Differential effects of glycine on the anticonvulsant activity of D-cycloserine and L-701,324 in mice

doi:10.1016/S1734-1140(11)70643-0

Pharmacological Reports

Volume 63, Issue 5, September–October 2011, Pages 1231-1234

https://doi.org/10.1016/S1734-1140(11)70643-0 Get rights and content

Abstract

The anticonvulsant effects of D-cycloserine, which is a partial agonist of the glycine/N-methyl-D-aspartate (NMDA) receptor, and L-701,324, which is a selective and potent antagonist that acts at the glycine site, were studied in electroshock-induced seizures in mice. Glycine, which is a natural full agonist that acts at the glycine site, enhanced the seizure threshold-increasing effect of D-cycloserine. L-701,324 produced a marked increase in the seizure threshold, which was significantly reversed by the administration of glycine. These results suggest that indirect glycine/NMDA antagonistic mechanisms may be responsible for the anticonvulsant action of D-cycloserine.

Introduction

D-Cycloserine is a moderate efficacy partial agonist that acts at the strychnine-insensitive glycine modula-tory site within the N-methyl-D-aspartate (NMDA)-receptor/ionophore complex [8]. The anticonvulsant effects of D-cycloserine were reported in several models of epilepsy, including maximal electroshock seizures and pentylenetetrazole-induced tonic seizures, and in the kindling model of epilepsy [10., 11., 12., 17, 18]. The mechanism of the anticonvulsant action of D-cycloserine is not fully delineated. Because its intrinsic efficacy at the glycine site represents 40–70% of the intrinsic efficacy of glycine [8], the anticonvulsant effects of D-cycloserine might be attributed to either an agonist (desensitization of the NMDA receptor) or antagonist effect (inhibition of the NMDA receptor). Therefore, we investigated the anticonvulsant activity of D-cycloserine in the absence or presence of exogenous glycine, which is a natural full agonist at the glycine site. The potent antagonist L-701,324 that acts at this site and has adequate central availability after systemic administration [3, 7, 13, 14, 19] was used for comparison with D-cycloserine.

Section snippets

Materials and Methods

The experiments were performed on experimentally naive male Swiss mice weighing 23–27 g and maintained under standard environmental conditions. The experimental protocol was approved by the institutional ethical committee, and all the procedures complied with the European Communities Council Directive of 24 November 1986 (86/609/EEC).

The maximal electroshock seizure threshold (MEST) test, which is a sensitive and reliable test to determine the threshold of grand-mal type seizures in humans [9],

Results and Discussion

Administration of D-cycloserine at a dose of 320 mg/ kg resulted in a significant threshold increase by 66%. Administration of glycine alone (200 mg/kg, ip) induced no anticonvulsant effect or neurotoxicity. Glycine at a dose of 200 mg/kg was administered 4 h before the test and significantly potentiated the ability of D-cycloserine to increase the seizure threshold (Fig. 1A ). Similar to D-cycloserine, L-701,324 was administered at a dose of 2 mg/kg and increased the seizure threshold by

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To our knowledge, this is the first comprehensive study exploring the antidepressant-like actions of L-701,324 in the CUMS model of depression. L-701,324 has been demonstrated to possess anxiolytic and anticonvulsant actions [37,38]. Our study further extends the understanding of L-70,1324′s pharmacological effects.
Antidepressants currently used in clinical practice have limitations such as low efficacy, slow onset and various adverse reactions. It has become necessary to develop novel antidepressants beyond monoaminergic drugs. L-701,324 is a potent NMDA receptor antagonist, and the purpose of this study was to investigate the possible antidepressant effects of L-701,324 in mice. Here, various methods including the forced swim test (FST), tail suspension test (TST), chronic unpredictable mild stress (CUMS) model of depression, western blotting and immunofluorescence, were used together. A single injection of L-701,324 exhibited antidepressant-like potential in the FST and TST without affecting the locomotor activity of mice. Repeated injection of L-701,324 not only prevented CUMS-induced depressive-like behaviors in mice, but also ameliorated the downregulating effects of CUMS on the hippocampal BDNF signaling cascade and neurogenesis. Furthermore, K252a, a potent inhibitor of the BDNF system, fully blocked the antidepressant-like activity of L-701,324 in mice. K252a administration also abolished the activating actions of L-701,324 on the hippocampal BDNF signaling cascade and neurogenesis in CUMS-treated mice. Collectively, these data indicated that L-701,324 possesses antidepressant-like activity in mice, which was mediated, at least in part, by promoting the hippocampal BDNF system.
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The anticonvulsant effect of the partial agonist of the glycine-binding site, D-cycloserine, probably involves desensitization of the NMDA receptor. Moreover, D-cycloserine potentiates anticonvulsant effects of some antiepileptic drugs and in low doses has a positive influence on memory processes [134, 135]. The new generation antiepileptic drug, harcoseride is an antagonist of the glycine binding site on NMDA receptor complex.
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Differential effects of glycine on the anticonvulsant activity of D-cycloserine and L-701,324 in mice

Abstract

Introduction

Section snippets

Materials and Methods

Results and Discussion

Eur J Pharmacol

Brain Res

Epilepsy Res

Epilepsy Res

Epilepsy Res

Pharmacol Rep

Eur J Pharmacol

Brain Res Bull

Eur J Pharmacol