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At least 217 records · Page 12Linked to original sources
PubMed2001

Synergic activity of D-cycloserine and beta-chloro-D-alanine against Mycobacterium tuberculosis.

D-Cycloserine (DCS) is a peptidoglycan inhibitor. Although very effective against Mycobacterium tuberculosis, it is seldom employed in the management of this infection due to its high toxicity. beta-Chloro-D-alanine (another peptidoglycan inhibitor) reduces the MIC of DCS from 50 to 2.5 mg/L at a concentration significantly below its MIC for this organism. A reduction in bacterial viability and significant growth inhibition (as quantified by the X/Y quotient for the Bactec radiometric procedure) were observed with subinhibitory concentrations of both drugs. It is suggested that this powerful synergic effect should be the object of in vivo and eventually clinical trials.

Cycloserine↗
PubMed1997

Nicotine and D-cycloserine enhance acquisition of water maze spatial navigation in aged rats.

We investigated the effect of nicotine, a nicotinic agonist, and D-cycloserine (DCS, a partial glycine-B agonist of the N-methyl-D-aspartate (NMDA) receptor complex) on aging-induced defects of water maze (WM) spatial navigation in rats. Nicotine (0.3 mg kg-1, s.c.) or DCS (10 mg kg-1, i.p.) enhanced acquisition of the WM task. A combination of subthreshold doses of nicotine (0.1 mg kg-1) and DCS (3 mg kg-1) improved WM acquisition. A subthreshold dose of a competitive NMDA antagonist, CPP (1 mg kg-1), blocked the effect of nicotine (0.3 mg kg-1) on WM acquisition. A nicotine antagonist, mecamylamine (10 mg kg-1), impaired WM acquisition and had no effect on retention, but did not block the effect of DCS 10 mg kg-1. The results suggest that nicotine and DCS synergistically enhance spatial navigation in aged rats.

Aging↗
PubMed1998

Tetrahydroaminoacridine, a cholinesterase inhibitor, and D-cycloserine, a partial NMDA receptor-associated glycine site agonist, enhances acquisition of spatial navigation.

The present study examines the efficacy of single and combined treatments with an antiocholinesterase, tetrahydroaminoacridine (THA, i.p.), and a glycine-B site partial agonist, D-cycloserine (DCS, i.p.) to alleviate water maze (WM) spatial navigation defect induced by medial septal (MS) lesion. THA 3 and DCS at 3 or 10 mg/kg improved acquisition of the WM test, but only DCS improved spatial bias. These drugs had no effect on consolidation. A combination of THA 3 and DCS 10 mg/kg enhanced WM acquisition more effectively than either of the treatments on their own. This suggests that combined modulation of acetylcholine and NMDA mechanisms may have greater therapeutic effect to stimulate cognitive dysfunctions.

Animals↗
PubMed1996

L-cycloserine, an inhibitor of sphingolipid biosynthesis, inhibits HIV-1 cytopathic effects, replication, and infectivity.

Drugs that reduce viral production or prevent viral spread by interference with the host's cellular components are unlikely to induce resistance, in contrast to treatment modalities that interact with the HIV-1 life cycle. Two features make L-cycloserine (L-CS) a candidate drug of this kind: (a) L-CS is a potent inhibitor of the sphingolipid pathway (b) sphingolipids, galactocerebrosides, and sulfatides have been shown, by others, to bind gp120. In a feasibility and efficacy study, we have found that L-CS inhibits HIV-1 replication in a CD4+ lymphoid cell line (CEM) as documented by the reduction of syncytium formation, the number of HIV-1 infected cells, and p24 protein production. This observation may lead to a new strategy for the treatment of HIV-1 infection.

Antimetabolites↗
PubMedDate not supplied

Facilitation of fear extinction by D-cycloserine: theoretical and clinical implications.

Anxiety disorders are among the most common psychological disturbances in the industrialized world. Current behavioral therapy procedures for these disorders are somewhat effective, but their efficacy could be substantially improved. Because these procedures are largely based on the process of extinction, manipulations that enhance extinction may lead to improvements in treatment effectiveness. We review the evidence that D-cycloserine (DCS), a partial NMDA agonist, facilitates extinction of learned fear in rats. Although only a few studies have examined the effects of DCS on extinction of learned fear, this work suggests that this drug may have a number of potential clinical benefits. In addition, attempts at interpreting this research illustrate our limited understanding of the processes involved in extinction.

Animals↗
PubMed2005

Characterization of Chlamydia MurC-Ddl, a fusion protein exhibiting D-alanyl-D-alanine ligase activity involved in peptidoglycan synthesis and D-cycloserine sensitivity.

