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Journal of Neural Transmission

, Volume 119, Issue 5, pp 545–556 | Cite as

Basic cell physiological activities (cell adhesion, chemotaxis and proliferation) induced by selegiline and its derivatives in Mono Mac 6 human monocytes

  • Eszter Lajkó
  • Lívia Polgár
  • Orsolya Láng
  • József Lengyel
  • László KőhidaiEmail author
  • Kálmán Magyar
Basic Neurosciences, Genetics and Immunology - Original Article

Abstract

Selegiline (R-deprenyl), a monoamine oxidase-B (MAO-B) inhibitor, has complex pharmacological effect that contributes to treatment of neurodegenerative diseases such as Parkinson’s and presumably Alzheimer’s disease and might work as an inhibitor of tumor growth. In respect of tumorigenesis and metastasis formation, the controlled modifications of adhesion and migration have high therapeutic significance. In the present study, our purpose was to investigate cell physiological responses (adhesion, chemotaxis and proliferation) induced by selegiline, its metabolites and synthetic derivatives and to find some correlations between the molecular structure and the reported antitumor behavior of the derivatives. Our results demonstrated that both R- and S-deprenyls have the potency to elicit increased adhesion and a chemorepellent activity in monocyte model (Mono Mac 6 cell line derived from monoblastic leukemia); however, only the R-enantiomer proved to be cytotoxic. Among the metabolites R-amphetamine has retained the adhesion inducer and the chemorepellent effect of the parent drug on the most significant level. In contrast, a reversed chemotactic effect and an improved cytotoxic character were detected in the presence of fluoro group (p-fluoro-S-deprenyl). In summary, the adhesion inducer activity, chemorepellent and advantageous cytotoxic effects of selegiline and some derivatives indicate that these drug molecules might have inhibitory effects in metastasis formation in primary tumors.

Keywords

Chemotaxis Cell adhesion Monocyte Tumor Selegiline 

Notes

Acknowledgments

Authors express their gratitude to Professor Gyorgy Csaba for his suggestions and critical reading of the manuscript and to Ms Maria Knippel, Andrea Orban, and Andrea Kovács for their expert technical assistance. This study was supported by the Neurochemical Research Group of Hungarian Academy of Sciences, Hungarian Academy of Sciences Foundation OTKA 63415 and ETT 141/2003 Grants.

Conflict of interest

None of the authors of the above manuscript has declared any conflict of interest.

