Advertisement

Derivatization of common antidepressant drugs increases inhibition of acid sphingomyelinase and reduces induction of phospholipidosis

  • Cosima Rhein
  • Stefan Löber
  • Peter Gmeiner
  • Erich Gulbins
  • Philipp Tripal
  • Johannes Kornhuber
Psychiatry and Preclinical Psychiatric Studies - Original Article
  • 95 Downloads

Abstract

In recent studies, major depressive disorder (MDD) was linked to an increase in acid sphingomyelinase (ASM) activity. Several drugs that are commonly used to treat MDD functionally inhibit the lysosomal enzyme ASM and are called functional inhibitors of ASM (FIASMAs). These drugs are classified as cationic amphiphilic drugs (CADs) that influence the catalytic activities of different lysosomal enzymes. This action results in the side effect of phospholipidosis (PLD), which describes a detrimental increase in the phospholipid content in lysosomes. FIASMAs differ only slightly in their physico-chemical properties, but their effects on ASM activity and induction of the lysosomal phospholipid content vary significantly. In this study, we systematically induced minor chemical modifications to the FIASMAs imipramine, desipramine and fluoxetine. We generated a library of 45 new CADs with slightly different log P (logarithmic partition coefficient) and pKa (logarithmic acid dissociation constant) values. The effects of the compounds on the ASM activity and lysosomal phospholipid content were assessed in cell culture assays. We identified four compounds with beneficial effects, i.e., increased ASM activity inhibition and reduced PLD induction compared with the original drugs. The compounds HT04, RH272B and RH272D outperformed the original imipramine, whereas RH281A performed better than desipramine. Thus, minor chemical variations of CADs impact lysosomal metabolism in a specific manner and can lead to antidepressant drugs with less deleterious side effects.

Keywords

Acid sphingomyelinase Functional inhibitors of ASM activity (FIASMAs) Imipramine Desipramine Fluoxetine Phospholipidosis Major depression 

Notes

Acknowledgements

We thank Michaela Henkel and Alice Konrad for excellent technical assistance. We are grateful to Lydia Pettermann and Heike Thomas for generating the chemical compounds. We thank Christiane Mühle for helpful comments on the manuscript and preparation of Fig. 3. This work was supported by funding from the Forschungsstiftung Medizin at the University Hospital Erlangen, the German Federal Ministry of Education and Research (BMBF, 01 EE1401C, to J. K.), and DFG grants KO 947/13-1 and GU 335/29-1 (to J.K. and E.G.).

Author contributions

PT and JK conceived and designed the experiments; PT and SL designed and performed the experiments and wrote parts of the paper; CR, JK and EG analyzed the data; SL, PG and JK contributed reagents/study materials/analysis tools; CR and PT wrote the paper. All authors read the paper and provided intellectual input.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

