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Effects of selegiline, a monoamine oxidase B inhibitor, on differentiation of P19 embryonal carcinoma stem cells, into neuron-like cells

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Abstract

Selegiline, the irreversible inhibitor of monoamine oxidase B (MAO-B), is currently used to treat Parkinson’s disease. However, the mechanism of action of selegiline is complex and cannot be explained solely by its MAO-B inhibitory action. It stimulates gene expression, as well as expression of a number of mRNAs or proteins in nerve and glial cells. Direct neuroprotective and anti-apoptotic actions of selegiline have previously been observed in vitro. Previous studies showed that selegiline can induce neuronal phenotype in cultured bone marrow stem cells and embryonic stem cells. Embryonal carcinoma (EC) cells are developmentaly pluripotene cells which can be differentiated into all cell types under the appropriate conditions. The present study was carried out to examine the effects of selegiline on undifferentiated P19 EC cells. The results showed that selegiline treatment had a dramatic effect on neuronal morphology. It induced the differentiation of EC cells into neuron-like cells in a concentration-dependent manner. The peak response was in a dose of selegiline significantly lower than required for MAO-B inhibition. The differentiated cells were immunoreactive for neuron-specific proteins, synaptophysin, and β-III tubulin. Stem cell therapy has been considered as an ideal option for the treatment of neurodegenerative diseases. Generation of neurons from stem cells could serve as a source for potential cell therapy. This study suggests the potential use of combined selegiline and stem cell therapy to improve deficits in neurodegenerative diseases.

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References

  • Andrews P. W.; Damjanov I.; Simon D.; Banting G. S.; Carlin C.; Dracopoli N. C.; Føgh J. Pluripotent embryonal carcinoma clones derived from the human teratocarcinoma cell line tera-2. Differentiation in vivo and in vitro. Laboratory investigation; a journal of technical methods and pathology 50: 147–162; 1984.

    PubMed  CAS  Google Scholar 

  • Astigiano S.; Damonte P.; Fossati S.; Boni L.; Barbieri O. Fate of embryonal carcinoma cells injected into postimplantation mouse embryos. Differentiation 73: 484–490; 2005.

    Article  PubMed  CAS  Google Scholar 

  • Bailey J. A.; Lahiri D. K. A novel effect of rivastigmine on pre synaptic proteins and neuronal viability in a neurodegeneration model of fetal rat primary cortical cultures and its implication in alzheimer’s disease. Journal of neurochemistry 112: 843–853; 2010.

    Article  PubMed  CAS  Google Scholar 

  • Bain G.; Kitchens D.; Yao M.; Huettner J. E.; Gottlieb D. I. Embryonic stem cells express neuronal properties in vitro. Developmental biology 168: 342–357; 1995.

    Article  PubMed  CAS  Google Scholar 

  • Bain G.; Ray W. J.; Yao M.; Gottlieb D. I. From embryonal carcinoma cells to neurons: The p19 pathway. Bioessays 16: 343–348; 1994.

    Article  PubMed  CAS  Google Scholar 

  • Davidson C.; Chen Q.; Zhang X.; Xiong X.; Lazarus C.; Lee T. H.; Ellinwood E. H. Deprenyl treatment attenuates long-term pre-and post-synaptic changes evoked by chronic methamphetamine. European journal of pharmacology 573: 100–110; 2007.

    Article  PubMed  CAS  Google Scholar 

  • Dinsmore J.; Ratliff J.; Deacon T.; Pakzaban P.; Jacoby D.; Galpern W.; Isacson O. Embryonic stem cells differentiated in vitro as a novel source of cells for transplantation. Cell transplantation 5: 131–143; 1996.

    Article  PubMed  CAS  Google Scholar 

  • Ebadi M.; Sharma S.; Shavali S.; El Refaey H. Neuroprotective actions of selegiline. Journal of neuroscience research 67: 285–289; 2002.

    Article  PubMed  CAS  Google Scholar 

  • Esmaeili F.; Tiraihi T.; Movahedin M.; Mowla S. J. Selegiline induces neuronal phenotype and neurotrophins expression in embryonic stem cells. Rejuvenation Research 9: 475–484; 2006.

    Article  PubMed  CAS  Google Scholar 

  • Falconer M. M.; Echeverri C. J.; Brown D. L. Differential sorting of beta tubulin isotypes into colchicine stable microtubules during neuronal and muscle differentiation of embryonal carcinoma cells. Cell motility and the cytoskeleton 21: 313–325; 1992.

    Article  PubMed  CAS  Google Scholar 

  • Fedchenko V.; Globa A.; Kaloshin A.; Kapitsa I.; Nerobkova L.; Val'Dman E.; Buneeva O.; Glover V.; Medvedev A. The effect of short-term administration of (−)-deprenyl and isatin on the expressions of some genes in the mouse brain cortex. Medical science monitor 14: BR269–73; 2008.

    PubMed  Google Scholar 

  • Finley M. F.; Kulkarni N.; Huettner J. E. Synapse formation and establishment of neuronal polarity by p19 embryonic carcinoma cells and embryonic stem cells. Journal of Neuroscience 16: 1056–1065; 1996.

