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

Karsten Kirkegaard Madsen; Bjarke Ebert; Rasmus Prætorius Clausen; Povl Krogsgaard-Larsen; Arne Schousboe; H Steve White

doi:10.1124/jpet.111.179671

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

Karsten Kirkegaard Madsen, Bjarke Ebert, Rasmus Prætorius Clausen, Povl Krogsgaard-Larsen, Arne Schousboe, H Steve White

38 Citations (Scopus)

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 GABAA 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 α4-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.

Original language	English
Journal	Journal of Pharmacology and Experimental Therapeutics
Volume	338
Issue number	1
Pages (from-to)	214-219
ISSN	0022-3565
DOIs	https://doi.org/10.1124/jpet.111.179671
Publication status	Published - 1 Jul 2011

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Former Faculty of Pharmaceutical Sciences

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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

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

Research output: Contribution to journal › Journal article › Research › peer-review

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

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. doi: 10.1124/jpet.111.179671

Madsen, Karsten Kirkegaard ; Ebert, Bjarke ; Clausen, Rasmus Prætorius et al. / 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.

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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 GABAA 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 α4-containing GABAA 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 GABAA receptors.",

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