Recent characterization of chlamydial genes encoding functional peptidoglycan (PG)-synthesis proteins suggests that the Chlamydiaceae possess the ability to synthesize PG yet biochemical evidence for the synthesis of PG has yet to be demonstrated. The presence of D-amino acids in PG is a hallmark of bacteria. Chlamydiaceae do not appear to encode amino acid racemases however, a D-alanyl-D-alanine (D-Ala-D-Ala) ligase homologue (Ddl) is encoded in the genome. Thus, we undertook a genetics-based approach to demonstrate and characterize the D-Ala-D-Ala ligase activity of chlamydial Ddl, a protein encoded as a fusion with MurC. The full-length murC-ddl fusion gene from Chlamydia trachomatis serovar L2 was cloned and placed under the control of the arabinose-inducible ara promoter and transformed into a D-Ala-D-Ala ligase auxotroph of Escherichia coli possessing deletions of both the ddlA and ddlB genes. Viability of the E. coliDeltaddlADeltaddlB mutant in the absence of exogenous D-Ala-D-Ala dipeptide became dependent on the expression of the chlamydial murC-ddl thus demonstrating functional ligase activity. Domain mapping of the full-length fusion protein and site-directed mutagenesis of the MurC domain revealed that the structure of the full fusion protein but not MurC enzymatic activity was required for ligase activity in vivo. Recombinant MurC-Ddl exhibited substrate specificity for D-Ala. Chlamydia growth is inhibited by D-cycloserine (DCS) and in vitro analysis provided evidence for the chlamydial MurC-Ddl as the target for DCS sensitivity. In vivo sensitivity to DCS could be reversed by addition of exogenous D-Ala and D-Ala-D-Ala. Together, these findings further support our hypothesis that PG is synthesized by members of the Chlamydiaceae family and suggest that D-amino acids, specifically D-Ala, are present in chlamydial PG.

Amino Acid Sequence↗
PubMed1977

An autopsy case of cycloserine poisoning.

Cycloserine was given to a 29-year-old girl with pulmonary tuberculosis for 500 days (total dose 250 g). Following this treatment, she began to show several psychiatric and neurologic symptoms and died. Histopathologically, deletion of the nerve cells in the cerebrum was diffusely observed, especially in the IIIrd layer of the frontal and temporal cortex and patchy demyelinations were found in the white matter of the parietal lobe. Characteristic findings were the change of small blood vessels and deletion of the nerve cell around the area of vessels in the hypothalamus, putamen and pallidum. The same changes of the blood vessels were found in the internal capsule. In the cerebellum, shrinkage of Purkinje cells and increase of Bergmann's glia were observed.

Adult↗
PubMedDate not supplied

Augmentation treatment of psychotherapy for anxiety disorders with D-cycloserine.

Anxiety disorders are among the most common mental disorders. One of the most effective strategies to treat anxiety disorders is exposure therapy with or without cognitive intervention. Fear reduction in exposure therapy is similar to extinction learning. Preclinical studies suggest that extinction learning can be blocked by antagonists at the glutamatergic N-methyl-D-aspartate (NMDA) receptor, and facilitated with D-cycloserine (DCS), a partial agonist at the glycine recognition site of the NMDA receptor in the amygdala. DCS is an established antibiotic drug for the chronic treatment of tuberculosis in humans, but has only recently been investigated as an augmentation therapy for psychological treatment procedures. The review of the literature provides preliminary support for the use of acute dosing of DCS as an adjunctive intervention to exposure therapy for anxiety disorders, including specific phobia and social anxiety disorder. Negative results have recently been reported in the treatment of subclinical fears of animals. These studies suggest that DCS needs to be administered on an acute rather than a chronic dosing schedule, include sufficient time for memory consolidation, and be administered together with psychological treatment that leaves sufficient room for further improvement. It remains to be seen whether these highly promising findings represent reliable pharmacological strategies to enhance exposure therapy of anxiety disorders.

Animals↗
PubMed1996

Influence of D-cycloserine on the anticonvulsant activity of phenytoin and carbamazepine against electroconvulsions in mice.

