Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P80404 (GABA transaminase)
 786 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gabapentin is a novel anticonvulsant drug. The anticonvulsant mechanism of gabapentin is not known. Based on the amino acid structure of gabapentin we explored its possible effects on glutamate and gamma-aminobutyric acid (GABA) metabolism in brain as they may relate to its anticonvulsant mechanisms of action. Gabapentin was tested for its effects on seven enzymes in the metabolic pathways of these two neurotransmitters: alanine aminotransferase (AL-T), aspartate aminotransferase (AS-T), GABA aminotransferase (GABA-T), branched-chain amino acid aminotransferase (BCAA-T), glutamine synthetase (Gln-S), glutaminase (GLNase), and glutamate dehydrogenase (GDH). In the presence of 10 mM gabapentin, only GABA-T, BCAA-T, and GDH activities were affected by this drug. Inhibition of GABA-T by gabapentin was weak (33%). The Ki values for inhibition of cytosolic and mitochondrial forms of GABA-T (17-20 mM) were much higher than the Km values for GABA (1.5-1.9 mM). It is, therefore, unlikely that inhibition of GABA-T by gabapentin is clinically relevant. As with leucine, gabapentin stimulated GDH activity. The GDH activity in rat brain synaptosomes was activated 6-fold and 3.4-fold, respectively, at saturating concentrations (10 mM) of leucine and gabapentin. The half-maximal stimulation by gabapentin was observed at approximately 1.5 mM. Gabapentin is not a substrate of BCAA-T, but it exhibited a potent competitive inhibition of both cytosolic and mitochondrial forms of brain BCAA-T. Inhibition of BCAA-T by this drug was reversible. The Ki values (0.8-1.4 mM) for inhibition of transamination by gabapentin were close to the apparent Km values for the branched-chain amino acids (BCAA) L-leucine, L-isoleucine, and L-valine (0.6-1.2 mM), suggesting that gabapentin may significantly reduce synthesis of glutamate from BCAA in brain by acting on BCAA-T.
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PMID:Effects of anticonvulsant drug gabapentin on the enzymes in metabolic pathways of glutamate and GABA. 856 62

Nearly three-fourths of all newly diagnosed cases of epilepsy are easily controlled with our current drug armamentarium. Further progress will undoubtedly come with use of three new drugs, gabapentin, lamotrigine, and vigabatrin now in diverse stages of clinical trials. Gabapentin is a gamma-aminobutyric acid (GABA) analog which passes the blood-brain barrier. Its mode of action is unknown. The anti-convultion effect of lamotrigine apparently results from its capacity to stabilize voltage-dependent sodium channels and thus limit release of the excitory neuromediator glutamate. Vigabatrin produces irreversible inhibition of GABA transaminase, increasing the concentration of this neurotransmittor inhibitor in the brain. The pharmacokinetic properties of these three anti-epileptics are more favorable than those of earlier drugs. Renal excretion is proportional to creatinine clearance allowing better dose adjustment and all three can be associated with oral contraception. They are as effective as the classical agents although indications may vary. There are fewer adverse effects and no teratogenic effect has been observed in animal studies. Clinical surveillance is usually sufficient without laboratory tests. One handicap is the increased cost although it has been demonstrated that the overall cost for the society for a patient with well controlled epilepsy is less. The prescription of a third-generation anti-epileptic drug is justified immediately whenever treatment with one of the classical drugs has been unsuccessful; however, in case of failure the new drug should not be continued.
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PMID:[New medical treatment of epilepsy]. 868 6

