l-Cycloserine: Behavioural and biochemical effects after single and repeated administration to mice, rats and cats

Polc, P.; Pieri, L.; Bonetti, E. P.; Scherschlicht, R.; Moehler, H; Kettler, R.; Burkard, W. P.; Haefely, W.

doi:10.1016/0028-3908(86)90236-4

Cited by 19 publications

(20 citation statements)

References 24 publications

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“…Linked to its capacity to raise intracerebral GABA levels (Fig. 1), LCS has been piloted in several seizure models, including petit-mal seizures in the rat (Marescaux et al 1985) and audiogenic seizures in mice (Polc et al 1986). Nonetheless, clinical development of LCS has been hampered because it also inhibits the first enzyme of sphingolipid formation, 3-ketodihydrosphingosine synthase (serine palmitoyltransferase; Cho 2007).…”

Section: Treatment Strategies For Ssadh Deficiencymentioning

confidence: 99%

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Thirty years beyond discovery—Clinical trials in succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism

Vogel

Pearl

Theodore

et al. 2012

J of Inher Metab Disea

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Summary This review summarizes a presentation made at the retirement Symposium of Prof. dr. Cornelis Jakobs in November of 2011, highlighting the progress toward clinical trials in succinic semialdehyde dehydrogenase (SSADH) deficiency, a disorder first recognized in 1981. Active and potential clinical interventions, including vigabatrin, L-cycloserine, the GHB receptor antagonist NCS-382, and the ketogenic diet, are discussed. Several biomarkers to gauge clinical efficacy have been identified, including cerebrospinal fluid metabolites, neuropsychiatric testing, MRI, EEG, and measures of GABAergic function including (11C)flumazenil positron emission tomography (PET) and transcranial magnetic stimulation (TMS). Thirty years after its discovery, encompassing extensive studies in both patients and the corresponding murine model, we are now running an open-label trial of taurine intervention, and are poised to undertake a phase II trial of the GABAB receptor antagonist SGS742.

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Section: Treatment Strategies For Ssadh Deficiencymentioning

confidence: 99%

“…or i.p. in rodents) reducing hyperexcitability, while higher doses (30–100 mg/kg) evoke central depressant actions (Polc et al 1986). As well, the literature indicates that inhibition of sphingomyelin formation may be dose-dependent, and may not be substantial at low pharmacologic doses of LCS.…”

Section: Treatment Strategies For Ssadh Deficiencymentioning

confidence: 99%

Thirty years beyond discovery—Clinical trials in succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism

Vogel

Pearl

Theodore

et al. 2012

J of Inher Metab Disea

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“…Early LCS response was also described in rats, where inhibition of ALAT activity rapidly reached a peak merely 30–60 minutes post LCS injection [ 34 ]. One hour LCS-perfusion also resulted in a fast decrease of ALAT in rats [ 45 ]; whereas in mice an intra-peritoneal injection of the inhibitor affected ALAT and induced a moderate impairment of motor performance three hours after administration [ 46 ]. The recovery observed in surviving LCS-blood fed mosquitoes might indicate that the inhibitor acts rapidly on tissues, but somehow it is then detoxified or removed from the system.…”

Section: Discussionmentioning

confidence: 99%

“…Despite high specificity of LCS for ALAT, it is known that LCS can interact with other transaminases in animals [ 11 , 34 , 46 ]. Therefore, we cannot exclude the possible side effects of the LCS treatment on additional targets in mosquitoes.…”

Section: Discussionmentioning

confidence: 99%

Exposure to L-cycloserine incurs survival costs and behavioral alterations in Aedes aegypti females

Belloni

Scaraffia

2014

Parasit Vectors

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BackgroundIt was previously demonstrated that alanine aminotransferase (ALAT, EC 2.6.1.2) participates in maintaining the alanine-proline cycle between flight muscles and fat body during Aedes aegypti flight. ALAT is also actively involved in the metabolism of ammonia in A. aegypti. Here, we investigated the survival and behavioral costs of ALAT inhibition in A. aegypti females to better understand the role of ALAT in blood-fed mosquitoes.MethodsWe analyzed how A. aegypti female mosquitoes respond to blood meals supplemented with 0, 2.5, 5 and 10 mM L-cycloserine, a well-known inhibitor of ALAT in animals. Mosquitoes were also exposed to blood meals supplemented with L-cycloserine and different concentrations of glucose (0, 10 and 100 mM). Additionally, the effects of ALAT inhibitor and glucose in mosquitoes starved for 24 or 48 h were investigated. Survival and behavioral phenotypes were analyzed during a time course (1, 2, 4, 6, 12, 24, 48 and 72 h after feeding).ResultsL-cycloserine at 10 mM resulted in high mortality relative to control, with an acute effect during the first 6 h after treatment. A significant decrease in the number of active mosquitoes coinciding with an increase in futile wing fanning during the first 24 h was observed at all inhibitor concentrations. A high occurrence of knockdown phenotype was also recorded at this time for both 5 and 10 mM L-cycloserine. The supplementation of glucose in the blood meal amplified the effects of the ALAT inhibitor. In particular, we observed a higher mortality rate concomitant with an increase in the knockdown phenotype. Starvation prior to blood feeding also increased the effects of L-cycloserine with a rapid increase in mortality.ConclusionsOur results provide evidence that exposure of high doses of L-cycloserine during A. aegypti blood feeding affects mosquito survival and motor activity, suggesting an interference with carbohydrate and ammonia metabolism in a time-dependent manner.Electronic supplementary materialThe online version of this article (doi:10.1186/1756-3305-7-373) contains supplementary material, which is available to authorized users.

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“…in mice and rats, with maximal electroshock (MES, 5 or 13 mA) in mice and rats, with intracerebroventricular (i.c.v.) injection of N-methyl-D-aspartic acid in mice (NMDA, 1 nmol/1 PI), or with acoustic stimulation (1 10 dB) in the genetically seizuresusceptible mouse strain DBA/2J (A.S.) were evaluated by standard methods [e.g., Pieri et al, 1981;Polc et al, 1986;Moreau et al, 19891 and these results were compared to those of the BZR full agonist diazepam. ED,, values were calculated by probit analysis.…”

Section: Convulsion Tests (Mice Rats)mentioning

confidence: 99%

Novel long‐acting benzodiazepine receptor ligands Ro 41‐7812 and Ro 42‐8773: Neurological and behavioral profile

Moreau

Jenck

Bonetti

et al. 1991

Drug Development Research

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and Ro 42-8773, were assessed in various tests in mice, rats, and monkeys. Both compounds were orally active, exhibiting clear anticonvulsant activity within a dose range devoid of sedation or motor impairment, as well as effects in an operant conflict test and in a palatable food consumption paradigm. Furthermore, these two compounds attenuated, with a long duration of action, the sedation and motor impairment induced by classical benzodiazepine receptor full agonists but failed to exhibit proconvulsant activity even at high doses. Thus, despite a predominantly antagonist pharmacological profile, these two benzodiazepine receptor ligands appear to exhibit relatively clear anticonvulsant effects and might prove to be of value in the treatment of epilepsies.

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l-Cycloserine: Behavioural and biochemical effects after single and repeated administration to mice, rats and cats

Cited by 19 publications

References 24 publications

Thirty years beyond discovery—Clinical trials in succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism

Thirty years beyond discovery—Clinical trials in succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism

Exposure to L-cycloserine incurs survival costs and behavioral alterations in Aedes aegypti females

Novel long‐acting benzodiazepine receptor ligands Ro 41‐7812 and Ro 42‐8773: Neurological and behavioral profile

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