Influence of inhibitors of the high affinity GABA uptake on seizure thresholds in mice

Frey, H.‐H.; Popp, Claudia; Löscher, Wolfgang

doi:10.1016/0028-3908(79)90108-4

Cited by 128 publications

(51 citation statements)

References 30 publications

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“…Three patients, two men and one woman, were studied while receiving vigabatrin for various periods of time as part of a phase-three trial. The first patient was taking vigabatrin (6 gm/day) and carbamazepine (1.6 gm/day), while patient two was treated with vigabatrin (6 gm (35,36). Briefly threedimensional (3-D) localization was achieved by using the 3-D-image-selected in vivo spectroscopy (ISIS) (37) sequence with 8-msec phase-swept hyperbolic secant inversion pulses (30) (,u=5; bandwidth=2000 Hz).…”

Section: Methodsmentioning

confidence: 99%

“…The GABAergic system is believed to have an important role in the origin and spread of seizure activity (3). Anticonvulsant properties have been shown for compounds that act to reduce the uptake of GABA from the extracellular space (4)(5)(6), enhance the activity of the GABA-benzodiazapine receptor complex, and block the degradation of GABA by GABA transaminase (7)(8)(9). Vigabatrin (4-aminohex-5-enoic acid) is a highly specific inhibitor of GABA transaminase (10).…”

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confidence: 99%

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Localized 1H NMR measurements of gamma-aminobutyric acid in human brain in vivo.

Rothman

Petroff

Behar

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

487

530

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Localized 'H NMR spectroscopy in conjunction with J editing was used to measure the concentration of -aminobutyric acid (GABA) in the occipital lobe of four control human volunteers and four epileptic volunteers who were receiving the drug vigabatrin. The GABA concentration measured in four nonepileptic subjects was 1.1 ± 0.1 #mol/cm3 of brain, which is in good agreement with previous values measured in surgicaly removed human cortex. A dosedependent elevation of GABA concentration was measured in patients receiving the GABA tra inhibitor vigabatrin, with the maximum measured level of 3.7 pmol/cm3 of brain measured at the highest dose (6 g per day) studied. 'H NMR measurements of GABA in those patients receiving GABA-elevating agents such as vigabatrin wiUl be of importance in establishing the relationship between seizure suppression and the concentration of brain GABA.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Localized 1H NMR measurements of gamma-aminobutyric acid in human brain in vivo.

Rothman

Petroff

Behar

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

487

530

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“…Since preferential inhibition of glial GABA uptake is assumed to lead to increased synaptic GABA levels, these compounds are putative anticonvulsant drugs. In agreement with this, it has recently been observed that intramuscular injection of THPO or ethylnipecotate in mice leads to increased synaptosomal GABA levels [Wood et al, 19801. In this context, it should be mentioned that ethylnipecotate, which is hydrolyzed in the brain to give nipecotic acid, has anticonvulsant properties in animals [Frey et al, 1979;Horton et al, 19791. These aspects are currently under further investigation.…”

Section: Discussionmentioning

confidence: 99%

Heterocyclic GABA analogues as new selective inhibitors of astroglial GABA transport

Schousboe

Larsson

Hertz

et al. 1981

Drug Development Research

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A series of heterocyclic GABA analogues were tested as inhibitors of neuronal and glial GABA transport and GABA-receptor binding. Four compounds were shown to be selective inhibitors of glial GABA uptake, and the inhibition was in each case of the competitive type. The compounds are: P-proline, homonipecotic acid, and the bicyclic isoxazoles THPO and THAO, the Ki values for the glial uptake of these compounds were 400, 700, 550, and 600 FM, respectively. The two latter compounds may be putative anticonvulsant drugs since they are likely to cross the blood-brain barrier, and since they almost exclusively interfere with glial GABA uptake, which presumably would lead to increased synaptic GABA levels in vivo. Key words: astrocytes, GABA transport, GABA analogues, GABA transport inhibitors, anticonvulsant drugsGABAergic neurotransmission, which is of major importance in the mammalian central nervous system [McGeer et al., 1978; Curtis, 19791, involves at least three different recognition sites. These are the neuronal [Sano and Roberts, 1961, 1963;Weinstein et al., 1965;Bloom and Iversen, 1971; Storm-Mathisen, 19761 and glial [Henn and Hamberger, 1971;Schon and Kelly, 1975; Schousboe et al., 1977al sodium-dependent carriers and the postsynaptic sodium-independent receptor [Peck et al

