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James H Naismith - One of the best experts on this subject based on the ideXlab platform.
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pmp diketopiperazine adducts form at the active site of a plp dependent enzyme involved in formycin biosynthesis
Chemical Communications, 2019Co-Authors: Sisi Gao, H Liu, Valerie De Crecylagard, Wen Zhu, Nigel G J Richards, James H NaismithAbstract:ForI is a PLP-dependent enzyme from the biosynthetic pathway of the C-nucleoside antibiotic formycin. Cycloserine is thought to inhibit PLP-dependent enzymes by irreversibly forming a PMP–isoxazole. We now report that ForI forms novel PMP–diketopiperazine derivatives following incubation with both D and L Cycloserine. This unexpected result suggests chemical diversity in the chemistry of Cycloserine inhibition.
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inhibition of the plp dependent enzyme serine palmitoyltransferase by Cycloserine evidence for a novel decarboxylative mechanism of inactivation
Molecular BioSystems, 2010Co-Authors: Jonathan Lowther, David J. Clarke, Beverley A Yard, K A Johnson, L G Carter, Venugopal T Bhat, Marine C C Raman, Britta Ramakers, Stephen A Mcmahon, James H NaismithAbstract:Cycloserine (CS, 4-amino-3-isoxazolidone) is a cyclic amino acid mimic that is known to inhibit many essential pyridoxal 5′-phosphate (PLP)-dependent enzymes. Two CS enantiomers are known; D-Cycloserine (DCS, also known as Seromycin) is a natural product that is used to treat resistant Mycobacterium tuberculosis infections as well as neurological disorders since it is a potent NMDA receptor agonist, and L-Cycloserine (LCS) is a synthetic enantiomer whose usefulness as a drug has been hampered by its inherent toxicity arising through inhibition of sphingolipid metabolism. Previous studies on various PLP-dependent enzymes revealed a common mechanism of inhibition by both enantiomers of CS; the PLP cofactor is disabled by forming a stable 3-hydroxyisoxazole/pyridoxamine 5′-phosphate (PMP) adduct at the active site where the Cycloserine ring remains intact. Here we describe a novel mechanism of CS inactivation of the PLP-dependent enzyme serine palmitoyltransferase (SPT) from Sphingomonas paucimobilis. SPT catalyses the condensation of L-serine and palmitoyl-CoA, the first step in the de novo sphingolipid biosynthetic pathway. We have used a range of kinetic, spectroscopic and structural techniques to postulate that both LCS and DCS inactivate SPT by transamination to form a free pyridoxamine 5′-phosphate (PMP) and β-aminooxyacetaldehyde that remain bound at the active site. We suggest this occurs by ring opening of the Cycloserine ring followed by decarboxylation. Enzyme kinetics show that inhibition is reversed by incubation with excess PLP and that LCS is a more effective SPT inhibitor than DCS. UV-visible spectroscopic data, combined with site-directed mutagenesis, suggest that a mobile Arg378 residue is involved in Cycloserine inactivation of SPT.
Michael W. Otto - One of the best experts on this subject based on the ideXlab platform.
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a placebo controlled randomized trial of d Cycloserine augmentation of cue exposure therapy for smoking cessation
Cognitive Behaviour Therapy, 2019Co-Authors: Michael W. Otto, Jasper A. J. Smits, Gladys N Pachas, Corinne Cather, Susanne S Hoeppner, Samantha J Moshier, Bridget A Hearon, Heather Burrell Ward, Alexandra Laffer, Eden A EvinsAbstract:Recent studies underscore the importance of studying d-Cycloserine (DCS) augmentation under conditions of adequate cue exposure treatment (CET) and protection from reconditioning experiences. In th...
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d Cycloserine as an augmentation strategy with cognitive behavioral therapy for social anxiety disorder
American Journal of Psychiatry, 2013Co-Authors: Stefan G Hofmann, David Rosenfield, Jasper A. J. Smits, Michael W. Otto, Alicia E. Meuret, Naomi M. Simon, Luana Marques, Angela Fang, Candyce D Tart, Mark H. PollackAbstract:d-Cycloserine does not enhance the effectiveness of CBT for social anxiety disorder but could temporarily accelerate the speed of treatment response, reducing patient distress and limiting the avoidance tendencies of patients with anxiety disorders during exposure treatments.