PURPOSE: D-Cycloserine (DCS) is a high-efficacy partial agonist at the strychnine-insensitive glycine modulatory site within the N-methyl-D-aspartate (NMDA)-receptor/ionophore complex. Previous studies demonstrated that DCS exhibits anticonvulsant activity in a variety of experimental epilepsy models. In this study, we determined the influence of DCS in subprotective doses on the anticonvulsant action of phenytoin (PHT) and carbamazepine (CBZ) in mice. METHODS: Two electroconvulsive tests were used, i.e., determination of seizure threshold and maximal electroshock seizures. Antiepileptic drug-induced motor and long-term memory deficits were quantified by using the chimney test and the passive-avoidance test, respectively. In addition, plasma levels of PHT and CBZ were measured by fluorescence polarization immunoassay to exclude any pharmacokinetic interactions. RESULTS: DCS, when used alone in doses of 80 and 160 mg/kg, significantly increased the threshold for electroconvulsive seizures. DCS in a wide range of doses (1.25-40 mg/kg) was combined with either PHT or CBZ and tested in electroconvulsive tests. DCS, at doses of 2.5 and 10 mg/kg, was the most effective in potentiating the threshold-increasing action of PHT; higher doses of DCS (20 and 40 mg/kg) were required to achieve a similar effect of CBZ. In maximal electroshock-induced seizures, DCS (10 mg/kg) augmented the protective action of PHT, but was ineffective at a dose of 40 mg/kg with CBZ. DCS did not potentiate the neurotoxicity produced by PHT and CBZ in the chimney test. Both PHT and CBZ induced impairments of long-term memory; PHT-induced memory adverse effects were counteracted by DCS (10 mg/kg). There was no such effect on CBZ-induced memory impairment, and a worsening influence was observed. Any pharmacokinetic interactions were excluded by measuring total and free plasma levels of both antiepileptic drugs. CONCLUSION: Our results suggest that combining DCS with PHT and CBZ may be beneficial in treating epileptic seizures.

Animals↗
PubMed2000

Characterization of a Mycobacterium smegmatis mutant that is simultaneously resistant to D-cycloserine and vancomycin.

A mutant of Mycobacterium smegmatis has been isolated that is simultaneously resistant to both D-cycloserine (D-CS) and vancomycin. Genetic complementation with a PBP4 homolog restores sensitivity to both drugs. Resistance to D-CS and vancomycin in this mutant is most likely due to a novel mechanism involving peptidoglycan assembly at the cell surface.

Amino Acid Sequence↗
PubMed2003

Roles of Mycobacterium smegmatis D-alanine:D-alanine ligase and D-alanine racemase in the mechanisms of action of and resistance to the peptidoglycan inhibitor D-cycloserine.

D-Cycloserine (DCS) targets the peptidoglycan biosynthetic enzymes D-alanine racemase (Alr) and D-alanine:D-alanine ligase (Ddl). Previously, we demonstrated that the overproduction of Alr in Mycobacterium smegmatis determines a DCS resistance phenotype. In this study, we investigated the roles of both Alr and Ddl in the mechanisms of action of and resistance to DCS in M. smegmatis. We found that the overexpression of either the M. smegmatis or the Mycobacterium tuberculosis ddl gene in M. smegmatis confers resistance to DCS, but at lower levels than the overexpression of the alr gene. Furthermore, a strain overexpressing both the alr and ddl genes displayed an eightfold-higher level of resistance. To test the hypothesis that inhibition of Alr by DCS decreases the intracellular pool of D-alanine, we determined the alanine pools in M. smegmatis wild-type and recombinant strains with or without DCS treatment. Alr-overproducing strain GPM14 cells not exposed to DCS displayed almost equimolar amounts of L- and D-alanine in the steady state. The wild-type strain and Ddl-overproducing strains contained a twofold excess of L- over D-alanine. In all strains, DCS treatment led to a significant accumulation of L-alanine and a concomitant decease of D-alanine, with approximately a 20-fold excess of L-alanine in the Ddl-overproducing strains. These data suggest that Ddl is not significantly inhibited by DCS at concentrations that inhibit Alr. This study is of significance for the identification of the lethal target(s) of DCS and the development of novel drugs targeting the D-alanine branch of mycobacterial peptidoglycan biosynthesis.

Alanine Racemase↗
PubMed1974

Enumeration of food-borne Clostridium perfringens in egg yolk-free tryptose-sulfite-cycloserine agar.

The SFP (Shahidi-Ferguson perfringens), TSC (tryptose-sulfite-cycloserine), EY (egg yolk)-free TSC, and OPSP (oleandomycin-polymyxin-sulfadiazine perfringens) agars have been tested for their suitability to enumerate Clostridium perfringens in naturally contaminated foods. Complete recoveries of C. perfringens were obtained in each of the four media, but only the TSC and EY-free TSC agars were sufficiently selective to ensure subsequent confirmatory tests without interference from facultative anaerobes. Because of some disadvantages associated with the use of egg yolk, EY-free TSC agar is recommended for enumeration of C. perfringens in foods. Several conditions for convenient shipment of foods and C. perfringens isolates with minimum loss of viability have been tested. The highest viable counts were preserved when foods were mixed 1:1 (wt/vol) with 20% glycerol and kept in a container with dry ice. Isolated C. perfringens strains remained viable for at least 2 weeks at ambient temperatures on blood agar slopes with a 2% agar overlay in screw-cap culture tubes.

