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)

Because of its abundance in the brain, its ability to produce hyperpolarizing inhibition of almost all neurons, its association with benzodiazepines, and the discovery that many convulsants inhibited its synthesis, gamma-aminobutyric acid (GABA) has often appeared to be the key to epilepsy. Many assumed that "primary" or "genetic" epilepsy must be a disorder of GABA synapses and that GABA agonists would be universal anticonvulsants if permeability and drug metabolism were controlled. The GABA synthetic gene was a logical "candidate gene" for epilepsy. However, the GABA-deficiency theory of epilepsy is less convincing today. GABA agonists were found to intensify seizures in some rodent and human cases. Absence and other generalized seizures in humans often worsened when treated with GABA transaminase inhibitors such as gamma-vinyl-GABA. Surprisingly, the GABA transaminase inhibitors appear to be more useful in partial than in generalized epilepsies. Neuronal GABA uptake blockers are proconvulsant. GABA agonists aggravate seizures in several mutants, ranging from the photosensitive baboon to the genetically epilepsy-prone rat. How can this be understood? Muscimol injections into the pedunculopontine nucleus increase seizures due to systematically administered convulsants, while the receptor blocker bicuculline suppresses seizures after injection into several brain regions, including the striatum. The result of inhibiting inhibitory circuits is excitation. Studies with GABA uptake blockers and the GABAB agonist baclofen are presented in which their combined administration provoked seizures in rats. Baclofen was shown also to increase the incidence of seizures evoked by pentylenetetrazole without increasing seizures due to local injections of excitatory amino acids. Baclofen antagonized the myoclonic effect of 5-hydroxytryptophan in rats with serotonin lesions. Baclofen augments some seizures and inhibits others. Selective inhibition of a particular tract, whether GABAergic or not, may have convulsant or anticonvulsant effects, depending on its connections and the state of the organism. GABAA receptor stimulation is usually but not always anticonvulsant. GABAB receptor stimulation may facilitate absence seizures and related primary generalized seizures. GABAB receptors may be abnormal in some forms of nonfocal epilepsy seen in childhood. It is likely that mutations of GABA transporter and GABAA receptor genes will be found in humans but they will probably not be patients with "pure epilepsy."
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PMID:GABA and epilepsy: their complex relationship and the evolution of our understanding. 131 57

The anticonvulsant gabapentin (1-(aminomethyl)cyclohexane acetic acid) has been found to be effective for treatment of partial seizures, but the mechanism of action is unknown. Recent evidence from the rat optic nerve suggests that gabapentin may enhance promoted release of GABA, which is thought to be due to reverse operation of the GABA transporter. We have used whole-cell patch clamp recordings from CA1 pyramidal neurons in hippocampal slices to directly measure currents induced by nipecotic acid (NPA) during exposure to gabapentin. Under control conditions, pressure microejection of NPA increased whole-cell conductance with a reversal potential equal to the chloride equilibrium potential. This response was mimicked by GABA application, and blocked by bicuculline. The response to NPA was also present after blockade of synaptic transmission in the presence of calcium-free solution. These results are consistent with NPA promoting nonvesicular release of GABA from neighboring neurons or glia via reverse operation of the GABA uptake system, which then activated GABAA receptors on the recorded neurons. In control solution, the response to NPA slowly decreased over 45 min to approximately 50% of the initial response, consistent with GABAA receptor 'rundown'. However, in the presence of gabapentin there was a slow increase in the response, reaching approximately 170% of the control level after 45 min of gabapentin exposure. These results demonstrate that gabapentin enhances the promoted release of GABA by more than three-fold. The potentiation of the NPA response may be due to gabapentin increasing cytosolic GABA in neighboring cells via a delayed metabolic effect, and would have the functional effect of increasing neuronal inhibition during periods of hyperexcitability.
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PMID:Gabapentin potentiates the conductance increase induced by nipecotic acid in CA1 pyramidal neurons in vitro. 779 91