References

  1. Atienza JM, Zhu J, Wang X, Xu X, Abassi Y (2005) Dynamic monitoring of cell adhesion and spreading on microelectronic sensor arrays. J Biomol Screen 10:795–805PubMedCrossRefGoogle Scholar
  2. Barrett JS, Hochadel TJ, Morales RJ, Rohatagi S, DeWitt KE, Watson SK, DiSanto AR (1996a) Pharmacokinetics and safety of a selegiline transdermal system relative to single dose oral administration in the elderly. Am J Ther 3:688–698PubMedCrossRefGoogle Scholar
  3. Barrett JS, Szego P, Rohatagi S, Morales RJ, DeWitt KE, Rajewski G, Ireland J (1996b) Absorption and presystemic metabolism of selegiline hydrochloride at different regions in the gastrointestinal tract in healthy males. Pharm Res 13:1535–1540PubMedCrossRefGoogle Scholar
  4. Birkmayer W, Riederer P, Youdim MB, Linauer W (1975) The potentiation of the anti- akinetic effect after l-dopa treatment by an inhibitor of MAO-B, deprenyl. J Neural Transm 36:303–326PubMedCrossRefGoogle Scholar
  5. Birkmayer W, Riederer P, Ambrozi L, Youdim MB (1977) Implications of combined treatment with ‘Madopar’ and l-deprenyl in Parkinson’s disease. A long-term study. Lancet 1:439–443PubMedCrossRefGoogle Scholar
  6. Birkmayer W, Knoll J, Riederer P, Youdim MB (1983) (—)-Deprenyl leads to prolongation of l-dopa efficacy in Parkinson’s disease. Mod Probl Pharmacopsychiatry 19:170–176PubMedGoogle Scholar
  7. Birkmayer W, Knoll J, Riederer P, Youdim MB, Hars V, Marton J (1985) Increased life expectancy resulting from addition of l-deprenyl to Madopar treatment in Parkinson’s disease: a longterm study. J Neural Transm 64:113–127PubMedCrossRefGoogle Scholar
  8. Buu NT, Angers M, Duhaime J, Kuchel O (1987) Modification of dopamine and norepinephrine metabolism in the rat brain by monoamine oxidase inhibitors. J Neural Transm 70:39–50PubMedCrossRefGoogle Scholar
  9. Carrillo MC, Kanai S, Nokubo M, Kitani K (1991) (−)-Deprenyl induces activities of both superoxide dismutase and catalase but not of glutathione peroxidase in the striatum of young male rats. Life Sci 48:517–521PubMedCrossRefGoogle Scholar
  10. Clement B, Behrens D, Möller W, Cashman JR (2000) Reduction of amphetamine hydroxylamine and other aliphatic hydroxylamines by benzamidoxime reductase and human liver microsomes. Chem Res Toxicol 13:1037–1045PubMedCrossRefGoogle Scholar
  11. Erdö F, Baranyi A, Takács J, Arányi P (2000) Different neurorescue profiles of selegiline and p-fluoro-selegiline in gerbils. Neuroreport 11:2597–2600PubMedCrossRefGoogle Scholar
  12. Fowler JS, Volkow ND, Wang GJ, Logan J, Pappas N, Shea C, MacGregor R (1997) Age-related increases in brain monoamine oxidase B in living healthy human subjects. Neurobiol Aging 18:431–435PubMedCrossRefGoogle Scholar
  13. Giaever I, Keese CR (1984) Monitoring fibroblast behavior with an applied electric field. Proc Natl Acad Sci USA 81:3761–3764PubMedCrossRefGoogle Scholar
  14. Haberle D, Szökö E, Halász AS, Magyar K (2001) The effect of low oral dose of (−)-deprenyl and its metabolites on DSP-4 toxicity. J Neural Transm 108:1239–1247PubMedCrossRefGoogle Scholar
  15. Heinonen EH, Myllyla V, Sotaniemi K (1989) Pharmacokinetics and metabolism of selegiline. Acta Neurol Scand 126:93–99Google Scholar
  16. Jenei V, Zor K, Magyar K, Jakus J (2005) Increased cell–cell adhesion, a novel effect of R-(–)-deprenyl. J Neural Transm 112:1433–1445PubMedCrossRefGoogle Scholar
  17. Knoll J, Magyar K (1972) Some puzzling pharmacological effects of monoamine oxidase inhibitors. Adv Biochem Psychopharmacol 5:393–408PubMedGoogle Scholar
  18. Knoll J, Ecseri Z, Kelemen K, Nievel J, Knoll B (1965) Phenylisopropylmethylpropinylamine (E-250), a new spectrum psychic energizer. Arch Int Pharmacodyn Ther 155:154–164PubMedGoogle Scholar