Established antiepileptic drugs (AEDs) decrease membrane excitability by interacting with neurotransmitter receptors or ion channels. AEDs developed before 1980 appear to act on sodium channels, gamma-aminobutyric acid type A (GABAA) receptors, or calcium channels. Benzodiazepines and barbiturates enhance GABAA receptor-mediated inhibition. Phenytoin (PHT), carbamazepine (CBZ), and possibly valproate (VPA) decrease high-frequency repetitive firing of action potentials by enhancing sodium-channel inactivation. Ethosuximide (ESM) and VPA reduce a low threshold (T-type) calcium-channel current. The mechanisms of action of the new AEDs are not fully established. Gabapentin (GBP) binds to a high-affinity site on neuronal membranes in a restricted regional distribution of the central nervous system. This binding site may be related to a possible active transport process of GBP into neurons; however, this has not been proven, and the mechanism of action of GBP remains uncertain. Lamotrigine (LTG) decreases sustained high-frequency repetitive firing of voltage-dependent sodium action potentials that may result in a preferential decreased release of presynaptic glutamate. The mechanism of action of oxcarbazepine (OCBZ) is not known; however, its similarity in structure and clinical efficacy to CBZ suggests that its mechanism of action may involve inhibition of sustained high-frequency repetitive firing of voltage-dependent sodium action potentials. Vigabatrin (VGB) irreversibly inhibits GABA transaminase, the enzyme that degrades GABA, thereby producing greater available pools of presynaptic GABA for release in central synapses. Increased activity of GABA at postsynaptic receptors may underline the clinical efficacy of VGB.
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PMID:Antiepileptic drug mechanisms of action. 878 10

Great progress has been made in the development of antiepileptic drugs (AEDs) from their early empirical stage until the current scientifically-founded advancement based on our greater understanding of the genesis of epilepsy. Available AEDs decrease neuronal membrane excitability, acting on ion channels or synaptic receptors. The classic AEDs act on sodium channels (phenytoin and carbamazepine); increase GABA-A receptor-mediated inhibition (benzodiazepines and barbiturates); and on T-type Ca2+ channels (sodium valproate and ethosuximide). Many patients are resistant to these AEDs. The introduction of new drugs whose mechanisms of action are not well established has improved therapeutic prospects. Four promising new AEDs are now available in many countries. Vigabatrin is an irreversible inhibitor of GABA transaminase. Lamotrigine blocks Na+ channels, thereby inhibiting the presynaptic release of excitatory neurotransmitters. Gabapentin increases GABAergic inhibition and Felbamate acts on the NMDA receptor and Na+ channels. New techniques in molecular biology are likely to facilitate the design of better AEDs.
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PMID:[Antiepileptic drugs: mechanism of action]. 905 61

Established antiepileptic drugs (AEDs) decrease membrane excitability by interacting with neurotransmitter receptors or ion channels. AEDs developed prior to 1980 appear to act on sodium channels. gamma-amino butyric acid type A (GABAA) receptors (GABARs) or calcium channels. Benzodiazepines and barbiturates enhance GABAR-mediated inhibition. Phenytion, carbamazepine and possibly sodium valproate decrease high-frequency repetitive firing of action potentials by enhancing sodium channel inactivation. Ethosuximide and sodium valproate reduce a low threshold (T-type) calcium channel current. The mechanisms of action of the new AEDs are not fully established. Gabapentin binds to a high affinity site on neuronal membranes in a restricted regional distribution of the central nervous system. This binding site may be related to a possible active transport process of gabapentin into neurons; however, this has not been proven and the mechanism of action of gabapentin remains uncertain. Lamotrigine decreases sustained high-frequency repetitive firing of voltage-dependent sodium actin potentials that may result in a preferential decreased release of presynaptic glutamate. Oxcarbazepine's mechanism of action is not known; however, its similarity in structure and clinical efficacy to that of carbamazepine suggests that its mechanism of action may involve inhibition of sustained high-frequency repetitive firing of voltage-dependent sodium action potentials. Vigabatrin irreversibly inhibits GABA transaminase, the enzyme that degrades GABA, thereby producing greater available pools of presynaptic GABA for release in central synapses. Increased activity of GABA at postsynaptic receptors may underlie the clinical efficacy of vigabatrin. The potential mechanistic bases for rational polypharmacy are reviewed.
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PMID:Is there a mechanistic basis for rational polypharmacy? 929 30

