Selective GABA transporter inhibitors tiagabine and EF1502 exhibit mechanistic differences in their ability to modulate the ataxia and anticonvulsant action of the extrasynaptic GABA(A) receptor agonist gaboxadol

Research output: Contribution to journalJournal articleResearchpeer-review

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Selective GABA transporter inhibitors tiagabine and EF1502 exhibit mechanistic differences in their ability to modulate the ataxia and anticonvulsant action of the extrasynaptic GABA(A) receptor agonist gaboxadol. / Madsen, Karsten Kirkegaard; Ebert, Bjarke; Clausen, Rasmus Prætorius; Krogsgaard-Larsen, Povl; Schousboe, Arne; White, H Steve.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 338, No. 1, 01.07.2011, p. 214-219.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Madsen, KK, Ebert, B, Clausen, RP, Krogsgaard-Larsen, P, Schousboe, A & White, HS 2011, 'Selective GABA transporter inhibitors tiagabine and EF1502 exhibit mechanistic differences in their ability to modulate the ataxia and anticonvulsant action of the extrasynaptic GABA(A) receptor agonist gaboxadol', Journal of Pharmacology and Experimental Therapeutics, vol. 338, no. 1, pp. 214-219. https://doi.org/10.1124/jpet.111.179671

APA

Madsen, K. K., Ebert, B., Clausen, R. P., Krogsgaard-Larsen, P., Schousboe, A., & White, H. S. (2011). Selective GABA transporter inhibitors tiagabine and EF1502 exhibit mechanistic differences in their ability to modulate the ataxia and anticonvulsant action of the extrasynaptic GABA(A) receptor agonist gaboxadol. Journal of Pharmacology and Experimental Therapeutics, 338(1), 214-219. https://doi.org/10.1124/jpet.111.179671

Vancouver

Madsen KK, Ebert B, Clausen RP, Krogsgaard-Larsen P, Schousboe A, White HS. Selective GABA transporter inhibitors tiagabine and EF1502 exhibit mechanistic differences in their ability to modulate the ataxia and anticonvulsant action of the extrasynaptic GABA(A) receptor agonist gaboxadol. Journal of Pharmacology and Experimental Therapeutics. 2011 Jul 1;338(1):214-219. https://doi.org/10.1124/jpet.111.179671

Author

Madsen, Karsten Kirkegaard ; Ebert, Bjarke ; Clausen, Rasmus Prætorius ; Krogsgaard-Larsen, Povl ; Schousboe, Arne ; White, H Steve. / Selective GABA transporter inhibitors tiagabine and EF1502 exhibit mechanistic differences in their ability to modulate the ataxia and anticonvulsant action of the extrasynaptic GABA(A) receptor agonist gaboxadol. In: Journal of Pharmacology and Experimental Therapeutics. 2011 ; Vol. 338, No. 1. pp. 214-219.

Bibtex

@article{b5e89529d46b4880ab3cb4c3c0716c96,
title = "Selective GABA transporter inhibitors tiagabine and EF1502 exhibit mechanistic differences in their ability to modulate the ataxia and anticonvulsant action of the extrasynaptic GABA(A) receptor agonist gaboxadol",
abstract = "Modulation of the extracellular levels of GABA via inhibition of the synaptic GABA transporter GAT1 by the clinically effective and selective GAT1 inhibitor tiagabine [(R)-N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]nipecotic acid; Gabitril] has proven to be an effective treatment strategy for focal seizures. Even though less is known about the therapeutic potential of other GABA transport inhibitors, previous investigations have demonstrated that N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-hydroxy-4-(methylamino)-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol (EF1502), which, like tiagabine, is inactive on GABA(A) receptors, inhibits both GAT1 and the extrasynaptic GABA and betaine transporter BGT1, and exerts a synergistic anticonvulsant effect when tested in combination with tiagabine. In the present study, the anticonvulsant activity and motor impairment associated with systemic administration of gaboxadol (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol), which, at the doses used in this study (i.e., 1-5 mg/kg) selectively activates extrasynaptic a4-containing GABA(A) receptors, was determined alone and in combination with either tiagabine or EF1502 using Frings audiogenic seizure-susceptible and CF1 mice. EF1502, when administered in combination with gaboxadol, resulted in reduced anticonvulsant efficacy and Rotarod impairment associated with gaboxadol. In contrast, tiagabine, when administered in combination with gaboxadol, did not modify the anticonvulsant action of gaboxadol or reverse its Rotarod impairment. Taken together, these results highlight the mechanistic differences between tiagabine and EF1502 and support a functional role for BGT1 and extrasynaptic GABA(A) receptors.",
keywords = "Former Faculty of Pharmaceutical Sciences",
author = "Madsen, {Karsten Kirkegaard} and Bjarke Ebert and Clausen, {Rasmus Pr{\ae}torius} and Povl Krogsgaard-Larsen and Arne Schousboe and White, {H Steve}",
year = "2011",
month = "7",
day = "1",
doi = "10.1124/jpet.111.179671",
language = "English",
volume = "338",
pages = "214--219",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "1",