  19. Kőhidai L, Lajkó E, Láng O, Igaz A, Lengyel J, Magyar K (2010) Cell adhesion induced by deprenyl and its derivatives—investigations of adenocarcinoma cell lines (LM2, LM3) by ECIS technique and introduction Cell-LED® a new lighting equipment dedicated to ECIS (2010 ECIS Users Meeting, Rensselaerville, USA)Google Scholar
  20. Lamensdorf I, Youdim MB, Finberg JP (1996) Effect of long-term treatment with selective monoamine oxidase A and B inhibitors on dopamine release from rat striatum in vivo. J Neurochem 67:1532–1539PubMedCrossRefGoogle Scholar
  21. Magyar K (1994) Behaviour of (−)-deprenyl and its analogues. J Neural Transm Suppl 41:167–175PubMedGoogle Scholar
  22. Magyar K (1997) Effect of selegiline against selective neurotoxins. Vopr Med Khim 43:504–514PubMedGoogle Scholar
  23. Magyar K, Szende B (2004) (−)-Deprenyl, a selective MAO-B inhibitor, with apoptotic and antiapoptotic properties. Neurotoxicology 25:233–242PubMedCrossRefGoogle Scholar
  24. Magyar K, Vizi ES, Ecseri Z, Knoll J (1967) Comparative pharmacological analysis of the optical isomers of phenyl-isopropyl-methyl-propinylam.ine (E-250). Acta Physiol Hung 32:377–387Google Scholar
  25. Magyar K, Ecseri Z, Bernáth G, Sátory É, Knoll J (1979) Structure–activity relationship of selective inhibitors of MAO-B. In: Magyar K (ed) Advances in pharmacological research and practice, proceedings of the 3rd congress of the Hungarian Pharmacological Society, Budapest, vol IV. Monoamine oxidases and their selective inhibition. Pergamon Press, Akadémiai kiadó, Budapest, pp 11–21Google Scholar
  26. Magyar K, Szende B, Lengyel J, Tarczali J, Szatmáry I (1998) The neuroprotective and neuronal rescue effects of (−)-deprenyl. J Neural Transm Suppl 52:109–123PubMedGoogle Scholar
  27. Magyar K, Pálfi M, Tábi T, Kalász H, Szende B, Szökő E (2004) Pharmacological aspect of (−)-deprenyl. Curr Med Chem 11:2017–2031PubMedGoogle Scholar
  28. Mannerström M, Toimela T, Ylikomi T, Tähti H (2006) The combined use of human neuronal and liver cell lines and mouse hepatocytes improves the predictability of the neurotoxicity of selected drugs. Toxicol Lett 165:195–202PubMedCrossRefGoogle Scholar
  29. Moh MC, Shen S (2009) The roles of cell adhesion molecules in tumor suppression and cell migration: a new paradox. Cell Adhesion Migr 3:334–336CrossRefGoogle Scholar
  30. Reynolds GP, Elsworth JD, Blau K, Sandler M, Lees AJ, Stern GM (1978) Deprenyl is metabolized to methamphetamine and amphetamine in man. Br J Clin Pharmacol 6:542–544PubMedGoogle Scholar
  31. Riederer P, Youdim MB (1986) Monoamine oxidase activity and monoamine metabolism in brains of parkinsonian patients treated with l-deprenyl. J Neurochem 46:1359–1365PubMedCrossRefGoogle Scholar
  32. Schmidt S, Friedl P (2010) Interstitial cell migration: integrin-dependent and alternative adhesion mechanisms. Cell Tissue Res 339:83–92PubMedCrossRefGoogle Scholar
  33. Shin HS (1997) Metabolism of selegiline in humans. Identification, excretion, and stereochemistry of urine metabolites. Drug Metab Dispos 25:657–662PubMedGoogle Scholar
  34. Szende B, Magyar K, Szegedi Z (2000) Apoptotic and antiapoptotic effect of (−)-deprenyl and (−)-desmethyl-deprenyl on human cell lines. Neurobiology (Bp) 8:249–255Google Scholar
  35. Szende B, Bökönyi G, Bocsi J, Kéri G, Timár F, Magyar K (2001) Anti-apoptotic and apoptotic action of (–)-deprenyl and its metabolites. J Neural Transm 108:25–33PubMedCrossRefGoogle Scholar
  36. Szende B, Barna G, Magyar K (2010) Cytoprotective effect of (−)-deprenyl, (−)desmethyl-deprenyl and (−)deprenyl-N-oxide on glutathione depleted A-2058 melanoma cells. J Neural Transm 117:695–698PubMedCrossRefGoogle Scholar
