and K+-evoked release of GABA and glutamate in the superficial laminae of frontal cortex during GHB-induced absence seizures. Our data indicate that both the basal and K+-evoked release of GABA were significantly decreased in laminae I-III of frontal cortex at the onset of GHB-induced absence seizures. The appearance and disappearance of the observed changes in basal and K+-evoked extracellular levels of GABA correlated with the onset and offset of absence seizures. In contrast, neither the basal nor the K+-evoked release of glutamate was altered in superficial laminae of cerebral cortex at any time during the absence seizures. Intracortical perfusion of the GABA(B) receptor antagonists, CGP 35348 and phaclofen as well as the GHB receptor antagonist, NCS 382 attenuated GHB-mediated changes in the basal and K+-evoked release of GABA. These data suggest that GHB induces a selective decrease in the basal and depolarization-induced release of GABA in cerebral cortex, and further, that this action of GHB may play a role in the mechanism by which GHB induces absence seizures.
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PMID:Regulation of gamma-aminobutyric acid (GABA) release in cerebral cortex in the gamma-hydroxybutyric acid (GHB) model of absence seizures in rat. 1069 9

In this study we show that single, physiologically-active and non-convulsive doses of the three GABA(B) receptor antagonists CGP 36742, CGP 56433A and CGP 56999A increase NGF and BDNF mRNA levels by 200-400% and protein levels by 200-250% in rat neocortex, hippocampus as well as spinal cord. In all areas examined the increase in NGF protein preceded that of BDNF. Peak levels of both neurotrophins are transient and occur between 24 and 72 h, depending on the region. In contrast, NT-3 protein concentrations in the neocortex and hippocampus were decreased significantly to 50% of control values within 48-96 h. The decrease in the spinal cord was less than 30% and did not reach significant levels. These data clearly demonstrate that GABA(B) receptor antagonists induce a specific neurotrophin expression in the central nervous system at physiologically relevant doses, as opposed to the extreme conditions of seizure paradigms. The results are in line with the concept that neuronal neurotrophin synthesis and release in brain are controlled by afferent nerve activity. GABA(B) receptor antagonists could therefore be a valuable new approach to selectively increase endogenous neurotrophin levels in the central nervous system.
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PMID:GABA(B) receptor antagonists elevate both mRNA and protein levels of the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) but not neurotrophin-3 (NT-3) in brain and spinal cord of rats. 1069 11

Absence seizures (3-4 Hz) and sleep spindles (6-14 Hz) occur mostly during slow-wave sleep and have been hypothesized to involve the same corticothalamic network. However, the mechanism by which this network transforms from one form of activity to the other is not well understood. Here we examine this question using ferret lateral geniculate nucleus slices and stimulation of the corticothalamic tract. A feedback circuit, meant to mimic the cortical influence in vivo, was arranged such that thalamic burst firing resulted in stimulation of the corticothalamic tract. Stimuli were either single shocks to mimic normal action potential firing by cortical neurons or high-frequency bursts (six shocks at 200 Hz) to simulate increased cortical firing, such as during seizures. With one corticothalamic stimulus per thalamic burst, 6-10 Hz oscillations resembling spindle waves were generated. However, if the stimulation was a burst, the network immediately transformed into a 3-4 Hz paroxysmal oscillation. This transition was associated with a strong increase in the burst firing of GABAergic perigeniculate neurons. In addition, thalamocortical neurons showed a transition from fast (100-150 msec) IPSPs to slow ( approximately 300 msec) IPSPs. The GABA(B) receptor antagonist CGP 35348 blocked the slow IPSPs and converted the 3-4 Hz paroxysmal oscillations back to 6-10 Hz spindle waves. Conversely, the GABA(A) receptor antagonist picrotoxin blocked spindle frequency oscillations resulting in 3-4 Hz oscillations with either single or burst stimuli. We suggest that differential activation of thalamic GABA(A) and GABA(B) receptors in response to varying corticothalamic input patterns may be critical in setting the oscillation frequency of thalamocortical network interactions.
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PMID:Corticothalamic inputs control the pattern of activity generated in thalamocortical networks. 1086 72


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