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efficacy of d Cycloserine for enhancing response to cognitive behavior therapy for panic disorder
Biological Psychiatry, 2010Co-Authors: Michael W. Otto, Naomi M. Simon, David F Tolin, Godfrey D Pearlson, Shawnee L Basden, Suzanne A Meunier, Stefan G Hofmann, Katherine EisenmengerAbstract:Background Traditional combination strategies of cognitive-behavior therapy plus pharmacotherapy have met with disappointing results for anxiety disorders. Enhancement of cognitive-behavior therapy with d-Cycloserine (DCS) pharmacotherapy represents a novel strategy for improving therapeutic learning from cognitive-behavior therapy that remains untested in panic disorder. Method This is a randomized, double-blind, placebo-controlled augmentation trial examining the addition of isolated doses of 50 mg d-Cycloserine or pill placebo to brief exposure-based cognitive-behavior therapy. Randomized participants were 31 outpatients meeting DSM-IV criteria for panic disorder with or without agoraphobia, who were offered five sessions of manualized cognitive-behavior therapy emphasizing exposure to feared internal sensations (interoceptive exposure) but also including informational, cognitive, and situational exposure interventions. Doses of study drug were administered 1 hour before cognitive-behavior therapy sessions 3 to 5. The primary outcome measures were the Panic Disorder Severity Scale (PDSS) and Clinicians' Global Impressions of Severity. Results Results indicated large effect sizes for the additive benefit of d-Cycloserine augmentation of cognitive-behavior therapy for panic disorder. At posttreatment and 1 month follow-up, participants who received d-Cycloserine versus placebo had better outcomes on the PDSS and global severity of disorder and were significantly more likely to have achieved clinically significant change status (77% vs. 33%). There were no significant adverse effects associated with DCS administration. Conclusions This pilot study extends support for the role of d-Cycloserine in enhancing therapeutic learning from exposure-based cognitive-behavior therapy and is the first to do so in a protocol emphasizing exposure to feared internal sensations of anxiety in panic disorder.
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Augmentation of Exposure Therapy With D-Cycloserine for Social Anxiety Disorder
Archives of general psychiatry, 2006Co-Authors: Alicia E. Meuret, Jasper A. J. Smits, Naomi M. Simon, Mark H. Pollack, Katherine Eisenmenger, Michael Shiekh, Michael W. OttoAbstract:Context:Social anxiety disorder (SAD) is common and debilitating.Althoughexposuretherapyisoneofthemost effective forms of psychotherapy for this disorder, many patients remain symptomatic. Fear reduction in exposure therapy is similar to extinction learning, and early clinical data with specific phobias suggest that the treatment effects of exposure therapy for SAD may be enhanced with D-Cycloserine, an agonist at the glutamatergic N-methyl-D-aspartate receptor.
Wolfgang Loscher - One of the best experts on this subject based on the ideXlab platform.
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alterations in plasma and brain amino acids after administration of the glycine nmda receptor partial agonist d Cycloserine to mice and rats
European Journal of Pharmacology, 1995Co-Authors: Halina Baran, Martina Gramer, Wolfgang LoscherAbstract:The NMDA/glycine receptor partial agonist, D-Cycloserine, has recently been reported to exert anticonvulsant effects in different seizure models in mice and rats. In view of the high doses (> 100 mg/kg) needed for these effects, actions other than those mediated by the glycine site might be involved. In this respect, inhibition of pyridoxal phosphate-dependent enzymes involved in amino acid metabolism might play a role. In the present experiments, D-Cycloserine was administered at an anticonvulsant dose (320 mg/kg) to mice and rats and levels of 11 amino acids, including several neurotransmitters, were determined in brain cortex and plasma at different times after administration. In addition, the concentration of D-Cycloserine was determined in plasma and brain. Compared to peak concentrations of D-Cycloserine in plasma, only about 20% of D-Cycloserine appeared in the brain. The only marked alteration in brain amino acids was an increase in alanine levels, while amino acids acting as neurotransmitters were hardly altered. The data indicate that the anticonvulsant action of D-Cycloserine is not secondary to changes in levels of amino acid neurotransmitters.
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effect of the glycine nmda receptor partial agonist d Cycloserine on seizure threshold and some pharmacodynamic effects of mk 801 in mice
European Journal of Pharmacology, 1994Co-Authors: Piotr Wlaź, Halina Baran, Wolfgang LoscherAbstract:Acute treatment of mice with D-Cycloserine (a high efficacy, partial agonist at strychnine-insensitive glycine receptors) resulted in dose- and time-dependent increases in the threshold for electrically induced tonic seizures. This anticonvulsant effect was observed at doses which did not induce motor impairment, as determined by the rotarod test. Despite the relatively high intrinsic efficacy of D-Cycloserine at glycine receptors, this drug did not produce proconvulsant effects in mice at any of the doses (5-320 mg/kg) or time points examined. Prolonged treatment with D-Cycloserine led to a reduction of its anticonvulsant effect. Similar to D-Cycloserine, the uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 (dizocilpine), dose dependently increased the electroconvulsive threshold. Combined treatment with MK-801 and D-Cycloserine led to significant anticonvulsant effects, but these effects were simply additive and not synergistic. In contrast to anticonvulsant activity, the motor impairing effect of MK-801 was markedly potentiated by D-Cycloserine. The data substantiate that high efficacy glycine/NMDA receptor partial agonists such as D-Cycloserine exert anticonvulsant activity at non-toxic doses. The finding that motor impairing but not anticonvulsant effects of MK-801 were potentiated by D-Cycloserine suggests that different pharmacodynamic actions of NMDA receptor antagonists are differentially modulated by the glycine receptor, which could be related to the regional heterogeneity of the NMDA receptor complex in the brain.