Agar↗
PubMed1974

Enumeration of fecal Clostridium perfringens spores in egg yolk-free tryptose-sulfite-cycloserine agar.

The Shahidi-Ferguson perfringens, tryptose-sulfite-cycloserine (TSC), and egg yolk-free TSC agars have been tested for their suitability to enumerate fecal spores of Clostridium perfringens. When these spores comprised at least 20% of the total anaerobe spores, equally accurate counts were obtained in the three media. With lower ratios of C. perfringens spores, the most accurate counts were obtained in egg yolk-free TSC agar. The median C. perfringens spore count of 60 normal fecal specimens was log 3.4/g. A nonmotile, sulfite- and nitrate-reducing Clostridium, not identifiable with any known clostridial species, was isolated from 14 out of 60 fecal specimans. It was not differentiated from C. perfringens in the nitrite motility test, but could be distinguished by its inability to liquefy gelatin.

Agar↗
PubMed1972

Effect of D-cycloserine on transformation in group H streptococcus, strain Challis.

d-Cycloserine (d-CS), a selective inhibitor of bacterial cell wall biosynthesis, inhibited transformation in group H streptococcus, strain Challis, by preventing the development of the competent state. The incubation of strain Challis cells with d-CS resulted in the production of a substance which inhibited the action of competence factor on these cells. d-CS had an enhancing effect on transformation when deoxyribonucleic acid uptake or phenotypic expression was allowed to occur in its presence.

Cell Wall↗
PubMed1997

Use of cycloserine-cefoxitin-fructose agar and L-proline-aminopeptidase (PRO Discs) in the rapid identification of Clostridium difficile.

The PRO Disc (Carr-Scarborough Microbiologicals, Inc., Decatur, Ga.) can be used to screen for L-proline-aminopeptidase produced by Clostridium difficile grown on cycloserine-cefoxitin-fructose agar (CCFA). Fifty stored isolates of C. difficile (48 toxin-positive and 2 toxin-negative isolates) and 47 fresh C. difficile isolates (39 toxin-positive and 8 toxin-negative isolates) were all PRO Disc positive. Other Clostridium species that were PRO Disc positive could be differentiated from C. difficile by failure to grow on CCFA, different colonial morphology on CCFA, or morphology upon Gram staining.

Agar↗
PubMed1999

Effects of D-cycloserine, a positive modulator of N-methyl-D-aspartate receptors, and ST 587, a putative alpha-1 adrenergic agonist, individually and in combination, on the non-delayed and delayed foraging behaviour of rats assessed in the radial arm maze.

The present study investigated whether alpha-1 adrenergic and glutamatergic N-methyl-D-aspartate (NMDA) receptor-mediated mechanisms interact in memory processes, by examining the effects of individual and combined systemic administration of ST 587, a putative alpha-1 agonist, and D-cycloserine (DCS), a partial agonist at the glycine-B binding site of the NMDA receptor, on the performance of rats in non-delayed and delayed (4-6 h) foraging behaviour in the radial arm maze task, using the delayed non-matching to sample (DNMTS) version. The results indicated that DCS (5.0 mg/kg) decreased working memory errors, i.e. the number of re-entries into the previously visited arms during the sampling phase. In addition, both ST 587 (100 microg/kg) and DCS (10 mg/kg), when administered alone 30 min before a sampling phase, improved retention of this task as reflected by the increased number of correct choices before the first error during the retention phase. The combined administration of ST 587 and DCS, however, did not lead to better retention in the DNMTS task compared with the administration of each of the drugs alone. Combinations of sub-threshold doses of ST 587 (50 or 75 microg/kg) and DCS (5.0 or 7.5 mg/kg) also did not improve retention in this task. DCS (5.0 or 7.5 mg/kg) increased activity as indicated by the increased number of arm entries in a given time during the sampling phase. These findings suggest that the systemic administration of a positive modulator of the NMDA receptor facilitates hippocampal-dependent memory functions, but that these effects are not enhanced by combined administration with an alpha-1 agonist, even though the alpha-1 agonist is effective when given alone. The results support the idea that NMDA receptors modulate both mnemonic and non-mnemonic functions in the brain.

Adrenergic alpha-Agonists↗