Tiagabine (TGB) is a novel antiepileptic drug whose anticonvulsant effects are due to inhibition of gamma-aminobutyric acid (GABA) transport mediated by the GABA transporter-1. We have previously shown that TGB is effective in acute amygdala kindled seizures, and consequently we wanted to test the hypothesis that TGB also could suppress the development of kindling epileptogenesis. Rats had stereotaxically implanted stimulating/recording electrodes in the basolateral amygdala and recording electrode in the contralateral occipital cortex. Rats were divided in three groups (n = 8 for each group) intraperitoneally (i.p.) administered vehicle, TGB 7.3 micromol/kg and TGB 24.3 micromol/kg, respectively, 30 min before stimulation. TGB dose-dependently suppressed the development of the behavioral seizure score and afterdischarge (AD) duration recorded from the amygdala and cortex. Vehicle treated animals displayed at the 16th stimulation an average behavioral score of 4.7 +/- 0.2 (mean +/- SEM) compared to 3.9 +/- 0.2 in the 7.3 micromol/kg TGB treated group and 1.4 +/- 0.3 in the 24.3 micromol/kg TGB treated group. Amygdaloid AD in controls on the 16th stimulation was 92 +/- 10 s compared to 56 +/- 12 s in group 2 and 25 +/- 3 s in group 3. Cortical AD was at the same time 92 +/- 10, 55 +/- 13 and 20 +/- 5 s, respectively. Groups 2 and 3 required four and seven further stimulations, respectively, without TGB administration to reach the AD level in the control group. At the 17th stimulation, rats in group 1 were administered TGB 24.3 micromol/kg and displayed an average behavioral score of 0.5 +/- 0.2. Amygdaloid and cortical AD were both 6 +/- 1 s. Tiagabine 24.3 micromol/kg suppresses both the kindling process and the expression of the fully kindled seizure.
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PMID:Tiagabine exerts an anti-epileptogenic effect in amygdala kindling epileptogenesis in the rat. 922 9

Two novel nipecotic acid derivatives, 1-(3-(9H-Carbazol-9-yl)-1-propyl)-4-(4-methoxyphenyl)-4-piperidino l (NNC 05-2045) and 1-(3-(9H-Carbazol-9-yl)-l-propyl)-4-(2-methoxyphenyl)-4-piperidino l (NNC 05-2090) have been tested for inhibition of gamma-amino butyric acid (GABA) transporters in synaptosomal preparations of rat cerebral cortex and inferior colliculus and found to differ markedly from gabitril (tiagabine), a selective GAT-1 inhibitor. IC50 values for inhibition of [3H]GABA uptake into synaptosomes from cerebral cortex for NNC 05-2045 and NNC 05-2090 were 12 +/- 2 and 4.4 +/- 0.8 microM, respectively. In synaptosomes from inferior colliculus in the presence of 1 microM 1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid (NNC 05-0711), a highly potent and selective GAT-1 inhibitor, IC50 values for inhibition of [3H]GABA uptake were 1.0 +/- 0.1 and 2.5 +/- 0.7 microM, respectively. A receptor profile showed that NNC 05-2045 has binding affinities to sigma-, alpha 1- and D2-receptors of 113, 550 and 122 nM, respectively. NNC 05-2090 displayed alpha 1- and D2-receptor affinity of 266 and 1632 nM, respectively. The anticonvulsant action of both compounds was tested in four rodent models after intra peritoneal (i.p.) injection. Both NNC 05-2090 dose-dependently inhibited sound-induced tonic and clonic convulsions in DBA/2 mice with ED50 values of 6 and 19 mumol/kg, respectively. NNC 05-2045 also antagonized sound-induced seizures in genetic epilepsy prone rats (GEP rats) with ED50 values against wild running, clonic and tonic convulsions of 33, 39 and 39 mumol/kg, respectively (NNC 05-2090 was not tested in GEP rats). Both NNC 05-2045 and NNC 05-2090 dose-dependently antagonized tonic hindlimb extension in the maximal electroshock (MES) test with ED50 values of 29 and 73 mumol/kg, respectively. In amygdala kindled rats NNC 05-2045 and NNC 05-2090 significantly (P < 0.05) reduced generalized seizure severity (seizure grade 3-5) at highest doses (72-242 mumol/kg) and NNC 05-2090 also significantly reduced afterdischarge duration at these doses (P < 0.05). These data show that inhibition of GABA uptake through non-GAT-1 transporters has different anticonvulsant effects than selective GAT-1 inhibitors (e.g. tiagabine) in that enhanced efficacy against MES and reduced efficacy against kindled seizures is observed. Although a contribution of adrenergic agonistic effects cannot be entirely ruled out, it is proposed that inhibition of GAT-3 (mouse GAT4) is primarily responsible for the anticonvulsant action of these two nipecotic acid derivatives in MES, amygdala kindled rats and in sound-induced seizures in GEP-rats and DBA/2 mice.
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PMID:Anticonvulsant properties of two GABA uptake inhibitors NNC 05-2045 and NNC 05-2090, not acting preferentially on GAT-1. 925 99