gamma-Aminobutyric acid (GABA) belongs to main inhibitory neurotransmitters in the central nervous system and activates three types of specific receptors--GABAA, GABAB i GABAC. At present, little is known about GABAC-mediated events. GABAB receptors are metabotropic, whilst stimulation of ionotropic GABAA receptors results in opening the chloride channel, followed by influx of chloride ions and hyperpolarization. The GABAA receptor possesses also binding sites for benzodiazepines and barbiturates which, via these sites, enhance GABAA-mediated events. Another antiepileptic drug potentiating GABA-ergic inhibition is valproate, which increases synthesis of GABA and reduces its metabolism. Among new antiepileptic drugs associated with the GABA-ergic system are tiagabine, vigabatrin, and to a certain degree--gabapentin. Tiagabine blocks neuronal and glial uptake of GABA whilst vigabatrin increases the synaptic concentration of GABA by inhibition of GABA aminotransferase. Gabapentin, probably through the activation of glutamic acid decarboxylase, leads to the increase in synaptic GABA. However, this antiepileptic drugs is also binds to specific sites within voltage-dependent calcium channels, which results in the reduced intraneuronal concentration of calcium ions. Presumably, tiagabine and vigabatrin possess only one mechanism of action, associated with the increased GABA-ergic inhibition. Although topiramate and felbamate were shown to enhance GABA-mediated events, they have additional mechanisms of action, including blockade of voltage-dependent sodium channels and inhibition of glutamatergic neurotransmission.
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PMID:[GABA-ergic system and antiepileptic drugs]. 1076 41

gamma-Aminobutyric acid (GABA) belongs to the main inhibitory neurotransmitters in the central nervous system and activates three types of specific receptors--GABAA, GABAB i GABAC. At present, little is known about GABAC-mediated events. GABAB receptors are metabotropic, whilst stimulation of ionotropic GABAA receptors results in opening the chloride channel, followed by influx of chloride ions and hyperpolarization. The GABAA receptor possesses also binding sites for benzodiazepines and barbiturates which, via these sites, enhance GABAA-mediated events. Another antiepileptic drug potentiating GABA-ergic inhibition is valproate, which increases synthesis of GABA and reduces its metabolism. Among new antiepileptic drugs associated with the GABA-ergic system are tiagabine, vigabatrin, and to a certain degree--gabapentin. Tiagabine blocks neuronal and glial uptake of GABA whilst vigabatrin increases the synaptic concentration of GABA by inhibition of GABA aminotransferase. Gabapentin, probably through the activation of glutamic acid decarboxylase, leads to the increase in synaptic GABA. However, this antiepileptic drug also binds to specific sites within voltage-dependent calcium channels, which results in reduced intraneuronal concentration of calcium ions. Presumably, tiagabine and vigabatrin possess only one mechanism of action, associated with increased GABA-ergic inhibition. Although topiramate and felbamate were shown to enhance GABA-mediated events, they have additional mechanisms of action, including blockade of voltage-dependent sodium channels and inhibition of glutamatergic neurotransmission.
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PMID:[GABA-ergic system and antiepileptic drugs]. 1079 Oct 39

gamma-Aminobutyric acid (GABA) is considered to be the major inhibitory neurotransmitter in the brain and loss of GABA inhibition has been clearly implicated in epileptogenesis. GABA interacts with 3 types of receptor: GABAA, GABAB and GABAC. The GABAA receptor has provided an excellent target for the development of drugs with an anticonvulsant action. Some clinically useful anticonvulsants, such as the benzodiazepines and barbiturates and possibly valproic acid (sodium valproate), act at this receptor. In recent years 4 new anticonvulsants, namely vigabatrin, tiagabine, gabapentin and topiramate, with a mechanism of action considered to be primarily via an effect on GABA, have been licensed. Vigabatrin elevates brain GABA levels by inhibiting the enzyme GABA transaminase which is responsible for intracellular GABA catabolism. In contrast, tiagabine elevates synaptic GABA levels by inhibiting the GABA uptake transporter, GAT1, and preventing the uptake of GABA into neurons and glia. Gabapentin, a cyclic analogue of GABA, acts by enhancing GABA synthesis and also by decreasing neuronal calcium influx via a specific subunit of voltage-dependent calcium channels. Topiramate acts, in part, via an action on a novel site of the GABAA receptor. Although these drugs are useful in some patients, overall, they have proven to be disappointing as they have had little impact on the prognosis of patients with intractable epilepsy. Despite this, additional GABA enhancing anticonvulsants are presently under development. Ganaxolone, retigabine and pregabalin may prove to have a more advantageous therapeutic profile than the presently licensed GABA enhancing drugs. This anticipation is based on 2 characteristics. First, they act by hitherto unique mechanisms of action in enhancing GABA-induced neuronal inhibition. Secondly, they act on additional antiepileptogenic mechanisms. Finally, CGP 36742, a GABAB receptor antagonist, may prove to be particularly useful in the management of primary generalised absence seizures. The exact impact of these new GABA-enhancing drugs in the treatment of epilepsy will have to await their licensing and a period of postmarketing surveillance. As to clarification of their role in the management of epilepsy, this will have to await further clinical trials, particularly direct comparative trials with other anticonvulsants.
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PMID:The new generation of GABA enhancers. Potential in the treatment of epilepsy. 1147 40