    PubMed  CAS  Google Scholar 

  • Fraichard A.; Chassande O.; Bilbaut G.; Dehay C.; Savatier P.; Samarut J. In vitro differentiation of embryonic stem cells into glial cells and functional neurons. Journal of Cell Science 108: 3181–3188; 1995.

    PubMed  CAS  Google Scholar 

  • Freshney R. I. Culture of animal cells: a manual of basic technique. Wiley-Liss, New York; 1994.

    Google Scholar 

  • Ghorbanian M. T.; Tiraihi T.; Mesbah-Namin S. A.; Fathollahi Y. Selegiline is an efficient and potent inducer for bone marrow stromal cell differentiation into neuronal phenotype. Neurological Research 32: 185–193; 2010.

    Article  PubMed  CAS  Google Scholar 

  • He Q.; Li J.; Bettiol E.; Jaconi M. E. Embryonic stem cells: New possible therapy for degenerative diseases that affect elderly people. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 58: 279–287; 2003.

    Article  Google Scholar 

  • Hou Z.; Lei H.; Hong S.; Sun B.; Fang K.; Lin X.; Liu M.; Yew D. T. W.; Liu S. Functional changes in the frontal cortex in parkinson's disease using a rat model. Journal of Clinical Neuroscience 17: 628–633; 2010.

    Article  PubMed  CAS  Google Scholar 

  • Iwasaki Y.; Ikeda K.; Shiojima T.; Kobayashi T.; Tagaya N.; Kinoshita M. Deprenyl enhances neurite outgrowth in cultured rat spinal ventral horn neurons. Journal of the neurological sciences 125: 11–13; 1994.

    Article  PubMed  CAS  Google Scholar 

  • Jagla W.; Wiede A.; Dietzmann K.; Rutkowski K.; Hoffmann W. Co-localization of tff3 peptide and oxytocin in the human hypothalamus. The FASEB Journal 14: 1126–1131; 2000.

    PubMed  CAS  Google Scholar 

  • Jones-Villeneuve E. M.; McBurney M. W.; Rogers K. A.; Kalnins V. I. Retinoic acid induces embryonal carcinoma cells to differentiate into neurons and glial cells. The Journal of cell biology 94: 253–262; 1982.

    Article  PubMed  CAS  Google Scholar 

  • Klegeris A.; McGeer P. L. R-(−)-deprenyl inhibits monocytic thp-1 cell neurotoxicity independently of monoamine oxidase inhibition. Experimental neurology 166: 458–464; 2000.

    Article  PubMed  CAS  Google Scholar 

  • Knoll J. Deprenyl (selegiline): The history of its development and pharmacological action. Acta Neurologica Scandinavica 68: 57–80; 1983.

    Article  Google Scholar 

  • Kompisch K. M.; Lange C.; Steinemann D.; Skawran B.; Schlegelberger B.; Müller R.; Schumacher U. Neurogenic transdifferentiation of human adipose-derived stem cells? A critical protocol reevaluation with special emphasis on cell proliferation and cell cycle alterations. Histochemistry and cell biology 134: 453–68; 2010.

    Article  PubMed  CAS  Google Scholar 

  • MacPherson P. A.; Jones S.; Pawson P. A.; Marshall K. C.; McBurney M. W. P19 cells differentiate into glutamatergic and glutamate-responsive neurons in vitro. Neuroscience 80: 487–499; 1997.

    Article  PubMed  CAS  Google Scholar 

  • MacPherson P. A.; McBurney M. W. P19 embryonal carcinoma cells: A source of cultured neurons amenable to genetic manipulation. Methods 7: 238–252; 1995.

    Article  CAS  Google Scholar 

  • Martin G. R.; Evans M. J. Multiple differentiation of clonal teratocarcinoma stem cells following embryoid body formation in vitro. Cell 6: 467–474; 1975.

    Article  Google Scholar 

  • Masliah E.; Terry R. The role of synaptic proteins in the pathogenesis of disorders of the central nervous system. Brain Pathology 3: 77–85; 1993.

    Article  PubMed  CAS  Google Scholar 

  • McBurney M. W. Clonal lines of teratocarcinoma cells in vitro: Differentiation and cytogenetic characteristics. Journal of Cellular Physiology 89: 441–455; 1976.

    Article  PubMed  CAS  Google Scholar 

  • McBurney M. W. P19 embryonal carcinoma cells. The International journal of developmental biology 37: 135–140; 1993.

    PubMed  CAS  Google Scholar 

  • McBurney M. W.; Rogers B. J. Isolation of male embryonal carcinoma cells and their chromosome replication patterns* 1. Developmental biology 89: 503–508; 1982.

    Article  PubMed  CAS  Google Scholar 

  • Palfi M.; Szökó E.; Kalman M. Molecular mechanisms of the neuroprotective effect of (−)-deprenyl. Orvosi hetilap 147: 1251–7; 2006.

    PubMed  Google Scholar 

  • Passier R.; Mummery C. Origin and use of embryonic and adult stem cells in differentiation and tissue repair. Cardiovascular Research 58: 324; 2003.

