UMLS:C0036572 - FACTA Search

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Query: UMLS:C0036572 (seizures)
80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Repeated brief seizures evoked by kindling progressively increase seizure susceptibility and eventually induce spontaneous seizures. Previous studies have demonstrated that the initial seizures evoked by kindling increase paired-pulse inhibition at 15-25 msec interpulse intervals in the dentate gyrus and also induce apoptosis, progressive neuronal loss, mossy fiber sprouting, and neurogenesis, which could potentially alter the balance of excitation and/or inhibition and modify functional properties of hippocampal circuits. In these experiments, paired-pulse inhibition in the dentate gyrus was reduced or lost after approximately 90-100 evoked seizures in association with emergence of spontaneous seizures. Evoked IPSCs examined by single electrode voltage-clamp methods in granule cells from kindled rats experiencing spontaneous seizures demonstrated altered kinetics (reductions of approximately 48% in 10-90% decay time, approximately 40% in tau, and approximately 65% in charge transfer) and confirmed that decreased inhibition contributed to the reduced paired-pulse inhibition. The loss of inhibition was accompanied by loss of subclasses of inhibitory interneurons labeled by cholecystokinin and the neuronal GABA transporter GAT-1, which project axo-somatic and axo-axonic GABAergic inhibitory terminals to granule cells and axon initial segments. Seizure-induced loss of interneurons providing axo-somatic and axo-axonic inhibition may regulate spike output to pyramidal neurons in CA3 and could play an important role in generation of spontaneous seizures. The sequence of progressive cellular alterations induced by repeated seizures, particularly loss of GABAergic interneurons providing axo-somatic and axo-axonic inhibition, may be important in the development of intractable epilepsy.
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PMID:Spontaneous seizures and loss of axo-axonic and axo-somatic inhibition induced by repeated brief seizures in kindled rats. 1268 62

The genetically epileptic mouse strain (El) is used as a model for human temporal lobe epilepsy. To address the question of whether altered function of the neuronal GABA transporter GAT1 is involved in the pathology of epilepsy of El mice, we expressed in Xenopus oocytes cloned GAT1 of mouse brain by injection of complementary ribonucleic acid (cRNA) and co-injected messenger ribonucleic acid (mRNA) isolated from the hippocampus of non-epileptic control mother strain (ddY) mice and from El mice. GABA transporter activity was investigated by measurements of [(3)H]-GABA uptake as well as by steady-state and transient current measurements under voltage clamp.Co-injection of hippocampal mRNA into oocytes reduced GAT1-mediated transport. This effect was more pronounced for mRNA from ddY mice than for that from El mice that never experienced seizures, El(-), and being absent for mRNA from El mice that have had high seizure experience, El(+). The pronounced inhibition of GABA transport after injection of mRNA from the ddY strain results from reduced expression of functional GAT1, but to about one third also from a reduced GABA translocation rate. The reduced translocation can be attributed to a reduced forward rate of a step associated with extracellular Na(+) binding. If the results can be applied to the mouse brain, we may hypothesise that in ddY mice some GAT down-regulating factor translated from hippocampal mRNA may be involved to keep GAT1 activity low, and hence GABA concentration in synaptic cleft high. In El(-) mice such regulatory mechanism may be reduced or counteracted by another unknown factor present in El(-) brain. The repeated seizure experience in El(+) mice enhances this compensatory effect.
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PMID:Down-regulation of GABA-transporter function by hippocampal translation products: its possible role in epilepsy. 1269 73

In the last decade, nine new antiepileptic drugs have reached the global marketplace. These new agents can be categorised according to their principal mechanisms of action. Vigabatrin and tiagabine are the only new compounds with selective effects on inhibitory neurotransmission. The principal inhibitory neurotransmitter in mammalian brain is gamma-aminobutyric acid (GABA). Both vigabatrin and tiagabine exert their pharmacological effects by reducing the inactivation of GABA. Vigabatrin attenuates the metabolism of GABA by inhibiting the enzyme GABA-transaminase, whereas tiagabine blocks the uptake of GABA from the synaptic cleft by an action on the GAT-1 transporter. These mechanistic differences are borne out in a range of experimental seizure models in which vigabatrin and tiagabine have very different anticonvulsant profiles. Pre-clinical neurotoxicity and pharmacokinetic profiles also differ. Long-term vigabatrin treatment is associated with intramyelinic oedema in white matter tracts of several brain regions and further studies have revealed an accumulation of vigabatrin in the retina. In contrast, it seems that tiagabine does not precipitate any significant neurotoxicity and does not appear to accumulate in the retina. The results of these pre-clinical investigations suggest that vigabatrin and tiagabine are pharmacologically distinct compounds with different anticonvulsant, neurotoxicity and pharmacokinetic profiles. It is possible that they will ultimately prove to have different clinical efficacies and spectra of activity.
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PMID:Pre-clinical studies with the GABAergic compounds vigabatrin and tiagabine. 1277 97