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“…Also, low doses of CL 218,872 were proconvulsant in the bicuculline and picrotoxin assays but not in the pentylenetetrazol test, whereas high doses were anticonvulsant [Melchior et al, 19831. Most GABA-mimetic agents have shown anticonvulsant properties in various seizure models [Frey et al, 1979;Loscher, 19821. Muscimol, the GABAA agonist that is bicuculline sensitive [Enna and Maggi, 19791, aminooxyacetic acid (AOAA), the GABA transaminase inhibitor [Enna and Maggi, 19791, baclofen, the GABAB agonist that is bicuculline insensitive [Bowery et al, 1980;Wilkin et al, 19811, and the anti-epileptic, valproic acid [Browne, 1980;Chapman et al, 19821 all dose-dependently antagonized yohirnbine-induced seizures.…”

Section: Discussionmentioning

confidence: 99%

Yohimbine‐induced seizures in mice: A model predictive of potential anxiolytic and GABA‐mimetic agents

Dunn¹,

Fielding²

1987

Drug Development Research

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Dunn, R.W., and S. Fielding: Yohimbine-induced seizures in mice: A model predictive of potential anxiolytic and GABA-mimetic agents. Drug Dev. Res. 10:177-188, 1987.Yohimbine potentiation of lethality in mice has been used as a model for the prediction of antidepressant agents [Quinton, 19631. However, prior to death or at sublethal doses, yohimbine induces clonic convulsions. In Swiss-Webster mice (20-28 g) individually placed in clear plastic cylinders, the CD5o (median convulsive dose) for yohimbine-induced seizures was 22.7 (18.9-27.3) mglkg sc (subcutaneously). For anticonvulsant screening, compounds were administered intraperitoneally at appropriate pretreatment times prior to the CDg5 dose of yohimbine (45 mglkg sc). The following anxiolytic and GABA-mimetic agents administered intraperitoneally dose-dependently antagonized yohimbine-induced clonic convulsions: diazepam (ED50 = 0.26 mglkg); chlordiazepoxide (2.0 mglkg); CGS 9896 (0.82 mglkg); CL 218,872 (3.7 mglkg); zopiclone (19.0 mglkg); tracazolate (61.3 mg/ kg); clonazepam (0.02 mg/kg); phenobarbital (9.0 mglkg); valproic acid (81.1 mglkg); trimethadione (163.0 mglkg); muscimol (0.82 mglkg); AOAA (16.0 mglkg); clonidine (0.22 mg/kg); and baclofen (4.0 mglkg). On the other hand, the antiepileptic agents diphenylhydantoin, ethosuximide, and carbamazepine as well as the benzodiazepine antagonists CGS 8216 and RO 15 1788 were inactive. The neuroleptics haloperidol, chlorpromazine, and thioridazine were inactive, while clozapine displayed anticonvulsant activity (ED50 = 30.7 mglkg). Other inactive compounds include phenotolamine, propranolol, atropine, alpha-methyltyrosine, PCPA, reserpine, buspirone, DMI, and imipramine. Since yohimbine has been reported to be anxiogenic in animals and man, this assay may be relevant for

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Influence of inhibitors of the high affinity GABA uptake on seizure thresholds in mice

Cited by 128 publications

References 30 publications

Localized 1H NMR measurements of gamma-aminobutyric acid in human brain in vivo.

Localized 1H NMR measurements of gamma-aminobutyric acid in human brain in vivo.

Heterocyclic GABA analogues as new selective inhibitors of astroglial GABA transport

Yohimbine‐induced seizures in mice: A model predictive of potential anxiolytic and GABA‐mimetic agents

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