TY - JOUR

T1 - Synaptic and extrasynaptic GABA transporters as targets for anti-epileptic drugs

AU - Madsen, Karsten K

AU - Clausen, Rasmus P

AU - Larsson, Orla M

AU - Krogsgaard-Larsen, Povl

AU - Schousboe, Arne

AU - White, H Steve

N1 - Keywords: Acoustic Stimulation; Animals; Anisoles; Anticonvulsants; Behavior, Animal; Carrier Proteins; Cornea; Female; GABA Agonists; GABA Plasma Membrane Transport Proteins; Kindling, Neurologic; Male; Mice; Neuroprotective Agents; Nipecotic Acids; Seizures; Synapses

PY - 2009

Y1 - 2009

N2 - Inhibition of the GABA transporter subtype GAT1 by the clinically available anti-epileptic drug tiagabine has proven to be an effective strategy for the treatment of some patients with partial seizures. In 2005, the investigational drug EF1502 was described as possessing activity at both GAT1 and BGT-1. When combined with the GAT1 selective inhibitor tiagabine, EF1502 was found to possess a synergistic anti-convulsant action in the Frings audiogenic seizure-susceptible mouse model of reflex epilepsy. This effect was subsequently attributed to inhibition of BGT-1. In this study, the anti-convulsant effect of the GAT2/3 inhibitor SNAP-5114 was assessed in the Frings audiogenic seizure-susceptible mouse alone, and in combination with tiagabine and EF1502. The results showed that SNAP-5114 produced a synergistic anti-convulsant effect in combination with EF1502 but not when used in combination with tiagabine. These findings support anatomical evidence that GAT2/3 are most likely located at the synapse in close proximity to GAT1; whereas BGT-1 is located some distance away from the synapse and GAT1 and GAT2/3. Lastly, EF1502 and tiagabine were evaluated alone, and in combination, in the corneal kindled mouse model of partial epilepsy. The results of this evaluation provide further evidence in support of a role for BGT-1 in the control of seizure activity. In addition, they suggest that the combined inhibition of GAT1 and BGT-1 may afford some advantage over inhibiting either transporter alone.

AB - Inhibition of the GABA transporter subtype GAT1 by the clinically available anti-epileptic drug tiagabine has proven to be an effective strategy for the treatment of some patients with partial seizures. In 2005, the investigational drug EF1502 was described as possessing activity at both GAT1 and BGT-1. When combined with the GAT1 selective inhibitor tiagabine, EF1502 was found to possess a synergistic anti-convulsant action in the Frings audiogenic seizure-susceptible mouse model of reflex epilepsy. This effect was subsequently attributed to inhibition of BGT-1. In this study, the anti-convulsant effect of the GAT2/3 inhibitor SNAP-5114 was assessed in the Frings audiogenic seizure-susceptible mouse alone, and in combination with tiagabine and EF1502. The results showed that SNAP-5114 produced a synergistic anti-convulsant effect in combination with EF1502 but not when used in combination with tiagabine. These findings support anatomical evidence that GAT2/3 are most likely located at the synapse in close proximity to GAT1; whereas BGT-1 is located some distance away from the synapse and GAT1 and GAT2/3. Lastly, EF1502 and tiagabine were evaluated alone, and in combination, in the corneal kindled mouse model of partial epilepsy. The results of this evaluation provide further evidence in support of a role for BGT-1 in the control of seizure activity. In addition, they suggest that the combined inhibition of GAT1 and BGT-1 may afford some advantage over inhibiting either transporter alone.

U2 - 10.1111/j.1471-4159.2009.05982.x

DO - 10.1111/j.1471-4159.2009.05982.x

M3 - Journal article

C2 - 19393020

VL - 109

SP - 139

EP - 144

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

IS - Suppl. 1

ER -