}

RIS

TY - JOUR

T1 - Selective GABA transporter inhibitors tiagabine and EF1502 exhibit mechanistic differences in their ability to modulate the ataxia and anticonvulsant action of the extrasynaptic GABA(A) receptor agonist gaboxadol

AU - Madsen, Karsten Kirkegaard

AU - Ebert, Bjarke

AU - Clausen, Rasmus Prætorius

AU - Krogsgaard-Larsen, Povl

AU - Schousboe, Arne

AU - White, H Steve

PY - 2011/7/1

Y1 - 2011/7/1

N2 - Modulation of the extracellular levels of GABA via inhibition of the synaptic GABA transporter GAT1 by the clinically effective and selective GAT1 inhibitor tiagabine [(R)-N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]nipecotic acid; Gabitril] has proven to be an effective treatment strategy for focal seizures. Even though less is known about the therapeutic potential of other GABA transport inhibitors, previous investigations have demonstrated that N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-hydroxy-4-(methylamino)-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol (EF1502), which, like tiagabine, is inactive on GABA(A) receptors, inhibits both GAT1 and the extrasynaptic GABA and betaine transporter BGT1, and exerts a synergistic anticonvulsant effect when tested in combination with tiagabine. In the present study, the anticonvulsant activity and motor impairment associated with systemic administration of gaboxadol (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol), which, at the doses used in this study (i.e., 1-5 mg/kg) selectively activates extrasynaptic a4-containing GABA(A) receptors, was determined alone and in combination with either tiagabine or EF1502 using Frings audiogenic seizure-susceptible and CF1 mice. EF1502, when administered in combination with gaboxadol, resulted in reduced anticonvulsant efficacy and Rotarod impairment associated with gaboxadol. In contrast, tiagabine, when administered in combination with gaboxadol, did not modify the anticonvulsant action of gaboxadol or reverse its Rotarod impairment. Taken together, these results highlight the mechanistic differences between tiagabine and EF1502 and support a functional role for BGT1 and extrasynaptic GABA(A) receptors.

AB - Modulation of the extracellular levels of GABA via inhibition of the synaptic GABA transporter GAT1 by the clinically effective and selective GAT1 inhibitor tiagabine [(R)-N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]nipecotic acid; Gabitril] has proven to be an effective treatment strategy for focal seizures. Even though less is known about the therapeutic potential of other GABA transport inhibitors, previous investigations have demonstrated that N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-hydroxy-4-(methylamino)-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol (EF1502), which, like tiagabine, is inactive on GABA(A) receptors, inhibits both GAT1 and the extrasynaptic GABA and betaine transporter BGT1, and exerts a synergistic anticonvulsant effect when tested in combination with tiagabine. In the present study, the anticonvulsant activity and motor impairment associated with systemic administration of gaboxadol (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol), which, at the doses used in this study (i.e., 1-5 mg/kg) selectively activates extrasynaptic a4-containing GABA(A) receptors, was determined alone and in combination with either tiagabine or EF1502 using Frings audiogenic seizure-susceptible and CF1 mice. EF1502, when administered in combination with gaboxadol, resulted in reduced anticonvulsant efficacy and Rotarod impairment associated with gaboxadol. In contrast, tiagabine, when administered in combination with gaboxadol, did not modify the anticonvulsant action of gaboxadol or reverse its Rotarod impairment. Taken together, these results highlight the mechanistic differences between tiagabine and EF1502 and support a functional role for BGT1 and extrasynaptic GABA(A) receptors.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1124/jpet.111.179671

DO - 10.1124/jpet.111.179671

M3 - Journal article

C2 - 21450931

VL - 338

SP - 214

EP - 219

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 1

ER -

ID: 35037390