γ-Glutamyltaurine has potent and long-lasting antiepileptic action as demonstrated by intra-amygdaloid injection in amygdala-kindled rats

Uemura, Shuji; Ienaga, Kazuharu; Higashiura, Kunihiko; Kimura, Hiroshi

doi:10.1016/0006-8993(92)91150-d

Cited by 11 publications

(3 citation statements)

References 16 publications

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“…Several of the endogenous y-glutamyl peptides, including GSH and GSSH, interact with excitatory amino acid receptors (Varga et al, 1989;Leslie et al, 1992) . Some of these peptides have been shown to antagonize Glu-evoked excitatory amino acid receptor responses (Varga et al, 1992) and reduce excitatory amino acid-induced seizure activity (Mathis et al, 1990;Uemura et al, 1992) . These peptides may consequently attenuate Glu-induced neurotoxicity during ischemia and, if present in sufficient extracellular concentrations, act as endogenous neuroprotective agents .…”

Section: Microdialysis Experimentsmentioning

confidence: 99%

Increased Intra‐ and Extracellular Concentrations of γ‐Glutamylglutamate and Related Dipeptides in the Ischemic Rat Striatum: Involvement of γ‐Glutamyl Transpeptidase

Orwar

Andiné

et al. 1994

Journal of Neurochemistry

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The present work relates to the possibility that the ATP‐independent enzyme γ‐glutamyl transpeptidase (EC 2.3.2.2), which has been postulated to be part of an amino acid uptake system, is active during cerebral ischemia. This was evaluated in the ischemic rat striatum by determination of intra‐ and extracellular concentrations of γ‐glutamyl dipeptides (the products of the transpeptidation) and glutathione (the physiological γ‐glutamyl donor). An ischemic period (0–30 and 31–60 min) resulted in prominent increases in the respective concentration of extracellular γ‐glutamylglutamate (24‐ and 67‐fold), γ‐glutamyltaurine + γ‐glutamylglycine (5.8‐ and 19‐fold), and γ‐glutamylglutamine (2.6‐ and 6.8‐fold) as revealed using in vivo microdialysis. The changes coincided with increased respective extracellular concentrations of glutamate (83‐ and 115‐fold), taurine (17‐ and 25‐fold), glycine (4.6‐ and 6.1‐fold), and glutamine (1.7‐ and 2.1‐fold). Furthermore, under anoxic conditions in vitro (0–30 and 0–60 min), respective striatal tissue concentrations were increased for γ‐glutamylglutamate (20‐ and 17‐fold), γ‐glutamyltaurine (6.7‐ and 11‐fold), γ‐glutamylglutamine (1.7‐ and 1.2‐fold), and γ‐glutamylglycine (14‐ and 18‐fold), whereas glutathione levels were, on an average, decreased by ∼350 µM. In summary, γ‐glutamyl transpeptidase is involved in de novo dipeptide synthesis in the mammalian brain during anoxic conditions, indicating transport of amino acids such as glutamate.

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Section: Microdialysis Experimentsmentioning

confidence: 99%

Increased Intra‐ and Extracellular Concentrations of γ‐Glutamylglutamate and Related Dipeptides in the Ischemic Rat Striatum: Involvement of γ‐Glutamyl Transpeptidase

Orwar

Andiné

et al. 1994

Journal of Neurochemistry

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“…Our results indicate that, despite the high K m of taurine for the γ-GCS reaction, its abundant presence indeed also enables the generation of γ-Glu-Tau by γ-GCS [223,224]. The resulting γ-Glu-Tau may interact with excitatory aminoacidergic neurotransmission [225] and exert antiepileptic actions [226], although the nature of its function remains ambiguous [227]. GGT and γ-GCS appear to be the enzymes that are responsible for the production of various γ-glutamyl peptides, although the amount and diversity of γ-glutamyl peptides are small in the normal mouse brain compared to the liver and kidney [224].…”

Section: Production Of a Variety Of γ-Glutamyl Peptides By Means Of γ...mentioning

confidence: 88%

Critical Roles of the Cysteine–Glutathione Axis in the Production of γ-Glutamyl Peptides in the Nervous System

Fujii

Osaki

Soma

et al. 2023

IJMS

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γ-Glutamyl moiety that is attached to the cysteine (Cys) residue in glutathione (GSH) protects it from peptidase-mediated degradation. The sulfhydryl group of the Cys residue represents most of the functions of GSH, which include electron donation to peroxidases, protection of reactive sulfhydryl in proteins via glutaredoxin, and glutathione conjugation of xenobiotics, whereas Cys-derived sulfur is also a pivotal component of some redox-responsive molecules. The amount of Cys that is available tends to restrict the capacity of GSH synthesis. In in vitro systems, cystine is the major form in the extracellular milieu, and a specific cystine transporter, xCT, is essential for survival in most lines of cells and in many primary cultivated cells as well. A reduction in the supply of Cys causes GPX4 to be inhibited due to insufficient GSH synthesis, which leads to iron-dependent necrotic cell death, ferroptosis. Cells generally cannot take up GSH without the removal of γ-glutamyl moiety by γ-glutamyl transferase (GGT) on the cell surface. Meanwhile, the Cys–GSH axis is essentially common to certain types of cells; primarily, neuronal cells that contain a unique metabolic system for intercellular communication concerning γ-glutamyl peptides. After a general description of metabolic processes concerning the Cys–GSH axis, we provide an overview and discuss the significance of GSH-related compounds in the nervous system.

