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

Kindling is an animal model of epilepsy produced by focal electrical stimulation of the brain. This chapter: describes the kindling phenomenon; considers the validity of kindling as an animal model and proposes a hypothesis as to how kindling might contribute to human epileptogenesis; presents a critical review of current insights into the underlying mechanisms; and emphasizes that, if progress is to be made in understanding the mechanisms, the network of brain structures underlying kindling must be elucidated. Recent investigations directly related to the network issue are considered, namely studies demonstrating that a brainstem structure, the substantia nigra (SN), can regulate the kindled seizure threshold. Thus, either microinjection of a GABA receptor agonist or a GABA transaminase inhibitor into SN, but not into nearby sites, elevates kindled-seizure threshold. Likewise, destruction of SN, but not of adjacent structures, is associated with an increase of kindled-seizure threshold. These treatments suppress not only clonic motor seizures, but also complex partial seizures and afterdischarge at the site of stimulation. These findings demonstrate that the SN can regulate the intrinsic neuronal excitability of forebrain structures. A hypothesis is advanced that generation of a complex partial seizure requires activation of neurons in the SN which in turn feed back through polysynaptic connections to influence neurons at the site of seizure origin. This nigral influence on neurons at the site of seizure origin is either a direct excitation or a disinhibition. Thus, the seizure represents reverberatory activity within a network of brain structures which includes the SN. Other investigators have proposed that the centrencephalic system subserved seizure propagation; the relationship of the hypothesis proposed here to these earlier ideas is discussed.
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PMID:Kindling model of epilepsy. 287 21

Patients with epilepsy were found to have an increased 20 minute prolactin response to intravenous TRH stimulation when receiving the GABA-T inhibiting drug vigabatrin. Enhanced GABA activity may either reduce basal prolactin levels whilst allowing a normal pituitary response to TRH stimulation, or may overcome the inhibitory effects of dopamine on pituitary prolactin release.
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PMID:An enhanced serum prolactin response to TRH in the presence of GABA transaminase inhibition. 311 14

The high seizure susceptibility in epileptic chickens is due to an autosomal recessive mutation. In 3-day-old chicks homozygous for the epilepsy gene (epileptics), elevation of body temperature using microwave diathermy evoked an initial febrile seizure resembling the clonic seizures evoked in epileptic chicks by photic stimulation. After complete recovery, this was followed by a clonic-tonic seizure. In nonepileptic heterozygote hatchmates (carriers) of the same age, only the latter seizure pattern was observed. In 16- to 17-day-old chicks of either phenotype, both seizure patterns were observed during hyperthermia. In all cases, the temperature at which seizures occurred was significantly lower in epileptic than in nonepileptic chicks, indicating a lower threshold for febrile seizures when there is an inherited predisposition to convulse. The occurrence of seizures was dependent on the body temperature and not on the rate of rise of temperature. Elevation of the brain gamma-aminobutyric acid (GABA) concentrations by administration of the GABA transaminase inhibitor gamma-vinyl GABA reduced the incidence of the initial febrile seizures and increased the latency in those birds that were not fully protected.
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PMID:Experimental febrile convulsions in epileptic chickens: the anticonvulsant effect of elevated gamma-aminobutyric acid concentrations. 404 16

Alterations in gamma-aminobutyric acid (GABA) metabolism have been investigated in the kindling model of epilepsy. Numerous generalized seizures were induced by amygdala-kindling stimulations in rats. One week after the last stimulation, there were no changes in GABA levels nor in the activity of enzymes responsible for the synthesis (glutamic acid decarboxylase) and catabolism (GABA transaminase and succinyl semialdehyde dehydrogenase). These results do not exclude other changes in GABA function as modifications of transport or receptors.
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PMID:Absence of modifications in gamma-aminobutyric acid metabolism after repeated generalized seizures in amygdala-kindled rats. 408 36

One of the defects in human epilepsy appears to be the suboptimal functioning of at least certain central gamma-aminobutyric acid (GABA)-mediated synapses. Of the several approaches for the manipulation of the functional state of such synapses that have been investigated, the possibility of interference with GABA metabolism and GABA transport processes is reviewed. It is concluded that the efficiency of inhibitors of the GABA-metabolizing enzyme, GABA transaminase, as antiepileptic drugs is related to the ability of the inhibitors to increase selectively the synaptic or transmitter-related GABA levels. Whether or not this reflects different modes of action of these inhibitors on neuronal and glial GABA transaminase remains to be established. Inhibition of the GABA transport mechanisms seems to represent an alternative approach to increase synaptic GABA levels. Evidence is presented that inhibitors of glial GABA uptake possess anticonvulsant activity. A comparison of drugs that inhibit both neuronal and glial GABA uptake with selective glial GABA uptake inhibitors indicates that the latter type of inhibitor most effectively blocks seizure activity. Such a drug is 4,5,6,7-tetrahydroisoxazolo[4,5c]pyridin-3-ol (THPO), which unfortunately lacks the important property of easy penetration of the blood-brain barrier. Prodrugs of this glial-selective GABA uptake inhibitor may have pharmacological and therapeutic interest.
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PMID:Transport and metabolism of gamma-aminobutyric acid in neurons and glia: implications for epilepsy. 631 24