Epileptiform discharges and behavioral seizures may be the consequences of excess excitation associated with the neurotransmitter glutamate, or from inadequate inhibitory effects associated with gamma-aminobutyric acid (GABA). Synaptic effects of these neurotransmitters are terminated by the action of transporter proteins that remove amino acids from the synaptic cleft. Excitation initiated by the synaptic release of glutamate is attenuated by the action of glial transporters glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1), and the neuronal transporter excitatory amino-acid carrier-1 (EAAC-1). GABA is removed from synaptic regions by the action of the transporters proteins GABA transporter-1 (GAT-1) and GABA transporter-3 (GAT-3). In this experiment, albino rats with chronic, spontaneous recurrent seizures induced by the amygdalar injection of FeCl3 were treated for 14 days with zonisamide (ZNS) (40 mg/kg, i.p.). Control animals underwent saline injection into the same amygdalar regions. Treatment control for both groups of intracerebrally injected animals was i.p. injection of equal volumes of saline. Western blotting was used to measure the quantity of glutamate and GABA transporters in hippocampus and frontal cortex. ZNS caused increase in the quantity of EAAC-1 protein in hippocampus and cortex and down regulation of the GABA transporter GAT-1. These changes occurred in both experimental and ZNS treated control animals. These data show that the molecular effect of ZNS, with up-regulation of EAAC-1 and decreased production of GABA transporters, should result in increased tissue and synaptic concentrations of GABA. Although many antiepileptic drugs have effects on ion channels when measured in vitro our study suggests that additional mechanisms of action may be operant. Molecular effects on regulation of transporter proteins may aid in understanding epileptogenesis and inform investigators about future design and development of drugs to treat epilepsy.
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PMID:Effect of zonisamide on molecular regulation of glutamate and GABA transporter proteins during epileptogenesis in rats with hippocampal seizures. 1294 55

Impairment of GABA-mediated inhibition is one of the main hypotheses invoked to explain seizure activity, both in experimental models and in human epilepsy. We have studied the distribution and the neurochemical characteristics of certain GABAergic circuits in the normal and epileptic human sclerotic hippocampal formation. We have focused our attention mainly on chandelier cells because, together with basket cells, they are considered to have powerful effects on spike generation. Chandelier cells represent a unique type of interneuron whose axon terminals (Ch-terminals) form synapses with the axon initial segments of cortical pyramidal cells and granular cells of the dentate gyrus. Different neurochemical subpopulations of chandelier cells have been identified by immunocytochemistry, mainly in the neocortex. Markers for Ch-terminals include the GABA transporter 1 (GAT-1), the polysialylated form of the cell-surface glycoprotein neural cell adhesion molecule (PSA-NCAM) and the calcium-binding proteins parvalbumin (PV) and calbindin D-28k (CB). In the normal hippocampal formation, GAT-1- and PV-immunoreactive (-ir) Ch-terminals were identified in the granular and polymorphic layers of the dentate gyrus, in the strata pyramidale and oriens of the CA fields, and in the pyramidal layer of the subicular complex. In addition, and in contrast to the hippocampus and dentate gyrus, subsets of Ch-terminals in the upper pyramidal layer of the normal subiculum express CB and PSA-NCAM. The sclerotic hippocampus of epileptic patients presented an impressive morphological and neurochemical reorganization of Ch-terminals and basket formations. This was apparent in the dentate gyrus and hippocampal formation, but not in the subiculum, which appeared to remain unaltered. Principally, numerous and more complex PV- and CB-ir Ch-terminals, as well as dense PV-ir basket formations, appeared in some hippocampal segments, whereas in other regions there was a lack of labelled elements. These changes varied considerably not only between different patients, but also within different hippocampal fields in a given patient. In general, the changes were not correlated with the clinical characteristics or degree of histopathological alterations observed in the patients, such as granular cell dispersion, neuron loss and proliferation of mossy fibres. However, some surviving neurons in the regions adjacent to the areas of neuron loss were consistently innervated by dense basket formations and complex Ch-terminals. These results indicate that, in the human epileptic hippocampus, GABAergic circuits are more highly modified than previously thought. When considered along with other extrahippocampal alterations, we suggest that these changes are important in the pathophysiology of temporal lobe epilepsy associated with hippocampal sclerosis.
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PMID:Histopathology and reorganization of chandelier cells in the human epileptic sclerotic hippocampus. 1453 59

