TY - JOUR

T1 - Neuronal and non-neuronal GABA transporters as targets for antiepileptic drugs

AU - Madsen, Karsten K

AU - White, H Steve

AU - Schousboe, Arne

N1 - Copyright © 2009 Elsevier Inc. All rights reserved.

PY - 2010

Y1 - 2010

N2 - Epileptic seizure activity is associated with an imbalance between excitatory and inhibitory synaptic activities. The latter is mediated by GABA, and several currently used antiepileptic drugs target entities of the GABAergic synapse such as the receptors or the inactivation mechanism consisting of transmembrane transport and enzymatic degradation. The development of tiagabine selectively inhibiting the GABA transporter GAT1 constitutes a proof of concept that the GABA transporters are interesting drug targets in the context of antiepileptic drugs. The review provides a detailed analysis of the role of such transporters pointing in particular to an interesting role of the transporters located extrasynaptically. It is suggested that the betaine-GABA transporter BGT1 should receive particular interest in this context as the GABA analogue EF 1502 (N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-4-(methylamino)-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol) has been shown to possess a novel anticonvulsant profile in animal models of epilepsy, involving the ability to inhibit GABA transport mediated by GAT1 and BGT1 at the same time.

AB - Epileptic seizure activity is associated with an imbalance between excitatory and inhibitory synaptic activities. The latter is mediated by GABA, and several currently used antiepileptic drugs target entities of the GABAergic synapse such as the receptors or the inactivation mechanism consisting of transmembrane transport and enzymatic degradation. The development of tiagabine selectively inhibiting the GABA transporter GAT1 constitutes a proof of concept that the GABA transporters are interesting drug targets in the context of antiepileptic drugs. The review provides a detailed analysis of the role of such transporters pointing in particular to an interesting role of the transporters located extrasynaptically. It is suggested that the betaine-GABA transporter BGT1 should receive particular interest in this context as the GABA analogue EF 1502 (N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-4-(methylamino)-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol) has been shown to possess a novel anticonvulsant profile in animal models of epilepsy, involving the ability to inhibit GABA transport mediated by GAT1 and BGT1 at the same time.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1016/j.pharmthera.2009.11.007

DO - 10.1016/j.pharmthera.2009.11.007

M3 - Journal article

C2 - 20026354

VL - 125

SP - 394

EP - 401

JO - Pharmacology and Therapeutics, Part A: Chemotherapy, Toxicology and

JF - Pharmacology and Therapeutics, Part A: Chemotherapy, Toxicology and

SN - 0163-7258

IS - 3

ER -