References

  1. Albouz S, Le Saux F, Wenger D, Hauw JJ, Baumann N (1986) Modifications of sphingomyelin and phosphatidylcholine metabolism by tricyclic antidepressants and phenothiazines. Life Sci 38:357–363CrossRefPubMedGoogle Scholar
  2. Anderson N, Borlak J (2006) Drug-induced phospholipidosis. Febs Lett 580:5533–5540CrossRefPubMedGoogle Scholar
  3. de Duve C, de Barsy T, Poole B, Trouet A, Tulkens P, Van Hoof F (1974) Commentary. Lysosomotrop Agents Biochem Pharmacol 23:2495–2531CrossRefGoogle Scholar
  4. Dollinger S, Löber S, Klingenstein R, Korth C, Gmeiner P (2006) A chimeric ligand approach leading to potent antiprion active acridine derivatives: design, synthesis, and biological investigations. J Med Chem 49:6591–6595.  https://doi.org/10.1021/jm060773j CrossRefPubMedGoogle Scholar
  5. Gallala HD, Sandhoff K (2011) Biological function of the cellular lipid BMP-BMP as a key activator for cholesterol sorting and membrane digestion. Neurochem Res 36:1594–1600.  https://doi.org/10.1007/s11064-010-0337-6 CrossRefPubMedGoogle Scholar
  6. Glock M, Muehlbacher M, Hurtig H, Tripal P, Kornhuber J (2016) Drug-induced phospholipidosis caused by combinations of common drugs in vitro. Toxicol In Vitro 35:139–148.  https://doi.org/10.1016/j.tiv.2016.05.010 CrossRefPubMedGoogle Scholar
  7. Gulbins E, Grassme H (2002) Ceramide and cell death receptor clustering. Biochim Et Biophys Acta 1585:139–145CrossRefGoogle Scholar
  8. Gulbins E, Kolesnick R (2000) Measurement of sphingomyelinase activity. Methods Enzymol 322:382–388CrossRefPubMedGoogle Scholar
  9. Gulbins E, Kolesnick R (2002) Acid sphingomyelinase-derived ceramide signaling in apoptosis. Subcell Biochem 36:229–244CrossRefPubMedGoogle Scholar
  10. Gulbins E et al (2013) Acid sphingomyelinase-ceramide system mediates effects of antidepressant drugs. Nat Med 19:934–938.  https://doi.org/10.1038/nm.3214 CrossRefPubMedGoogle Scholar
  11. Halliwell WH (1997) Cationic amphiphilic drug-induced phospholipidosis. Toxicol Pathol 25:53–60CrossRefPubMedGoogle Scholar
  12. Hurwitz R, Ferlinz K, Sandhoff K (1994) The tricyclic antidepressant desipramine causes proteolytic degradation of lysosomal sphingomyelinase in human fibroblasts. Biol Chem Hoppe Seyler 375:447–450CrossRefPubMedGoogle Scholar
  13. Kobayashi T, Stang E, Fang KS, de Moerloose P, Parton RG, Gruenberg J (1998) A lipid associated with the antiphospholipid syndrome regulates endosome structure and function. Nature 392:193–197.  https://doi.org/10.1038/32440 CrossRefPubMedGoogle Scholar
  14. Kodavanti UP, Mehendale HM (1990) Cationic amphiphilic drugs and phospholipid storage disorder. Pharmacol Rev 42:327–354PubMedGoogle Scholar
  15. Kolter T, Sandhoff K (2010) Lysosomal degradation of membrane lipids. FEBS Lett 584:1700–1712CrossRefPubMedGoogle Scholar
  16. Kölzer M, Werth N, Sandhoff K (2004) Interactions of acid sphingomyelinase and lipid bilayers in the presence of the tricyclic antidepressant desipramine. FEBS Lett 559:96–98CrossRefPubMedGoogle Scholar
  17. Kornhuber J, Medlin A, Bleich S, Jendrossek V, Henkel AW, Wiltfang J, Gulbins E (2005) High activity of acid sphingomyelinase in major depression. J Neural Transm 112:1583–1590CrossRefPubMedGoogle Scholar
  18. Kornhuber J, Tripal P, Reichel M, Terfloth L, Bleich S, Wiltfang J, Gulbins E (2008) Identification of new functional inhibitors of acid sphingomyelinase using a structure-property-activity relation model. J Med Chem 51:219–237.  https://doi.org/10.1021/jm070524a CrossRefPubMedGoogle Scholar
  19. Kornhuber J et al (2010) Functional Inhibitors of acid sphingomyelinase (FIASMAs): a novel pharmacological group of drugs with broad clinical applications. Cell Physiol Biochem 26:9–20.  https://doi.org/10.1159/000315101 CrossRefPubMedGoogle Scholar
  20. Kornhuber J et al (2011) Identification of novel functional inhibitors of acid sphingomyelinase. PloS One 6:e23852.  https://doi.org/10.1371/journal.pone.0023852 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Kornhuber J, Müller CP, Becker KA, Reichel M, Gulbins E (2014) The ceramide system as a novel antidepressant target. Trends Pharmacol Sci 35:293–304.  https://doi.org/10.1016/j.tips.2014.04.003 CrossRefPubMedGoogle Scholar
  22. Kukreja S, Kalra G, Shah N, Shrivastava A (2013) Polypharmacy in psychiatry: a review. Mens Sana Monogr 11:82–99.  https://doi.org/10.4103/0973-1229.104497 CrossRefPubMedPubMedCentralGoogle Scholar
  23. Lowe R, Glen RC, Mitchell JBO (2010) Predicting phospholipidosis using machine learning. Mol Pharm 7:1708–1714CrossRefPubMedPubMedCentralGoogle Scholar
  24. Lüllmann H, Lüllmann-Rauch R, Wassermann O (1978) Lipidosis induced by amphiphilic cationic drugs. Biochem Pharmacol 27:1103–1108CrossRefPubMedGoogle Scholar
  25. Muehlbacher M, Tripal P, Roas F, Kornhuber J (2012) Identification of drugs inducing phospholipidosis by novel in vitro data. ChemMedChem.  https://doi.org/10.1002/cmdc.201200306 PubMedPubMedCentralCrossRefGoogle Scholar
  26. Nonoyama T, Fukuda R (2008) Drug-induced phospholipidosis—pathological aspects and its prediction. J Toxicol Pathol 21:9–24CrossRefGoogle Scholar
  27. Rhein C et al (2017) Alternative splicing of SMPD1 coding for acid sphingomyelinase in major depression. J Affect Disord 209:10–15.  https://doi.org/10.1016/j.jad.2016.09.019 CrossRefPubMedGoogle Scholar
  28. Schmidt M, Teitge M, Castillo ME, Brandt T, Dobner B, Langner A (2008) Synthesis and biochemical characterization of new phenothiazines and related drugs as MDR reversal agents. Arch Pharm 341:624–638.  https://doi.org/10.1002/ardp.200800115 CrossRefGoogle Scholar
  29. Trapp S, Rosania GR, Horobin RW, Kornhuber J (2008) Quantitative modeling of selective lysosomal targeting for drug design. EBJ 37:1317–1328.  https://doi.org/10.1007/s00249-008-0338-4 CrossRefPubMedGoogle Scholar
  30. Wilkening G, Linke T, Sandhoff K (1998) Lysosomal degradation on vesicular membrane surfaces. Enhanced glucosylceramide degradation by lysosomal anionic lipids and activators. J Biol Chem 273:30271–30278CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Psychiatry and Psychotherapy, University Hospital ErlangenFriedrich-Alexander Universität Erlangen-Nürnberg (FAU)ErlangenGermany
  2. 2.Pharmaceutical ChemistryFriedrich-Alexander Universität Erlangen-Nürnberg (FAU)ErlangenGermany
  3. 3.Department of Molecular BiologyUniversity of Duisburg-EssenEssenGermany
  4. 4.Optical Imaging Centre Erlangen (OICE)Friedrich-Alexander Universität Erlangen-Nürnberg (FAU)ErlangenGermany

Personalised recommendations