Tiagabine

Schachter, Steven C.

doi:10.1111/j.1528-1157.1999.tb00915.x

Cited by 43 publications

(43 citation statements)

References 34 publications

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“…GABA-A-Rs have a variety of allosteric modulators (41). Drugs targeting GATs are also in current use (42). Because these medications, some currently approved for other conditions like epilepsy and migraine, show significant promise in EAE, they are attractive for testing in MS patients.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory role for GABA in autoimmune inflammation

Bhat¹,

Axtell²,

Mitra

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

427

381

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GABA, the principal inhibitory neurotransmitter in the adult brain, has a parallel inhibitory role in the immune system. We demonstrate that immune cells synthesize GABA and have the machinery for GABA catabolism. Antigen-presenting cells (APCs) express functional GABA receptors and respond electrophysiologically to GABA. Thus, the immune system harbors all of the necessary constituents for GABA signaling, and GABA itself may function as a paracrine or autocrine factor. These observations led us to ask further whether manipulation of the GABA pathway influences an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Increasing GABAergic activity ameliorates ongoing paralysis in EAE via inhibition of inflammation. GABAergic agents act directly on APCs, decreasing MAPK signals and diminishing subsequent adaptive inflammatory responses to myelin proteins.

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Section: Discussionmentioning

confidence: 99%

Inhibitory role for GABA in autoimmune inflammation

Bhat¹,

Axtell²,

Mitra

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

427

381

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“…This is of importance because MDL decreased TGB clearance with 20 ± 7 ml/min/kg from 89 ± 6 ml/min/kg. In both humans and rat, TGB is extensively metabolized by isoform 3A of the cytochrome P 450 family of enzymes (6). MDL also is a wellknown competitive inhibitor of CYP 450 3A metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…1). TGB binds reversibly to the GABA-uptake carrier GAT-1 with high selectivity, resulting in an increase in synaptic GABA concentrations (6)(7)(8)(9). MDL is a representative of the benzodiazepines (BZDs), a class of drugs from which clonazepam (CZP) is sometimes used as adjunctive therapy in the management of seizures.…”

mentioning

confidence: 99%

Pharmacodynamic Analysis of the Interaction between Tiagabine and Midazolam with an Allosteric Model That Incorporates Signal Transduction

Jonker¹,

Vermeij²,

Edelbroek³

et al. 2003

Epilepsia

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Summary:Purpose: The objective of this study was to characterize quantitatively the pharmacodynamic interaction between midazolam (MDL), an allosteric modulator of the ␥-aminobutyric acid subtype A (GABA A ) receptor, and tiagabine (TGB), an inhibitor of synaptic GABA uptake.Methods: The in vivo concentration-response relation of TGB was determined through pharmacokinetic/pharmacodynamic (PK/PD) modeling. Rats received a single intravenous dose of 10 mg/kg TGB in the absence and the presence of a steady-state plasma concentration of MDL. The EEG response in the 11.5-to 30-Hz frequency band was used as the pharmacodynamic end point.Results: Infusion of MDL resulted in a mean steady-state plasma concentration of 66 ± 3 ng/ml. A significant pharmacokinetic interaction with TGB was observed. MDL inhibited TGB clearance by 20 ± 7 ml/min/kg from the original value of 89 ± 6 ml/min/kg. However, no changes in plasma protein binding of both drugs were observed. The concentration-EEG relation of TGB was described by the sigmoid-E max model. The pharmacodynamic parameter estimates of TGB were: E max ‫ס‬ 327 ± 10 V, EC 50 ‫ס‬ 392 ± 20 ng/ml, and n H ‫ס‬ 3.1 ± 0.3. These values were not significantly different in the presence of MDL. Factors that may explain the lack of synergism were identified by a mechanism-based interaction model that separates the receptor activation from the signal-transduction process. High efficiency of signal transduction and the presence of a baseline response were shown to diminish the degree of synergism.Conclusions: We conclude that the in vivo pharmacodynamic interaction between MDL and TGB is additive rather than synergistic. This strongly suggests that allosteric modulation of the antiseizure activity of a GAT-1 inhibitor by a benzodiazepine does not offer a therapeutic advantage.

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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%

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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Tiagabine

Cited by 43 publications

References 34 publications

Inhibitory role for GABA in autoimmune inflammation

Inhibitory role for GABA in autoimmune inflammation

Pharmacodynamic Analysis of the Interaction between Tiagabine and Midazolam with an Allosteric Model That Incorporates Signal Transduction

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

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