Kainic acid-induced seizures cause a marked increase in the expression of glutamate decarboxylase 67 (GAD67) in granule cells of the dentate gyrus. To determine the possible modes of sequestration of newly formed gamma-aminobutyric acid (GABA), we used in situ hybridization and immunocytochemistry to investigate the expression of several proteins related to GABA in dentate granule cells of rats 4 h to 60 days after kainic acid-induced status epilepticus and in controls. GAD67 and GAD65 mRNA levels were increased by up to 300% and 800%, respectively, in the granule cell layer 6-24 h after kainate injection. Subsequently, increased GAD and GABA immunoreactivity was observed in the terminal field of mossy fibers and in presumed dendrites of granule cells. mRNA of both known plasma membrane GABA transporters (GAT-1 and GAT-3) was expressed in granule cells of control rats. GAT-1 mRNA levels increased (by 30%) 9 h after kainate injection but were reduced by about 25% at later intervals. GAT-3 mRNA was reduced (by 35-75%) in granule cells 4 h to 30 days after kainic acid injection. In contrast, no expression of the mRNA or immunoreactivity of the vesicular GABA transporter was detected in granule cells or in mossy fibers, respectively. GABA transaminase mRNA was only faintly expressed in granule cells, and its levels were reduced (by 60-65%) 12 h to 30 days after kainate treatment. The results indicate that GABA can be taken up and synthesized in granule cells. No evidence for the expression of the vesicular GABA transporter (VGAT) in granule cells was obtained. After sustained epileptic seizures, the markedly increased expression of glutamate decarboxylase and the reduced expression of GABA transaminase may result in increased cytoplasmic GABA concentrations in granule cells. It is suggested that, during epileptic seizures, elevated intracellular GABA and sodium concentration could then result in nonvesicular release of GABA from granule cell dendrites. GABA could then act on GABA-A receptors, protecting granule cells from overexcitation.
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PMID:Expression of plasma membrane GABA transporters but not of the vesicular GABA transporter in dentate granule cells after kainic acid seizures. 1462 Aug 76

Glutamine (Gln), glutamate (Glu) and gamma-amino butyric acid (GABA) are essential amino acids for brain metabolism and function. Astrocytic-derived glutamine is the precursor of the two most important neurotransmitters: glutamate, an excitatory neurotransmitter, and GABA, an inhibitory neurotransmitter. In addition to their roles in neurotransmission these neurotransmitters act as alternative metabolic substrates that enable metabolic coupling between astrocytes and neurons. The relationships between Gln, Glu and GABA were studied under lead (Pb) toxicity conditions using synaptosomal fractions obtained from adult rat brains to investigate the cause of Pb neurotoxicity-induced seizures. We have found that diminished transport of [(14)C]GABA occurs after Pb treatment. Both uptake and depolarization-evoked release decrease by 40% and 30%, respectively, relative to controls. Lower expression of glutamate decarboxylase (GAD), the GABA synthesizing enzyme, is also observed. In contrast to impaired synaptosomal GABA function, the GABA transporter GAT-1 protein is overexpressed (possibly as a compensative mechanism). Furthermore, similar decreases in synaptosomal uptake of radioactive glutamine and glutamate are observed. However, the K(+)-evoked release of Glu increases by 20% over control values and the quantity of neuronal EAAC1 transporter for glutamate reaches remarkably higher levels after Pb treatment. In addition, Pb induces decreased activity of phosphate-activated glutaminase (PAG), which plays a role in glutamate metabolism. Most noteworthy is that the overexpression and reversed action of the EAAC1 transporter may be the cause of the elevated extracellular glutamate levels. In addition to the impairment of synaptosomal processes of glutamatergic and GABAergic transport, the results indicate perturbed relationships between Gln, Glu and GABA that may be the cause of altered neuronal-astrocytic interactions under conditions of Pb neurotoxicity.
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PMID:Relationships between glutamine, glutamate, and GABA in nerve endings under Pb-toxicity conditions. 1514 1

