The Inhibitory Neural Circuitry as Target of Antiepileptic Drugs

Böhme, Ingo; Lüddens, Hartmut

doi:10.2174/0929867013372319

Cited by 25 publications

(10 citation statements)

References 105 publications

(144 reference statements)

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“…This may partly re¯ect the dicult design of speci®c glycine agonists (Bohme & Luddens, 2001) and thereby a scarcity in relevant probes for pharmacological studies of the function of the glycine receptor. Another reason probably arises from the classical separation among inhibitory neurotransmitters: GABA for the upper part of the neuraxis and glycine for the lower part.…”

Section: Discussionmentioning

confidence: 99%

The anti‐epileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA‐ and glycine‐gated currents

Rigo

Hans

Nguyen

et al. 2002

British J Pharmacology

309

178

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1 In this study in vitro and in vivo approaches were combined in order to investigate if the antiepileptic mechanism(s) of action of levetiracetam (LEV; Keppra 1 ) may involve modulation of inhibitory neurotransmission. 2 GABA-and glycine-gated currents were studied in vitro using whole-cell patch-clamp techniques applied on cultured cerebellar granule, hippocampal and spinal neurons. Protection against clonic convulsions was assessed in vivo in sound-susceptible mice. The eect of LEV was compared with reference anti-epileptic drugs (AEDs): carbamazepine, phenytoin, valproate, clonazepam, phenobarbital and ethosuximide. 3 LEV contrasted the reference AEDs by an absence of any direct eect on glycine-gated currents. At high concentrations, beyond therapeutic relevance, it induced a small reduction in the peak amplitude and a prolongation of the decay phase of GABA-gated currents. A similar action on GABA-elicited currents was observed with the reference AEDs, except ethosuximide. 4 These minor direct eects contrasted with a potent ability of LEV (EC 50 =1 ± 10 mM) to reverse the inhibitory eects of the negative allosteric modulators zinc and b-carbolines on both GABA A and glycine receptor-mediated responses. . In contrast, the benzodiazepine receptor antagonist¯umazenil (up to 10 mg kg 71) was without any eect on the protection aorded by LEV. 7 The results of the present study suggest that a novel ability to oppose the action of negative modulators on the two main inhibitory ionotropic receptors may be of relevance for the antiepileptic mechanism(s) of action of LEV.

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Section: Discussionmentioning

confidence: 99%

The anti‐epileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA‐ and glycine‐gated currents

Rigo

Hans

Nguyen

et al. 2002

British J Pharmacology

309

178

View full text Add to dashboard Cite

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“…Diseases such as epilepsy, anxiety disorders, schizophrenia, drug addiction, and various pain states are related to the GABA system (24 -26), and pharmacological inhibition of GABA transport constitutes an attractive approach to increase overall GABA neurotransmission (27,28). So far, this concept has been exploited for the treatment of epilepsy where the GAT-1-selective inhibitor tiagabine is administered clinically as adjunctive therapy for partial seizures (29,30). Furthermore inhibition of GABA transport in general and tiagabine in particular has been suggested for the treatment of clinical conditions such as ischemia, anxiety, sleep disorders in the elderly, and neuropathic pain (31)(32)(33)(34).…”

mentioning

confidence: 99%

“…GAT-1 and GAT-3 are abundantly expressed throughout the rat, mouse, and human central nervous system and absent from the periphery (11-13, 28, 35-39), and thus these two subtypes have attracted considerable attention as potential drug targets (30,35,40). Mouse, rat, and human BGT-1 is expressed in both the brain and periphery (10,14,16,17) and believed to be involved in osmoregulation (18) but has recently also been suggested to play a role in the control of epilepsy (41)(42)(43).…”

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confidence: 99%

Cloning and Characterization of a Functional Human γ-Aminobutyric Acid (GABA) Transporter, Human GAT-2

Christiansen

Meinild

Jensen

et al. 2007

Journal of Biological Chemistry

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Plasma membrane ␥-aminobutyric acid (GABA) transporters act to terminate GABA neurotransmission in the mammalian brain. Intriguingly four distinct GABA transporters have been cloned from rat and mouse, whereas only three functional homologs of these transporters have been cloned from human. The aim of this study therefore was to search for this fourth missing human transporter. Using a bioinformatics approach, we successfully identified and cloned the full-length cDNA of a so far uncharacterized human GABA transporter (GAT). The predicted protein displays high sequence similarity to rat GAT-2 and mouse GAT3, and in accordance with the nomenclature for rat GABA transporters, we therefore refer to the transporter as human GAT-2. We used electrophysiological and cell-based methods to demonstrate that this protein is a functional transporter of GABA. The transport was saturable and dependent on both Na ؉ and Cl ؊ . Pharmacologically the transporter is distinct from the other human GABA transporters and similar to rat GAT-2 and mouse GAT3 with high sensitivity toward GABA and ␤-alanine. Furthermore the GABA transport inhibitor (S)-SNAP-5114 displayed some inhibitory activity at the transporter. Expression analysis by reverse transcription-PCR showed that GAT-2 mRNA is present in human brain, kidney, lung, and testis. The finding of the human GAT-2 demonstrates for the first time that the four plasma membrane GABA transporters identified in several mammalian species are all conserved in human. Furthermore the availability of human GAT-2 enables the use of all human clones of the GABA transporters in drug development programs and functional characterization of novel inhibitors of GABA transport.

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“…Conventional AEDs like VPA, benzodiazepines and phenobarbital are well known to enhance inhibitory events through inhibitory GABAergic system (Snyder and Badura 1998;Bohme and Luddens 2001). Primary afferent GABAergic neurons represent a predominantly inhibitory component of the GnRH neuronal network, which is important in pulsatile secretion of gonadotropins.…”

Section: Discussionmentioning

confidence: 99%