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.