The GABA transporter plays a well-established role in reuptake of GABA after synaptic release. The anticonvulsant effect of tiagabine appears to result largely from blocking this reuptake. However, there is another side to the GABA transporter, contributing to GABA release by reversing in response to depolarization. We have recently shown that this form of GABA release is induced by even small increases in extracellular [K+], and has a powerful inhibitory effect on surrounding neurons. This transporter-mediated GABA release is enhanced by the anticonvulsants gabapentin and vigabatrin. The latter drug also potently increases ambient [GABA], inducing tonic inhibition of neurons. Here we review the evidence in support of a physiological role for GABA transporter reversal, and the evidence that it is increased by high-frequency firing. We postulate that the GABA transporter is a major determinant of the level of tonic inhibition, and an important source of GABA release during seizures. These recent findings indicate that the GABA transporter plays a much more dynamic role in control of brain excitability than has previously been recognized. Further defining this role may lead to a better understanding of the mechanisms of epilepsy and new avenues for treatment.
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PMID:Role of the GABA transporter in epilepsy. 1525 May 87

The identification and subsequent development of the GABA transport inhibitor tiagabine has confirmed the important role that GABA transporters play in the control of CNS excitability. Tiagabine was later demonstrated to be a selective inhibitor of the GABA transporter GAT1. Although selective for GAT1, tiagabine lacks cell type selectivity and is an equipotent inhibitor of neuronal and glial GAT1. To date, four GABA transporters have been cloned, i.e., GAT1-4. The finding that some of these display differential cellular and regional expression patterns suggests that drugs targeting GABA transporters other than GAT1 might offer some therapeutic advantage over GAT1 selective inhibitors. Furthermore, it is particularly interesting that several recently defined GABA transport inhibitors have been demonstrated to display a preferential selectivity for the astrocytic GAT1 transporter. That cellular heterogeneity of GAT1 plays a role in the control of CNS function is confirmed by the demonstration that inhibition of astrocytic GABA uptake is highly correlated to anticonvulsant activity. At the present time, a functional role for the other GABA transporters is less well defined. However, recent findings have suggested a role for the mouse GAT2 (homologous to the human betaine transporter) in the control of seizure activity. In these studies, the non-selective GAT1 and mouse GAT2 transport inhibitor EF1502 (N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-hydroxy-4-(methylamino)-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol) was found to exert a synergistic anticonvulsant action when tested in combination with the GAT1 selective inhibitors tiagabine and LU-32-176B (N-[4,4-bis(4-fluorophenyl)-butyl]-3-hydroxy-4-amino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol). Additional studies will be required to define a role for the other GABA transporters and to further identify the functional importance of their demonstrated cellular and regional heterogeneity. A summary of these and other issues are discussed in this brief review.
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PMID:GABA transporters as drug targets for modulation of GABAergic activity. 1545 99

Epileptiform discharges and behavioral seizures may be the consequences of excess excitation from inadequate inhibitory effects associated with gamma-aminobutyric acid (GABA). GABA is taken up and accumulated in synaptic vesicles by the action of vesicular GABA transporter (VGAT) before its release into the synaptic cleft, and removed from synaptic regions by the action of transporter proteins GABA transporter-1 (GAT-1) and GABA transporter-3 (GAT-3). In this experiment, the effects of diazoxide (DIZ) on the VGAT, GAT-1 and GAT-3 mRNA and protein levels in hippocampus, and on the seizure activities of picrotoxin (PTX)-induced kindling rats were observed. DIZ caused increase in the quantity of VGAT mRNAs and proteins, and down regulation of GABA transporters GAT-1 and GAT-3 mRNAs and proteins after the PTX re-kindling. Furthermore, DIZ produced not only a prompt but also a later suppression of PTX-induced seizures. Although DIZ has effects on ATP-sensitive potassium (K(ATP)) channels when measured in vitro, our study suggests that additional mechanisms of action may involve the regulation of GABA transporters, which may aid in understanding epileptogenesis and inform investigators about future design and development of K(ATP) channel openers to treat epilepsy.
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PMID:Effect of diazoxide on regulation of vesicular and plasma membrane GABA transporter genes and proteins in hippocampus of rats subjected to picrotoxin-induced kindling. 1548 95

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