    Article  PubMed  CAS  Google Scholar 

  • Rak K.; Wasielewski N. V.; Radeloff A.; Völkers J.; Scherzed A.; Jablonka S.; Hagen R.; Mlynski R. Isolation and characterization of neural stem cells from the neonatal rat cochlear nucleus. Cell and Tissue Research 343: 499–508; 2011.

    Article  PubMed  Google Scholar 

  • Rohwedel J.; Guan K.; Wobus A. M. Induction of cellular differentiation by retinoic acid in vitro. Cells Tissues Organs 165: 190–202; 2000.

    Article  Google Scholar 

  • Rutten B. P. F.; Van der Kolk N. M.; Schafer S.; van Zandvoort M. A. M. J.; Bayer T. A.; Steinbusch H. W. M.; Schmitz C. Age-related loss of synaptophysin immunoreactive presynaptic boutons within the hippocampus of app 751sl, ps1m146l, and app751sl/ps1m146l transgenic mice. American Journal of Pathology 167: 161–173; 2005.

    Article  PubMed  CAS  Google Scholar 

  • Schmidt M. M.; Guan K.; Wobus A. M. Lithium influences differentiation and tissue-specific gene expression of mouse embryonic stem (es) cells in vitro. International Journal of Developmental Biology 45: 421–430; 2001.

    PubMed  CAS  Google Scholar 

  • Semkova I.; Wolz P.; Schilling M.; Krieglstein J. Selegiline enhances ngf synthesis and protects central nervous system neurons from excitotoxic and ischemic damage. European journal of pharmacology 315: 19–30; 1996.

    Article  PubMed  CAS  Google Scholar 

  • Sortwell C. E.; Blanchard B. C.; Collier T. J.; Elsworth J. D.; Taylor J. R.; Roth R. H.; Redmond Jr. D. E.; Sladek Jr. J. R. Pattern of synaptophysin immunoreactivity within mesencephalic grafts following transplantation in a parkinsonian primate model. Brain research 791: 117–124; 1998.

    Article  PubMed  CAS  Google Scholar 

  • Tampellini D.; Capetillo-Zarate E.; Dumont M.; Huang Z.; Yu F.; Lin M. T.; Gouras G. K. Effects of synaptic modulation on {beta}-amyloid, synaptophysin, and memory performance in alzheimer's disease transgenic mice. Journal of Neuroscience 30: 14299–304; 2010.

    Article  PubMed  CAS  Google Scholar 

  • Tatton W. G. Modulation of gene expression rather than monoamine oxidase inhibition:(−)-deprenyl-related compounds in controlling neurodegeneration. Neurology 47: S171–83; 1996.

    PubMed  CAS  Google Scholar 

  • Tatton W. G.; Ju W. Y. L.; Holland D. P.; Tai C.; Kwan M. (−) deprenyl reduces pc12 cell apoptosis by inducing new protein synthesis. Journal of neurochemistry 63: 1572–1575; 1994.

    Article  PubMed  CAS  Google Scholar 

  • Wobus A. M.; Grosse R.; Schöneich J. Specific effects of nerve growth factor on the differentiation pattern of mouse embryonic stem cells in vitro. Biomedica biochimica acta 47: 965–973; 1988.

    PubMed  CAS  Google Scholar 

  • Xu L.; Ma J.; Seigel G. M. L-deprenyl, blocking apoptosis and regulating gene expression in cultured retinal neurons1. Biochemical pharmacology 58: 1183–1190; 1999.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors especially would like to express deep thanks to Dr. Morteza Hashemzadeh (head of Cellular and Molecular Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran) for his excellent assistance. The work done in Cellular and Molecular Research Center was supported by grant from Shahrekord University of Medical Sciences, Shahrekord, Iran.

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Authors and Affiliations

  1. Department of Biology, Faculty of Basic Sciences, Shahrekord University, P.O. Box 115, Shahrekord, Iran

    Shabnam Bakhshalizadeh & Fariba Esmaeili

  2. Research Institute of Biotechnology, Shahrekord University, P.O. Box 115, Shahrekord, Iran

    Fariba Esmaeili

  3. Department of Physiology, Faculty of Medical Sciences, Shahrekord University of Medical Sciences, Shahrekord, Iran

    Fariba Houshmand

  4. Cellular and Molecular Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran

    Hedayatollah Shirzad & Mojtaba Saedi

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  1. Shabnam Bakhshalizadeh
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  2. Fariba Esmaeili
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  4. Hedayatollah Shirzad
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  5. Mojtaba Saedi
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Correspondence to Hedayatollah Shirzad.

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Editor: T. Okamoto

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Bakhshalizadeh, S., Esmaeili, F., Houshmand, F. et al. Effects of selegiline, a monoamine oxidase B inhibitor, on differentiation of P19 embryonal carcinoma stem cells, into neuron-like cells. In Vitro Cell.Dev.Biol.-Animal 47, 550–557 (2011). https://doi.org/10.1007/s11626-011-9442-3

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  • DOI: https://doi.org/10.1007/s11626-011-9442-3

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