Gabapentin (GBP) has been shown to reduce paired-pulse inhibition in the dentate gyrus of the urethane-anesthetized rat, which is a proconvulsant effect, and to shorten the afterdischarge duration, which is an antiepileptic effect. The mechanism by which GBP exerts these effects is not known, but a number of possibilities have been proposed. Here we tested the ability of vigabatrin (VGB), a GABA transaminase inhibitor, and SKF89976A, a selective GAT-1 blocker, to alter the effectiveness of GBP in the dentate gyrus in urethane-anesthetized adult Sprague-Dawley rats. VGB, alone at 100 mg/kg, had no effect on the evoked potentials or paired-pulse inhibition in the dentate gyrus, but did block lengthening of the afterdischarge. Pretreatment with VGB had no effect on the ability of GBP to reduce paired-pulse inhibition, but blocked the effect of GBP on seizure duration. SKF89976A, alone at 10 mg/kg, increased paired-pulse inhibition and blocked the lengthening of the afterdischarge in the seizure model. Pretreatment with SKF89976A had no effect on the actions of GBP on either paired-pulse inhibition or seizure duration. These results suggest that the action of GBP is not mediated through an inhibition of the GAT-1 transporter and probably not through an increase in basal levels of GABA. The data also suggest that the combination of VGB and GBP may be clinically less effective than the use of GBP alone.
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PMID:Modulation of the in vivo effects of gabapentin by vigabatrin and SKF89976A. 1245 29

To substantiate the notion that cocaine behavioral effects may be influenced by gamma-aminobutyric acid (GABA) neurotransmission male Wistar rats were injected with gabapentin (a cyclic GABA analogue), tiagabine (a GABA reuptake inhibitor), or vigabatrin (a GABA transaminase inhibitor) before acute or repeated treatment with cocaine evoking either locomotor hyperactivation or sensitization. Gabapentin (1-30 mg/kg), tiagabine (2.5-10 mg/kg) or vigabatrin (75-250 mg/kg) attenuated the cocaine (10 mg/kg)-induced hyperactivation and in the highest doses they also decreased basal locomotor activation. Vigabatrin (75-250 mg/kg) dose-dependently reduced the development of cocaine sensitization in rats treated repeatedly (days 1-5) with cocaine (10 mg/kg) and then challenged with cocaine (10 mg/kg) following 5-day withdrawal; the remaining drugs were ineffective. When injected acutely with a cocaine challenge dose, gabapentin (3-10 mg/kg) or vigabatrin (150 mg/kg), but not tiagabine, significantly attenuated the expression of cocaine sensitization. The present results show that enhanced GABA-ergic neurotransmission exerted inhibitory actions on acute responses to cocaine, however, only in a case of vigabatrin the inhibition seems to be unrelated to the inhibitory effect of the drugs on basal locomotor activity. The finding that vigabatrin protected against the development and the expression of cocaine sensitization further supports its therapeutic potential in the treatment of cocaine dependence.
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PMID:Various GABA-mimetic drugs differently affect cocaine-evoked hyperlocomotion and sensitization. 1677 90


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