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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(More)
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(More)
Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain. Once released, it is removed from the extracellular space by cellular uptake catalyzed by GABA transporter proteins. Four GABA transporters (GAT1, GAT2, GAT3 and BGT1) have been identified. Inhibition of the GAT1 by the clinically available anti-epileptic drug(More)
The synthesis, release, reuptake, and metabolism of the excitatory and inhibitory neurotransmitters glutamate and GABA, respectively, are tightly controlled. Given the role that these two neurotransmitters play in normal and abnormal neurotransmission, it is important to consider the processes whereby they are regulated. This brief review is focused(More)
β-Amino acids sharing a lipophilic diaromatic side chain were synthesized and characterized pharmacologically on mouse GABA transporter subtypes mGAT1-4. The parent amino acids were also characterized. Compounds 13a, 13b, and 17b displayed more than 6-fold selectivity for mGAT2 over mGAT1. Compound 17b displayed anticonvulsive properties inferring a role of(More)
It is clear that normal neuronal function relies on a tight balance between excitatory and inhibitory neurotransmission. Inhibitory signaling through the GABAergic system can be tightly regulated at the level of GABA uptake via GABA transporters (GAT). As such, selectively modulating the GABA uptake process through pharmacological agents has been an area of(More)
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(More)
Since it was first reported approximately 40 years ago that putative amino acid neurotransmitters, including GABA, would likely be inactivated by synaptic high-affinity transporters, there has been an exponential increase in interest in delineating the pharmacological characteristics of these transporters. During the 1980s and 1990s a large series of(More)
Astrocyte cultures were prepared from cerebral cortex of new-born and 7-day-old mice and additionally, the cultures from new-born animals were passaged as secondary cultures. The cultures were characterized by immunostaining for the astrocyte markers glutamine synthetase (GS), glial fibrillary acidic protein, and the glutamate transporters EAAT1 and EAAT2.(More)
The vast majority of excitatory synapses in the central nervous system (CNS) utilize glutamate as the neurotransmitter. The level of excitation appears to be under regulatory control by the major inhibitory neurotransmitter GABA, which is synthesized from glutamate by its decarboxylation catalysed by glutamate decarboxylase (GAD). The inactivation of GABA(More)