We studied the effects of microinjected drugs and brainstem lesions on motor and limbic seizures in the kindling model of epilepsy. The duration of motor seizures was determined by timing the colonic and tonic movements of the extremities. The duration of limbic seizures was determined by measuring afterdischarge recorded on the electroencephalogram. Bilateral microinjection of a gamma-aminobutyric acid (GABA) agonist, muscimol, into the area of the substantia nigra (SN) markedly suppressed both motor and limbic seizures induced by stimulation of amygdala, olfactory structures, or lateral entorhinal cortex. Microinjection of saline did not suppress seizures. The suppressive effect of muscimol: (i) dissipated after several hours and was dependent on dose; (ii) was due to an elevation of the seizure threshold, since typical seizures could be elicited with electrical current far exceeding the threshold; and (iii) exhibited spatial specificity since muscimol injections 1 to 2 mm dorsal to the SN or into neocortex did not suppress the seizures. The actions of muscimol were probably mediated by its GABA agonist properties, since microinjection of an irreversible inhibitor of GABA transaminase (gamma-vinyl GABA) into the area of the SN also suppressed kindled seizures. Destruction of brainstem structures was produced by microinjection of the neurotoxin, N-methyl-D,L-aspartate. Seizures were markedly suppressed in animals with bilateral destruction of the SN but not in animals in which the SN was spared bilaterally. We interpret the data to indicate that the SN is the site at which the GABA agonists and lesions act to raise the threshold for kindled seizures. The suppression of limbic seizures indicates that this brainstem nucleus can regulate the intrinsic neuronal excitability of hemispheric sites.
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PMID:Evidence implicating substantia nigra in regulation of kindled seizure threshold. 648 54

Vigabatrin (VGB) is an antiepileptic drug (AED) that acts by irreversibly inhibiting gamma-aminobutyric acid transaminase (GABA-T). To evaluate immune responses to GVG, we studied 29 idiopathic or symptomatic epileptic children and also examined a control group (n = 15). Epileptic children were tested before and after 1 and 3 months of VGB treatment. Whole blood was used to connect subsets with commercial monoclonal antibodies. Peripheral blood mononuclear cells (PBMC) were used to assess natural killer (NK) cell activity and lymphocyte response to phytohemagglutinin (PHA) and concavalin A (Con A). Immunoglobulin (Ig) levels were tested in serum. At baseline, no immunologic abnormalities were observed in either control or treated patients. During treatment, the percentage and absolute number of B lymphocytes, serum concentration of Ig, number of T total mature lymphocytes (CD3), T-rosetting lymphocytes (CD11), T-helper cells (CD4), and mitogenic response of lymphocytes remained unchanged. Several other immunologic responses showed a statistically significant increase after 1 and 3 months of VGB treatment, however, including the percentage and absolute number of T-suppressor cells (CD8) and NK cells and NK cell activity. The correlation between number of NK cells and NK cell activity was significant. Data obtained demonstrated that VGB may interfere with the modulation of the immune system, especially cytotoxic cell populations.
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PMID:Immunologic aspects of vigabatrin treatment in epileptic children. 760 23

Vigabatrin (gamma-vinyl-GABA or GVG) is an irreversible inhibitor of gamma-aminobutyric acid transaminase (GABA-T), which is an enzyme responsible for gamma-aminobutyric acid (GABA) catabolism. Inhibition of GABA catabolism increases brain concentration of GABA, a neural inhibitor. GVG has been found to be a potent new anti-epileptic drug, especially in the treatment of refractory epilepsy, in particular of complex partial seizures. Three patients who developed a severe status epilepitus while on GVG treatment are reported. A possible proconvulsive effect of GVG is hypothesized, which might result from disinhibition in the nigro-collicular pathway due to increased GABA-levels.
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PMID:Status epilepticus during vigabatrin treatment: a report of three cases. 767 Jul 70

Previous studies have implicated a decreased efficacy of GABA as an important defect subserving the audiogenic seizures of the genetically epilepsy-prone rat (GEPR-9). The inferior colliculus (IC) is a critical site for audiogenic seizure (AGS) initiation, and the pontine reticular formation (PRF) is implicated in the propagation of AGS and in other generalized seizure models. The present study observed that microinjection of baclofen, a GABA-B receptor agonist, into IC protects against AGS, and blockade of the breakdown of endogenous GABA by gabaculine, a GABA transaminase inhibitor, increased GABA levels and blocked AGS susceptibility in the GEPR-9. Microinjection of baclofen or gabaculine into the PRF reduced AGS severity, but the doses required were considerably greater and the degree of anticonvulsant effect was less. Uptake of [3H]GABA into GEPR-9 synaptosomes from the IC is significantly increased as compared to normal, which could contribute to the diminished effectiveness of GABA in the GEPR-9. Previous studies indicate that GABA-A receptor agonists block AGS with IC microinjection, and recent data indicate that blockade of GABA uptake in this nucleus significantly reduced AGS severity. These data taken together strongly support the critical importance of the defect in GABA function in the IC in modulating susceptibility to audiogenic seizure initiation in the GEPR-9.
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PMID:GABA in the inferior colliculus plays a critical role in control of audiogenic seizures. 800 65

A 32 year old patient with refractory complex partial seizures was treated with vigabatrin for 3.5 years. Before starting treatment and at 42 months, lumbar punctures were done and the CSF analyzed for amino acids including GABA. Although the patient experienced a 50% seizure reduction, he underwent a left sided temporal lobectomy, and the tissue sample was also analyzed for amino acid content. It was found that vigabatrin caused a three-fold increase in total and free GABA in both the tissue sample and CSF. There were no other significant changes in the other amino acids analyzed. Seizure reduction seen initially was maintained over the long-term observation period. The finding of a specific increase of GABA in brain tissue and CSF of this patient treated with vigabatrin provides additional support to the concept that the primary effect of vigabatrin is as a selective enzyme activated irreversible inhibitor of GABA transaminase.
Epilepsy Res 1993 Dec
PMID:Effect of long-term vigabatrin therapy on GABA and other amino acid concentrations in the central nervous system--a case study. 811 75


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