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“…In the past, structure–activity relation (SAR) studies have been performed on taurine, in order to create a CNS‐active taurine derivative that would penetrate the brain better than taurine itself. Of these derivatives, γ ‐glutamyltaurine showed potent and long‐lasting antiepileptic action in kindled rats (Uemura et al ., 1992). The most successful of the taurine derivatives was taltrimide (phtalimidoethanesulfo‐ N ‐isopropylamide), that reached phase II clinical trials in epileptic patients, but development was stopped possibly because of the pharmacokinetic interactions with other AEDs and lack of efficacy (Kontro et al ., 1983; Koivisto et al ., 1986; Keranen et al ., 1987).…”

Section: Introductionmentioning

confidence: 99%

Anticonvulsant activity, teratogenicity and pharmacokinetics of novel valproyltaurinamide derivatives in mice

Isoherranen

Yagen

Spiegelstein

et al. 2003

British J Pharmacology

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1 The purpose of this study was to synthesize novel valproyltaurine (VTA) derivatives including valproyltaurinamide (VTD), N-methyl-valproyltaurinamide (M-VTD), N,N-dimethyl-valproyltaurinamide (DM-VTD) and N-isopropyl-valproyltaurinamide (I-VTD) and evaluate their structurepharmacokinetic -pharmacodynamic relationships with respect to anticonvulsant activity and teratogenic potential. However, their hepatotoxic potential could not be evaluated. The metabolism and pharmacokinetics of these derivatives in mice were also studied. 2 VTA lacked anticonvulsant activity, but VTD, DM-VTD and I-VTD possessed anticonvulsant activity in the Frings audiogenic seizure susceptible mice (ED 50 values of 52, 134 and 126 mg kg À1 , respectively). 3 VTA did not have any adverse effect on the reproductive outcome in the Swiss Vancouver/Fnn mice following a single i.p. injection of 600 mg kg À1 on gestational day (GD) 8.5. VTD (600 mg kg À1 at GD 8.5) produced an increase in embryolethality, but unlike valproic acid, it did not induce congenital malformations. DM-VTD and I-VTD (600 mg kg À1 at GD 8.5) produced a significant increase in the incidence of gross malformations. The incidence of birth defects increased when the length of the alkyl substituent or the degree of N-alkylation increased. 4 In mice, N-alkylated VTDs underwent metabolic N-dealkylation to VTD. DM-VTD was first biotransformed to M-VTD and subsequently to VTD. I-VTD's fraction metabolized to VTD was 29%. The observed metabolic pathways suggest that active metabolites may contribute to the anticonvulsant activity of the N-alkylated VTDs and reactive intermediates may be formed during their metabolism. In mice, VTD had five to 10 times lower clearance (CL), and three times longer halflife than I-VTD and DM-VTD, making it a more attractive compound than DM-VTD and I-VTD for further development. VTD's extent of brain penetration was only half that observed for the Nalkylated taurinamides suggesting that it has a higher intrinsic activity that DM-VTD and I-VTD. 5 In conclusion, from this series of compounds, although VTD caused embryolethality, this compound emerged as the most promising new antiepileptic drug, having a preclinical spectrum characterized by the highest anticonvulsant potential, lowest potential for teratogenicity and favorable pharmacokinetics.

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γ-Glutamyltaurine has potent and long-lasting antiepileptic action as demonstrated by intra-amygdaloid injection in amygdala-kindled rats

Cited by 11 publications

References 16 publications

Increased Intra‐ and Extracellular Concentrations of γ‐Glutamylglutamate and Related Dipeptides in the Ischemic Rat Striatum: Involvement of γ‐Glutamyl Transpeptidase

Increased Intra‐ and Extracellular Concentrations of γ‐Glutamylglutamate and Related Dipeptides in the Ischemic Rat Striatum: Involvement of γ‐Glutamyl Transpeptidase

Critical Roles of the Cysteine–Glutathione Axis in the Production of γ-Glutamyl Peptides in the Nervous System

Anticonvulsant activity, teratogenicity and pharmacokinetics of novel valproyltaurinamide derivatives in mice

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