Disease relevance of cycloserine

• PDMP, sphingosine 1-phosphate, desipramine, fumonisin B(1), and L-cycloserine were able not to rescue the glioma cells from PA and TTA-induced growth inhibition, suggesting that increased ceramide production is not important in the growth reduction [1].
• Twitcher mice treated with L-cycloserine had a significantly longer life span and a delayed onset of weight loss than vehicle-injected twitcher mice [2].
• L-cycloserine inhibition of sphingolipid synthesis in the anaerobic bacterium Bacteroides levii [3].
• Selective inhibition of CD4 by L-cycloserine together with its antiviral effects may offer a novel approach for interfering with HIV cell binding and infectivity [4].
• We tested the effects of L-cycloserine (L-CS), a potent inhibitor of synthesis of glycosphingolipids, on the growth, viability and expression of GD2 and GM2 in neuroblastoma and medulloblastoma cells [5].

Psychiatry related information on cycloserine

• Larger doses of L-cycloserine (greater than 30-100 mg/kg) impaired the performance of mice in the rotarod, chimney and horizontal wire tests, and reduced spontaneous locomotor activity of rats [6].
• In contrast, L-cycloserine had no effect on the maximal electroshock seizures [7].

High impact information on cycloserine

• 1H nuclear magnetic resonance studies clearly demonstrate that the irreversible removal of pyruvate induced by L-cycloserine is caused by the decarboxylating action of the latter [8].
• Enhancement of ceramide formation by R(+)-MA was abolished by fumonisin B1, a ceramide synthase inhibitor, whereas inhibitors of neutral sphingomyelinase (spiroepoxide, glutathione) and serine palmitoyltransferase (l-cycloserine, ISP-1) were inactive in this respect [9].
• The structures of d and l-cycloserine bound to the active-site show that the l-isomer is deprotonated at C(alpha), presumably by Lys272, while the d-isomer is not [10].
• EGCg showed a synergistic effect with DL-cycloserine (an inhibitor of cell wall synthesis unrelated to PBP2') but additive or indifferent effect with inhibitors of protein and nuclear acid synthesis [11].
• In addition, reverse transcriptase polymerase chain reaction showed that L-cycloserine reduced the mRNA for ICAM-1, HLA-DR alpha, and HLA-DR beta induced by IFN-gamma, and C2-ceramide and sphingosine antagonized the effect of L-cycloserine [12].

Biological context of cycloserine

• In vitro studies showed that treatment of hippocampal slice cultures with SPT inhibitor ISP-1 (myriocin) or L-cycloserine modulated increases in 16:0, 18:0, and 20:0 ceramide species, and partially reduced kainate-induced cell death [13].
• The cell cycle effect was blocked by the antioxidants ADPC and ascorbate, the superoxide scavenger Tiron, and the sphingosine kinase inhibitor L-cycloserine, but not by inhibitors of nitric oxide synthase [14].
• L-Cycloserine reduced Taxol-induced apoptosis by 30% in MDA-MB-468 cells and totally blocked Taxol-induced apoptosis in MCF-7 cells [15].
• Recent studies have demonstrated that L-cycloserine, an inhibitor of sphingolipid biosynthesis, interferes with the life cycle of HIV [4].
• L-3-Chloroalanine hydroxamate was shown to undergo buffer-catalyzed cyclization to L-cycloserine, which is the actual inactivator of GABA-AT [16].

Anatomical context of cycloserine

• The enzyme was also inhibited in isolated mitochondria incubated with L-cycloserine [17].
• Isolated hepatocytes were incubated with L-cycloserine and then treated with digitonin so that mitochondrial and cytosolic fractions were obtained in 5 s [17].
• In this study, L-cycloserine was shown to be a potent inhibitor of serine palmitoyltransferase in aortas from New Zealand White rabbits [18].
• Administration to rats of inhibitors of gamma-aminobutyric acid (GABA) degradation, such as gabaculine and L-cycloserine, resulted in elevated GABA levels in synaptoneurosomes and a decrease in muscimol-stimulated Cl- up-take by the organelles [19].
• Under similar incubation conditions, the entry of labeled APL and of PLP into the myelin membranes in the presence of L-cycloserine decreased markedly (50%) in comparison to controls [20].

Associations of cycloserine with other chemical compounds

• Subcutaneous injection of L-cycloserine resulted in a 28% reduction in cerebroside levels in mouse brain but had no effect on the levels of gangliosides [21].
• To assess in vivo inhibition, L-cycloserine was administered by intraperitoneal injection to rabbits maintained on either a standard Purina laboratory chow or one supplemented with 2% cholesterol [18].
• Daily dosages of L-cycloserine on a regimen of intraperitoneal injection for 7 days caused a significant reduction in total brain ganglioside and cerebroside plus sulfatide levels [22].
• At a concentration of 0.15 mM L-cycloserine, the incorporation of [3H] glycine into total proteins, proteolipid apoproteins (APL), PLP, and myelin basic proteins (MBP) of the total homogenate was unaffected by the presence of the inhibitor, whereas the incorporation of [3H] serine into glycosphingolipids decreased markedly [20].
• The aminotransferase inhibitors L-cycloserine and carboxymethoxylamine inhibited growth and selectively inhibited the production of alanine [23].

Gene context of cycloserine

• In the present study, using inhibitors of ceramide synthase (fumonisin B1), ketosphinganine synthetase (L-cycloserine), acid sphingomyelinase (D609 and desipramine) and neutral sphingomyelinase (GW4869), the role of ceramide in X-ray-induced apoptosis was investigated in MOLT-4 cells [24].
• Upon repeated administration the inhibitory effect of L-cycloserine on the activity of GABA-T and on seizures elicited by 3-MPA in mice increased [6].
• Twitcher mice given a short course of L-cycloserine + BMT at 18 d lived to 58 d (p = 0.0006) [25].
• From the resonance peaks of such an adduct, we have ascertained that a molecule of L-cycloserine forms an irreversible Schiff base with the 4-aldehyde group of PLP, and this adduct is stabilized by a zinc ion [26].
• L-cycloserine also inhibited T cell mitogen responses without affecting IL-2 production [4].

Analytical, diagnostic and therapeutic context of cycloserine

• Measurement of adenine nucleotide levels in A7r5 cell extracts by reverse-phase high-performance liquid chromatography indicated that treatment with L-cycloserine did not adversely affect cellular metabolism [27].

References