To investigate the role played by GABA transporters in epileptic seizures, we examined time-dependent and regional changes in expression of GAT-1 and GAT-3 GABA transporter mRNA in amygdala-kindled rat brain using an in situ hybridization method. GAT-1 mRNA was significantly increased bilaterally in the hippocampal dentate gyrus (111-116%) at 1 h after kindled generalized seizures. GAT-1 mRNA was also significantly increased bilaterally in the hippocampal subfields (CA1-4 and dentate gyrus [110-117%]) at 4 h after kindled seizures. There were no significant changes in GAT-1 mRNA level in the amygdalar nuclei, pyriform cortex or cerebral cortex either ipsilaterally or contralaterally at any time after kindled seizures. In contrast, GAT-3 mRNA was significantly increased bilaterally in the amygdalar nuclei and in the contralateral pyriform cortex and cerebral cortex 1 h after seizures. Since all these changes returned to control levels by 8 or 24 h after kindled seizures, the increases in GABA transporter mRNA appeared to be transient responses to seizure activity. These findings indicate that GAT-1 subtype transporter is specifically involved in seizure activity in the hippocampus, while GAT-3 subtype transporter is mainly involved in seizure activity in the amygdalar nuclei and pyriform cortex following amygdala-kindled generalized seizures.
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PMID:Time-dependent and regional expression of GABA transporter mRNAs following amygdala-kindled seizures in rats. 952 43

gamma-Aminobutyric acid (GABA) transporters are electrogenic and sodium-dependent and can operate in reverse when cells are depolarized or when there is reversal of the inward sodium gradient. However, the functional relevance of this phenomenon is unclear. We have examined whether depolarization induced by a physiologically relevant increase in extracellular [K+] leads to sufficient amounts of carrier-mediated GABA release to activate GABAA receptors on neurons. Patch-clamp recordings were made from rat hippocampal neurons in culture with solutions designed to isolate chloride currents in the recorded neuron. Pressure microejection was used to increase extracellular [K+] from 3 to 12 mM. After blockade of vesicular GABA release by removal of extracellular calcium, this stimulus induced a large conductance increase in hippocampal neurons [18.9 +/- 6.8 (SD) nS; n = 16]. This was blocked by the GABAA receptor antagonists picrotoxin and bicuculline and had a reversal potential that followed the Nernst potential for chloride, indicating that it was mediated by GABAA receptor activation. Similar responses occurred after block of vesicular neurotransmitter release by tetanus toxin. GABAA receptors also were activated when an increase in extracellular [K+] (from 3 to 13 mM) was combined with a reduction in extracellular [Na+] or when cells were exposed to a decrease in extracellular [Na+] alone. These results indicate that depolarization and/or reversal of the Na+ gradient activated GABA receptors via release of GABA from neighboring cells. We found that the GABA transporter antagonists 1-(4, 4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid hydrochloride (SKF89976A; 20-100 microM) and 1-(2-([(diphenylmethylene)amino]oxy)ethyl) -1, 2, 5, 6 - tetrahydro - 3 - pyridine - carboxylic acid hydrochloride (NO-711; 10 microM) both decreased the responses, indicating that the release of GABA resulted from reversal of the GABA transporter. We propose that carrier-mediated GABA release occurs in vivo during high-frequency neuronal firing and seizures, and dynamically modulates inhibitory tone.
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PMID:Carrier-mediated GABA release activates GABA receptors on hippocampal neurons. 965 49

The genetically epilepsy-prone rat is an animal model of inherited generalised tonic-clonic epilepsy that shows abnormal susceptibility to audiogenic seizures and a lowered threshold to a variety of seizure-inducing stimuli. Recent studies suggest a crucial role for glutamate and GABA transporters in epileptogenesis and seizure propagation. The present study examines the levels of expression of the messenger RNAs encoding the glial and neuronal glutamate transporters, GLT-1 and EAAC-1, and the neuronal GABA transporter, GAT-1, in paired male genetically epileptic-prone rats and Sprague Dawley control rats using the technique of in situ hybridization. In a parallel study, semiquantitative immunoblotting was used to assess GLT-1 and EAAC-1 protein levels in similarly paired animals. Animals were assessed for susceptibility to audiogenic seizures on six occasions, and killed seven days following the last audiogenic stimulus exposure. Rat brains were processed for in situ hybridization with radioactive 35S-labelled oligonucleotide probes (EAAC-1 and GAT-1), 35S-labelled riboprobes (GLT-1), and Fluorescein-labelled riboprobes (GLT-1 and GAT-1) or processed for immunoblotting using subtype-specific antibodies for GLT-1 and EAAC-1. Semiquantitative analyses were carried out on X-ray film autoradiograms in several brain regions for both in situ hybridization and immunoblotting studies. Reductions in GAT-1 messenger RNA were found in genetically epileptic-prone rats in all brain regions examined (-8 to -24% compared to control). Similar reductions in GLT-1 messenger RNA expression levels were seen in cortex, striatum, and CA1 (-8 to -12%) of genetically epileptic-prone rats; the largest reduction observed was in the inferior colliculus (-20%). There was a tendency for a reduced expression of EAAC-1 messenger RNA in most regions of the genetically epileptic-prone rat brain although this reached statistical significance only in the striatum (-12%). In contrast, no significant differences in GLT-1 and EAAC-1 protein between genetically epileptic-prone rats and control animals were observed in any region examined, although there was a tendency to follow the changes seen with the corresponding messenger RNAs. These results show differences in the messenger RNA expression levels of three crucial amino acid transporters. For the two glutamate transporters, GLT-1 and EAAC-1, differences in messenger RNA levels are not reflected or are only partially reflected in the expression of the corresponding proteins.
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PMID:Reduction of GABA and glutamate transporter messenger RNAs in the severe-seizure genetically epilepsy-prone rat. 968 60

