The effects of imipramine on the methylation of phosphatidylethanolamine (PE) in the cortical membranes of wistar rats

Melzacka, M; Janczar, L.; Nocon, Halina

doi:10.1016/0006-2952(93)90521-w

Cited by 2 publications

(1 citation statement)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Imipramine has also been demonstrated to inhibit the three main classes of methyltransferases (N, O and C-methyltransferases). The activity of phosphatidylethanolamine N-methyltransferase was also found to be inhibited by imipramine and chlorpromazine [ 33 ]. Moreover, imipramine has inhibitory effects on erythrocyte catechol-O-methyltransferase and indirectly inhibits DNA methylation by cytosine C-methyltransferase [ 17 , 34 ].…”

Section: Resultsmentioning

confidence: 99%

Imipramine alters the sterol profile in Leishmania amazonensis and increases its sensitivity to miconazole

et al. 2016

View full text Add to dashboard Cite

BackgroundImipramine, a tricyclic antidepressant widely used clinically, has other pharmacological effects, such as antileishmanial activity. Tricyclic antidepressants interact with lipid bilayers, and some studies have shown that imipramine inhibits methyltransferases. Leishmania spp. produces compounds with an ergostane skeleton instead of a cholesterol skeleton, and the inhibition of enzymes of the sterol biosynthesis pathway is an interesting therapeutic target. Among these enzymes, C-24 methyltransferase has been suggested to play an essential role, as its inhibition kills the parasites. In this context, we investigated whether imipramine alters the biosynthesis of sterols in L. amazonensis and evaluated the efficacy of imipramine alone and in combination with miconazole, a classical inhibitor of another step in this pathway.MethodsTo analyze the interference of imipramine with sterol metabolism, promastigotes of L. amazonensis were cultured with medium alone, 15 or 30 μM imipramine or 4 μM miconazole, and their lipids were extracted with methanol/chloroform/water (1:0.5:0.4 v/v) and analyzed by GC/MS. To assess the antileishmanial activity of the treatments, promastigotes of L. amazonensis were incubated with various concentrations of imipramine up to 100 μM and up to 24 μM miconazole. Promastigotes were also treated with the combination of imipramine and miconazole at concentrations up to 12.5 μM of imipramine and 24 μM of miconazole. Parasite growth was evaluated by the MTT assay. The fractional inhibitory concentration index (FICI) was calculated to determine whether there were synergistic effects. Peritoneal macrophages with and without L. amazonensis infection were treated with miconazole (0 – 16 μM) or imipramine (0 to 50 μM) for 72 hours. For assays of the combined treatment in amastigotes, the concentration of imipramine was fixed at 12.5 μM and various concentrations of miconazole were used up to 16 μM. The infection rate was determined by counting the infected macrophages under a light microscope.FindingsPromastigotes treated with imipramine accumulated cholesta-5,7,22-trien-3β-ol and cholesta-7-24-dien- 3β-ol, sterols that normally increase after treatment with classical inhibitors of C-24 methyltransferase. The IC50 of miconazole in promastigotes decreased when it was used in combination with imipramine, resulting in an additive effect, with a FICI value of 0.83. Imipramine also showed activity against intracellular amastigotes and enhanced the activity of miconazole, without apparent toxicity to the host cells.ConclusionsImipramine was confirmed to have antileishmanial activity in both forms of the parasite, affecting the sterol biosynthesis of the organisms. Using imipramine in combination with azoles may be advantageous for the treatment of leishmaniasis.

show abstract

Section: Resultsmentioning

confidence: 99%

Imipramine alters the sterol profile in Leishmania amazonensis and increases its sensitivity to miconazole

et al. 2016

View full text Add to dashboard Cite

show abstract

In Vitro and in Vivo¹³C and ³¹P NMR analyses of phosphocholine metabolism in rat glioma cells

Gillies¹,

Barry²,

Ross³

1994

Magnetic Resonance in Med

View full text Add to dashboard Cite

In vivo magnetic resonance spectroscopy (MRS) has revealed that phosphomonoesters (PME) such as phosphocholine (PCho) and phosphoethanolamine (PEth) are elevated in tumors and rapidly proliferating tissues. The regulation of PME levels and their relationship to proliferation are not well known. In the present study, we investigated the regulation of PCho and PEth levels in rat glioma cells grown in vivo and in vitro using 31P and 13C MRS. However, the ability of cells to produce choline endogenously is variable. To fully understand regulation of PCho levels, it is necessary to characterize the activity of the endogenous pathway, if it exists. This was first investigated by following the metabolic fate of 13C-labeled methionine of 9L glioma tumors in vivo. Our results indicate that there is a significant amount of de novo choline synthesis in vivo. However, similar experiments performed in vitro using cells cultured in bioreactors indicated that glioma cells themselves are unable to synthesize choline de novo, suggesting that the in vivo results were due to the involvement of extra-tumoral organs, e.g., liver. Further in vitro experiments demonstrated that the uptake and phosphorylation of physiologically relevant concentrations of exogenous choline is very active in these systems. Thus, it appears that the exogenous pathway for PCho biosynthesis predominates and regulates PCho levels in glioma cells. Our results also demonstrate that PCho levels are lowest, and PEth levels are highest, in non-proliferating cells. These observations indicate that there is a decrease in the biosynthesis of PCho concomitant with a reduction in culture growth. The source of the increased PEth is, as yet, undefined.

show abstract

The effects of imipramine on the methylation of phosphatidylethanolamine (PE) in the cortical membranes of wistar rats

Cited by 2 publications

References 20 publications

Imipramine alters the sterol profile in Leishmania amazonensis and increases its sensitivity to miconazole

Imipramine alters the sterol profile in Leishmania amazonensis and increases its sensitivity to miconazole

In Vitro and in Vivo¹³C and ³¹P NMR analyses of phosphocholine metabolism in rat glioma cells

Contact Info

Product

Resources

About

The effects of imipramine on the methylation of phosphatidylethanolamine (PE) in the cortical membranes of wistar rats

Cited by 2 publications

References 20 publications

Imipramine alters the sterol profile in Leishmania amazonensis and increases its sensitivity to miconazole

Imipramine alters the sterol profile in Leishmania amazonensis and increases its sensitivity to miconazole

In Vitro and in Vivo13C and 31P NMR analyses of phosphocholine metabolism in rat glioma cells

Contact Info

Product

Resources

About

In Vitro and in Vivo¹³C and ³¹P NMR analyses of phosphocholine metabolism in rat glioma cells