Opposite effects of GABAB receptor antagonists on absences and convulsive seizures

Vergnes, Marguerite; Boehrer, Anny; Simler, S; Bernasconi, R.; Marescaux, Christian

doi:10.1016/s0014-2999(97)01085-6

Cited by 127 publications

(80 citation statements)

References 27 publications

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“…There are, however, opposing effects for GABA B receptor antagonists that have been observed in absence and convulsive-type seizures. Although the GABA B receptor antagonist CGP 35348 suppresses absence seizures, it exacerbates convulsive seizures at the same doses that offset absence seizures (Vergnes et al, 1997;Motalli et al, 1999). For our mouse model, this would imply that although the absence seizures may be treatable, CGP 35348 would actually exacerbate tonic-clonic seizures that occur during the critical period.…”

Section: Discussionmentioning

confidence: 95%

Therapeutic Intervention in Mice Deficient for Succinate Semialdehyde Dehydrogenase (γ-Hydroxybutyric Aciduria)

Gupta¹,

Greven²,

Jansen³

et al. 2002

J Pharmacol Exp Ther

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Therapeutic intervention for human succinic semialdehyde dehydrogenase (SSADH) deficiency (␥-hydroxybutyric aciduria) has been limited to vigabatrin (VGB). Pharmacologically, VGB should be highly effective due to 4-aminobutyrate-transaminase (GABA-transaminase) inhibition, lowering succinic semialdehyde and, thereby, ␥-hydroxybutyric acid (GHB) levels. Unfortunately, clinical efficacy has been limited. Because GHB possesses a number of potential receptor interactions, we addressed the hypothesis that antagonism of these interactions in mice with SSADH deficiency could lead to the development of novel treatment strategies for human patients. SSADH-deficient mice have significantly elevated tissue GHB levels, are neurologically impaired, and die within 4 weeks postnatally. In the current report, we compared oral versus intraperitoneal administration of VGB, CGP 35348 [3-aminopropyl(diethoxymethyl)phosphinic acid, a GABA B receptor antagonist], and the nonprotein amino acid taurine in rescue of SSADH-deficient mice from early death. In addition, we assessed the efficacy of the specific GHB receptor antagonist NCS-382 (6,7,8,9-tetrahydro-5-[H]benzocycloheptene-5-ol-6-ylideneacetic acid) using i.p. administration. All interventions led to significant lifespan extension (22-61%), with NCS-382 being most effective (50 -61% survival). To explore the limited human clinical efficacy of VGB, we measured brain GHB and ␥-aminobutyric acid (GABA) levels in SSADH-deficient mice receiving VGB. Whereas high-dose VGB led to the expected elevation of brain GABA, we found no parallel decrease in GHB levels. Our data indicate that, at a minimum, GHB and GABA B receptors are involved in the pathophysiology of SSADH deficiency. We conclude that taurine and NCS-382 may have therapeutic relevance in human SSADH deficiency and that the poor clinical efficacy of VGB in this disease may relate to an inability to decrease brain GHB concentrations.

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Section: Discussionmentioning

confidence: 95%

Therapeutic Intervention in Mice Deficient for Succinate Semialdehyde Dehydrogenase (γ-Hydroxybutyric Aciduria)

Gupta¹,

Greven²,

Jansen³

et al. 2002

J Pharmacol Exp Ther

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“…Animal models provide further evidence for a critical role of GABA B Rs and associated effector systems (K ϩ ͞Ca 2ϩ channels) in epilepsy. For example, GABA B antagonists suppress absence seizures whereas agonists exacerbate seizures in lethargic (lh) mice (23) and in a strain of rats (GAERS) with genetic absence epilepsy (40). This, together with the chromosomal localization, identify the GABA B R1 gene as a valid candidate gene for inherited forms of idiopathic generalized epilepsy.…”

Section: Resultsmentioning

confidence: 99%

Human γ-aminobutyric acid type B receptors are differentially expressed and regulate inwardly rectifying K ⁺ channels

Kaupmann

Schuler²,

Mosbacher³

et al. 1998

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

167

135

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ABSTRACT␥-Aminobutyric acid type B receptors (GABA B Rs) are involved in the fine tuning of inhibitory synaptic transmission. Presynaptic GABA B Rs inhibit neurotransmitter release by down-regulating high-voltage activated Ca 2؉ channels, whereas postsynaptic GABA B Rs decrease neuronal excitability by activating a prominent inwardly rectifying K ؉ (Kir) conductance that underlies the late inhibitory postsynaptic potentials. Here we report the cloning and functional characterization of two human GABA B Rs, hGABA B R1a (hR1a) and hGABA B R1b (hR1b). These receptors closely match the pharmacological properties and molecular weights of the most abundant native GABA B Rs. We show that in transfected mammalian cells hR1a and hR1b can modulate heteromeric Kir3.1͞3.2 and Kir3.1͞3.4 channels. Heterologous expression therefore supports the notion that Kir3 channels are the postsynaptic effectors of GABA B Rs. Our data further demonstrate that in principle either of the cloned receptors could mediate inhibitory postsynaptic potentials. We find that in the cerebellum hR1a and hR1b transcripts are largely confined to granule and Purkinje cells, respectively. This finding supports a selective association of hR1b, and not hR1a, with postsynaptic Kir3 channels. The mapping of the GABA B R1 gene to human chromosome 6p21.3, in the vicinity of a susceptibility locus (EJM1) for idiopathic generalized epilepsies, identifies a candidate gene for inherited forms of epilepsy.

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“…GABAB receptor antagonists are effective in suppressing absence seizures in almost all rodent models tested (Hosford et al, 1992;Marescaux et al, 1992;Snead, 1992;Vergnes et al, 1997;Hu et al, 2000). More recent evidence suggests GABAB antagonists may have some efficacy as novel neuroprotectants (e.g.…”

Section: Discussionmentioning

confidence: 99%

Role of γ-aminobutyric acid B (GABAB) receptors in the regulation of kainic acid-induced cell death in mouse hippocampus

Lee

Seo²,

Choi³

et al. 2005

Exp Mol Med

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Opposite effects of GABAB receptor antagonists on absences and convulsive seizures

Cited by 127 publications

References 27 publications

Therapeutic Intervention in Mice Deficient for Succinate Semialdehyde Dehydrogenase (γ-Hydroxybutyric Aciduria)

Therapeutic Intervention in Mice Deficient for Succinate Semialdehyde Dehydrogenase (γ-Hydroxybutyric Aciduria)

Human γ-aminobutyric acid type B receptors are differentially expressed and regulate inwardly rectifying K ⁺ channels

Role of γ-aminobutyric acid B (GABAB) receptors in the regulation of kainic acid-induced cell death in mouse hippocampus

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Opposite effects of GABAB receptor antagonists on absences and convulsive seizures

Cited by 127 publications

References 27 publications

Therapeutic Intervention in Mice Deficient for Succinate Semialdehyde Dehydrogenase (γ-Hydroxybutyric Aciduria)

Therapeutic Intervention in Mice Deficient for Succinate Semialdehyde Dehydrogenase (γ-Hydroxybutyric Aciduria)

Human γ-aminobutyric acid type B receptors are differentially expressed and regulate inwardly rectifying K + channels

Role of γ-aminobutyric acid B (GABAB) receptors in the regulation of kainic acid-induced cell death in mouse hippocampus

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Human γ-aminobutyric acid type B receptors are differentially expressed and regulate inwardly rectifying K ⁺ channels