Steven M. Levine - One of the best experts on this subject based on the ideXlab platform.
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substrate reduction intervention by l Cycloserine in twitcher mice globoid cell leukodystrophy on a b6 cast ei background
Neuroscience Letters, 2003Co-Authors: Sangita Biswas, Homigol Biesiada, Todd D Williams, Steven M. LevineAbstract:Abstract Globoid cell leukodystrophy (GCL) is usually a fatal demyelinating disease caused by mutations in galactosylceramidase, which normally recycles galactosylceramide, a predominant glycolipid of myelin, and psychosine. The initial pathology is thought to be due to the accumulation of psychosine in myelin-forming cells leading to their death. In this study, substrate reduction therapy using l -Cycloserine, an inhibitor of 3-ketodihydrosphingosine synthase, was examined in twitcher mice on a C57BL/6×CAST/Ei (B6;CAST/Ei) background, which mimics a late onset variant of GCL. A graded dose regimen of l -Cycloserine initiated before the onset of symptoms increased the lifespan by ∼45% and delayed the onset of weight loss while the administration of l -Cycloserine beginning after the onset of symptoms had no effect. Despite the pronounced effect for the early treatment regimen, B6;CAST/Ei twitcher mice still displayed a progressive disease leading to an early death.
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substrate reduction therapy enhances the benefits of bone marrow transplantation in young mice with globoid cell leukodystrophy
Pediatric Research, 2002Co-Authors: Sangita Biswas, Steven M. LevineAbstract:Globoid cell leukodystrophy is an autosomal recessive disease with progressive demyelination caused by a deficiency of the lysosomal enzyme galactosylceramidase. Bone marrow transplantation (BMT) is a therapeutic option for patients with late-onset disease and for patients with early onset disease that had an early diagnosis owing to an affected sibling. This therapy, however, typically is not effective for early onset disease when the diagnosis occurs after several months of life. In an effort to enable a broader range of patients to benefit from BMT, we tested whether combining substrate-reduction therapy with BMT would result in a greater benefit than either treatment alone in the twitcher mouse model of globoid cell leukodystrophy. Twitcher mice treated with l-Cycloserine, an inhibitor of 3-ketodyhydrosphingosine synthase, and transplanted with 50 ± 5 × 106 bone marrow cells on d 10 had a mean life-span of 112 d compared with 51 d for BMT alone (p < 0.001) or l-Cycloserine alone, which was previously reported to be 56 d. l-Cycloserine treatment also was initiated neonatally to determine whether it would allow for a delayed BMT to have therapeutic value. Twitcher mice given only BMT at 18 d or only a short course of l-Cycloserine died at 36 and 37 d, respectively. Twitcher mice given a short course of l-Cycloserine + BMT at 18 d lived to 58 d (p = 0.0006). In conclusion, substrate-reduction therapy enhanced the value of BMT in twitcher mice, suggesting that this combination strategy might benefit patients with globoid cell leukodystrophy.
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L-Cycloserine slows the clinical and pathological course in mice with globoid cell leukodystrophy (twitcher mice).
Journal of neuroscience research, 2000Co-Authors: Steven M. Levine, Tetyana V. Pedchenko, Illya G. Bronshteyn, David M. PinsonAbstract:Globoid cell leukodystrophy (Krabbe's disease) is an autosomal recessive disease that affects the lysosomal enzyme galactosylceramidase. Galactosylceramidase removes galactose from galactosylceramide and psychosine, which are derived from sphingosine. In the present study, L-Cycloserine (an inhibitor of 3-ketodyhydrosphingosine synthase) was administered to the twitcher mouse, an authentic model of globoid cell leukodystrophy. Twitcher mice treated with L-Cycloserine had a significantly longer life span and a delayed onset of weight loss than vehicle-injected twitcher mice. Pathological features such as macrophage infiltration and astrocyte gliosis also were less in treated twitcher mice. These results indicate that substrate reduction therapy may have therapeutic value for individuals with residual enzymatic activity, e.g., individuals with late onset disease or individuals with partial enzyme replacement via bone marrow transplantation. In these cases, a reduction in galactosylceramide and psychosine synthesis would enable residual enzymatic activity to keep up with the accumulation of these substrates that would otherwise lead to pathology.
Halina Baran - One of the best experts on this subject based on the ideXlab platform.