  37. Szilágyi G, Simon L, Wappler E, Magyar K, Nagy Z (2009) (−)Deprenyl-N-oxide, a (−)deprenyl metabolite, is cytoprotective after hypoxic injury in PC12 cells, or after transient brain ischemia in gerbils. Neurol Sci 283:182–186CrossRefGoogle Scholar
  38. Szökő É, Tábi T, Halász AS, Pálfi M, Kalász H (2004) Identification of the enantiomer form of deprenyl metabolites and deprenyl-N-oxide in Rat Urine. In: Török T, Klebovich I (eds) Monoamine oxidase inhibitors and their role in neurotransmission (drug development). Medicina Kiadó, Budapest, pp 41–54Google Scholar
  39. Tatton WG, Chalmers-Redman RME (1996) Modulation of gene expression rather than monoamine oxidase inhibition: (−)-deprenyl-related compounds in controlling neurodegeneration. Neurology 47:S171–S183PubMedGoogle Scholar
  40. Tatton WG, Ju WY, Holland DP, Tai C, Kwan M (1994) (−)-Deprenyl reduces PC12 cell apoptosis by inducing new protein synthesis. J Neurochem 63:1572–1575PubMedCrossRefGoogle Scholar
  41. Tatton WG, Wadia JS, Ju WY, Chalmers-Redman RM, Tatton NA (1996) (−)-Deprenyl reduces neuronal apoptosis and facilitates neuronal outgrowth by altering protein synthesis without inhibiting monoamine oxidase. J Neural Transm Suppl 48:45–59PubMedGoogle Scholar
  42. Tekes K, Tóthfalusi L, Gaál J, Magyar K (1988) Effect of MAO inhibitors on the uptake and metabolism of dopamine in rat and human brain. Pol J Pharmacol Pharm 40:653–658PubMedGoogle Scholar
  43. Terleckyj IA, Heikkila RE (1992) In vivo and in vitro pharmacologic profile of two new irreversible MAO-B inhibitors: MDL 72, 974A and fluorodeprenyl. Ann NY Acad Sci 648:365–367PubMedCrossRefGoogle Scholar
  44. ThyagaRajan S, Meites J, Quadri SK (1995) Deprenyl reinitiates estrous cycles, reduces serum prolactin and decreases the incidence of mammary and pituitary tumors in old acyclic rats. Endocrinology 136:1103–1110PubMedCrossRefGoogle Scholar
  45. ThyagaRajan S, Madden KS, Stevens SY, Felten DL (1999) Inhibition of tumor growth by l-deprenyl involves neural-immune interactions in rats with spontaneously developing mammary tumors. Anticancer Res 19:5023–5028PubMedGoogle Scholar
  46. ThyagaRajan S, Madden KS, Stevens SY, Felten DL (2000) Antitumor effect of l-deprenyl is associated with enhanced central and peripheral neurotransmission and immune reactivity in rats with carcinogen-induced mammary tumors. J Neuroimmunol 109:95–104PubMedCrossRefGoogle Scholar
  47. Wu RF, Ichikawa Y (1995) Inhibition of 1-methyl-4.phenyl-1,2,3,6-tetrahydropyridine metabolic activity of porcine FAD-containing monooxygenase activity by selective monoamine oxidase-B inhibitors. FEBS Lett 358:145–148PubMedCrossRefGoogle Scholar
  48. Youdim MB, Weinstock M (2002) Novel neuroprotective anti-Alzheimer drugs with anti-depressant activity derived from the anti-Parkinson drug, rasagiline. Mech Ageing Dev 123:1081–1086PubMedCrossRefGoogle Scholar
  49. Youdim MB, Wadia A, Tatton W, Weinstock M (2006) The antiParkinson drug rasagiline and its cholinesterase inhibitor derivatives exert neuroprotection unrelated to MAO inhibition in cell culture and in vivo. Ann NY Acad Sci 939:450–458CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Eszter Lajkó
    • 1
  • Lívia Polgár
    • 1
  • Orsolya Láng
    • 1
  • József Lengyel
    • 2
  • László Kőhidai
    • 1
    Email author
  • Kálmán Magyar
    • 2
  1. 1.Department of Genetics Cell and ImmunobiologySemmelweis UniversityBudapestHungary
  2. 2.Department of PharmacodynamicsSemmelweis UniversityBudapestHungary

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