The anticonvulsant action of NNC 711 [(1-(2-((diphenylmethylene) amino) oxy) ethyl)-1,2,4,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride], an inhibitor of the GABA transporter GAT-1, was studied in a model of pentylenetetrazol-induced motor seizures in rats 7, 12, 18, 25, and 90 days old. NNC 711 at doses of 0.25-20 mg/kg i.p. exhibited two effects in rat pups: a suppression of minimal clonic seizures in age groups in which this type of seizure could be reliably elicited (i.e. in rats aged 18 and 25 days); and a specific suppression or restriction of the tonic phase of generalized tonic-clonic seizures (GTCS) expressed in 18- and especially 12-day-old rats. Effects of NNC 711 on GTCS in 7- and 25-day-old rats were irregular. Adult (i.e. 90-day-old) animals exhibited abolition of generalized tonic-clonic seizures; minimal clonic seizures were suppressed only after substantially higher doses. The abolition of minimal seizures by doses too low to influence generalized tonic-clonic seizures as observed in rat pups is unique among antiepileptic drugs. In addition, an EEG study in rat pups demonstrated dissociation of EEG signs and motor seizures in some animals.
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PMID:Effects of NNC 711, a GABA uptake inhibitor, on pentylenetetrazol-induced seizures in developing and adult rats. 977 21

(3R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid 1 (tiagabine, Gabitril) is a potent and selective gamma-aminobutyric acid (GABA) uptake inhibitor with proven anticonvulsant efficacy in humans. This drug, which has a unique mechanism of action among marketed anticonvulsant agents, has been launched for add-on treatment of partial seizures with or without secondary generalization in patients >12 years of age. Using this new agent as a benchmark, we have designed two series of novel GABA uptake inhibitors of remarkable potency, using a putative new model of ligand interaction at the GABA transporter type 1 (GAT-1) uptake site. This model involves the postulated interaction of an electronegative region in the GABA uptake inhibitor with a positively charged domain in the protein structure of the GAT-1 site. These two novel series of anticonvulsant agents contain diaryloxime or diarylvinyl ether functionalities linked to cyclic amino acid moieties and were derived utilizing the new model, via a series of design steps from the known 4,4-diarylbutenyl GABA uptake inhibitors. The new compounds are potent inhibitors of [(3)H]-GABA uptake in rat brain synaptosomes in vitro, and their antiepileptic potential was demonstrated in vivo by their ability to protect against seizures induced by the benzodiazepine receptor inverse agonist methyl 4-ethyl-6,7-dimethoxy-beta-carboline-3-carboxylate (DMCM) in mice. From structure-activity studies of these new GABA uptake inhibitors, we have shown that insertion of an ether oxygen in conjugation with the double bond in tiagabine (K(i) = 67 nM) improves in vitro potency by 5-fold to 14 nM.
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PMID:Synthesis of novel GABA uptake inhibitors. 3. Diaryloxime and diarylvinyl ether derivatives of nipecotic acid and guvacine as anticonvulsant agents. 1047 78

Gabitril (tiagabine) is a potent selective inhibitor of the principal neuronal gamma-aminobutyric acid (GABA) transporter (GAT-1) in the cortex and hippocampus. By slowing the reuptake of synaptically-released GABA, it prolongs inhibitory postsynaptic potentials. In animal models of epilepsy, tiagabine is particularly effective against kindled (limbic) seizures and against reflexly-induced generalized convulsive seizures. These data are predictive of its efficacy in complex partial seizures in humans. Possible clinical applications outside the field of epilepsy include bipolar disorder and pain.
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PMID:Basic mechanisms of gabitril (tiagabine) and future potential developments. 1061 55


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