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alterations in plasma and brain amino acids after administration of the glycine nmda receptor partial agonist d Cycloserine to mice and rats
European Journal of Pharmacology, 1995Co-Authors: Halina Baran, Martina Gramer, Wolfgang LoscherAbstract:The NMDA/glycine receptor partial agonist, D-Cycloserine, has recently been reported to exert anticonvulsant effects in different seizure models in mice and rats. In view of the high doses (> 100 mg/kg) needed for these effects, actions other than those mediated by the glycine site might be involved. In this respect, inhibition of pyridoxal phosphate-dependent enzymes involved in amino acid metabolism might play a role. In the present experiments, D-Cycloserine was administered at an anticonvulsant dose (320 mg/kg) to mice and rats and levels of 11 amino acids, including several neurotransmitters, were determined in brain cortex and plasma at different times after administration. In addition, the concentration of D-Cycloserine was determined in plasma and brain. Compared to peak concentrations of D-Cycloserine in plasma, only about 20% of D-Cycloserine appeared in the brain. The only marked alteration in brain amino acids was an increase in alanine levels, while amino acids acting as neurotransmitters were hardly altered. The data indicate that the anticonvulsant action of D-Cycloserine is not secondary to changes in levels of amino acid neurotransmitters.
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the glycine nmda receptor partial agonist d Cycloserine blocks kainate induced seizures in rats comparison with mk 801 and diazepam
Brain Research, 1994Co-Authors: Halina Baran, Wolfgang Lo Scher, Meike MevissenAbstract:Abstract Systemic administration of kainic acid in the rat results in the development of a characteristic excitotoxic syndrome, consisting of automatisms (wet dog shakes, WDS), sustained limbic seizures and brain damage. Since kainate increases the release of excitatory amino acid neurotransmitters such as glutamate, this syndrome is thought to be due, at least in part, to excessive activation of glutamate receptors, particularlyof theN-methyl- D -aspartate (NMDA) subtype. We examined the effect of D -Cycloserine, a partial agonist for the NMDA receptor-associated glycine binding site, in the kainate model of limbic seizures in rats. For comparison, the uncompetitive NMDA antagonist MK-801 (dizocilpine) and the GABAmimetic anticonvulsant diazepam were used. D -Cycloserine exerted a potent, dose-dependent and long-lasting anticonvulsant effect against kainate-induced seizures. At 160 mg/kg, seizures were almost completely suppressed by D -Cycloserine over a 3 h observation period. No adverse effects were observed at anticonvulsant doses of D -Cycloserine. In contrast to its potent effect on kainate-induced seizures, D -Cycloserine did not significantly alter the number of automatisms (WDS) determined after kainate. MK-801, 0.3 mg/kg, also markedly reduced seizure severity in response to kainate, but this anticonvulsant effect was accompanied by marked motor impairment. Similarly, diazepam, 5 mg/kg, significantly attenuated kainate-induced seizures but marked ataxia was observed at this dosage. In contrast to D -Cycloserine, both MK-801 and diazepam reduced WDS behaviour caused by kainate. The data demonstrate that pharmacological manipulation of the strychnine-insensitive glycine site is a powerful means of protecting against kainate-induced seizures.
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effect of the glycine nmda receptor partial agonist d Cycloserine on seizure threshold and some pharmacodynamic effects of mk 801 in mice
European Journal of Pharmacology, 1994Co-Authors: Piotr Wlaź, Halina Baran, Wolfgang LoscherAbstract:Acute treatment of mice with D-Cycloserine (a high efficacy, partial agonist at strychnine-insensitive glycine receptors) resulted in dose- and time-dependent increases in the threshold for electrically induced tonic seizures. This anticonvulsant effect was observed at doses which did not induce motor impairment, as determined by the rotarod test. Despite the relatively high intrinsic efficacy of D-Cycloserine at glycine receptors, this drug did not produce proconvulsant effects in mice at any of the doses (5-320 mg/kg) or time points examined. Prolonged treatment with D-Cycloserine led to a reduction of its anticonvulsant effect. Similar to D-Cycloserine, the uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 (dizocilpine), dose dependently increased the electroconvulsive threshold. Combined treatment with MK-801 and D-Cycloserine led to significant anticonvulsant effects, but these effects were simply additive and not synergistic. In contrast to anticonvulsant activity, the motor impairing effect of MK-801 was markedly potentiated by D-Cycloserine. The data substantiate that high efficacy glycine/NMDA receptor partial agonists such as D-Cycloserine exert anticonvulsant activity at non-toxic doses. The finding that motor impairing but not anticonvulsant effects of MK-801 were potentiated by D-Cycloserine suggests that different pharmacodynamic actions of NMDA receptor antagonists are differentially modulated by the glycine receptor, which could be related to the regional heterogeneity of the NMDA receptor complex in the brain.
