Neurochemical Journal

, Volume 13, Issue 2, pp 169–175 | Cite as

The Effect of Atypical Antipsychotic Drugs on the Neurotrophic Factors Gene Expression in the MPTP Model of Parkinson’s Disease

  • A. S. TsybkoEmail author
  • T. V. Il’chibaeva
  • N. V. Khotskin
  • A. I. Kovetskaya
  • V. S. Naumenko
  • N. K. Popova
Experimental Articles


Atypical antipsychotics (AAP) are used in the therapy of Parkinson’s disease (PD) for elimination of psychotic symptoms. As the brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and cerebral dopamine neurotrophic factor (CDNF) play a crucial role in the PD treatment, the aim of our study was the investigation of the effects of chronic treatment with commonly used AAP, clozapine and quetiapine, on the motor behavior and the BDNF, GDNF and CDNF genes expression in the mouse brain in the PD model produced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Clozapine and quetiapine (1 mg/kg, i.p.) were administered 48 hours after the last MPTP injection, and treatment continued for the following 16 days. Then animals were euthanized, substantia nigra (SN), striatum (St) and hippocampus (Hc) were extracted for RT-PCR and tyrosine hydroxylase (TH) western blot assessment. MPTP treatment led to 50% depletion in the TH protein level in the St. MPTP caused significant decrease in both BDNF and GDNF mRNA level in the Hc and St, respectively. At the same time, increase in the GDNF expression in the MPTP + clozapine group in the SN was found. MPTP caused dramatic decrease in the CDNF mRNA level in the SN with simultaneous increase in the St. Both clozapine and quetiapine decreased it to a normal level in the St. The effect of AAP clozapine and quetiapine on the GDNF and CDNF genes expression in the pharmacological model of PD has been shown for the first time.


clozapine quetiapine BDNF GDNF CDNF MPTP 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Friedman, J.H., Behav. Neurol., 2013, vol. 27, pp. 469–477.CrossRefGoogle Scholar
  2. 2.
    Zahodne, L.B. and Fernandez, H.H., Drugs Aging, 2008, vol. 25, no. 8, pp. 665–682.CrossRefGoogle Scholar
  3. 3.
    Seppi, K., Weintraub, D., Coelho, M., Perez-Lloret, S., Fox, S.H., Katzenschlager, R., Hametner, E.M., Poewe, W., Rascol, O., Goetz, C.G., and Sampaio, C., Mov. Disord., 2011, vol. 26, pp. 42–80.CrossRefGoogle Scholar
  4. 4.
    Hack, N., Fayad, S.M., Monari, E.H., Akbar, U., Hardwick, A., Rodriguez, R.L., Malaty, I.A., Romrell, J., Shukla, A.A., McFarland, N., Ward, H.E., and Okun, M.S., PLoS One, 2014, vol. 9, p. e91545. CrossRefGoogle Scholar
  5. 5.
    Bustos, G., Abarca, J., Campusano, J., Bustos, V., Noriega, V., and Aliaga, E., Brain Res. Brain Res. Rev., 2004, vol. 47, nos. 1–3, pp. 126–144.CrossRefGoogle Scholar
  6. 6.
    Guillin, O., Demily, C., and Thibaut, F., Int. Rev. Neurobiol., 2007, vol. 78, pp. 1–39.CrossRefGoogle Scholar
  7. 7.
    Pascual, A., Hidalgo-Figueroa, M., Gómez-Díaz, R., and López-Barneo, J., J. Mol. Endocrinol., 2011, vol. 46, pp. 83–92.CrossRefGoogle Scholar
  8. 8.
    Nagahara, A.H. and Tuszynski, M.H., Nat. Rev. Drug. Discov., 2011, vol. 10, pp. 209–219.CrossRefGoogle Scholar
  9. 9.
    de Tassigny, X., Pascual, A., and Lopez-Barneo, J., Front. Neuroanat., 2015, vol. 9,
  10. 10.
    Voutilainen, M.H., Arumäe, U., Airavaara, M., and Saarma, M., FEBS Lett., 2015, vol. 589. pp. 3739–3748.CrossRefGoogle Scholar
  11. 11.
    Tang, T., Li, Y., Jiao, Q., Du, X., and Jiang, H., Neurosci. Bull., 2017, vol. 33, pp. 568–575.CrossRefGoogle Scholar
  12. 12.
    Miranda, A.S., Moreira, F.A., and Teixeira, A.L., Expert Opin. Drug Discov., 2017, vol. 12, pp. 525–535.CrossRefGoogle Scholar
  13. 13.
    Bai, O., Chlan-Fourney, J., Bowen, R., Keegan, D., and Li, X.M., J. Neurosci. Res., 2003, vol. 71, pp. 127–131.CrossRefGoogle Scholar
  14. 14.
    Balu, D.T., Hoshaw, B.A., Malberg, J.E., Rosenzweig-Lipson, S., Schechter, L.E., and Lucki, I., Brain Res., 2008, vol. 1211, pp. 37–43.CrossRefGoogle Scholar
  15. 15.
    Fernandes, B.S., Steiner, J., Berk, M., Molendijk, M.L., Gonzalez-Pinto, A., Turck, C.W., Nardin, P., and Gonçalves, C.A., Mol. Psychiatry, 2015, vol. 20, pp. 1108–1119.CrossRefGoogle Scholar
  16. 16.
    Shao, Z., Dyck, L.E., Wang, H., and Li, X.M., J. Psychiatry Neurosci., 2006, vol. 31, pp. 32–37.Google Scholar
  17. 17.
    Di Benedetto, B., Kühn, R., Nothdurfter, C., Rein, T., Wurst, W., and Rupprecht, R., Neuropharmacology, 2012, vol. 62, pp. 209–216.CrossRefGoogle Scholar
  18. 18.
    Blesa, J., S. Przedborski S., Front. Neuroanat., 2014, vol. 8.
  19. 19.
    Jackson-Lewis, V. and Przedborski, S., Nat. Protoc, 2007, vol. 2, pp. 141–151.CrossRefGoogle Scholar
  20. 20.
    Kulikov, A.V., Tikhonova, M.A., and Kulikov, V.A., J. Neurosci. Methods, 2008, vol. 170, pp. 345–351.CrossRefGoogle Scholar
  21. 21.
    Kulikov, A.V., Naumenko, V.S., Voronova, I.P., Tikhonova, M.A., and Popova, N.K., J. Neurosci. Methods, 2005, vol. 141, pp. 97–101.CrossRefGoogle Scholar
  22. 22.
    Naumenko, V.S., Osipova, D.V., Kostina, E.V., and Kulikov, A.V., J. Neurosci. Methods, 2008, vol. 170, pp. 197–203.CrossRefGoogle Scholar
  23. 23.
    Sedelis, M., Schwarting, R.K., and Huston, J.P., Behav. Brain. Res., 2001, vol. 125, pp. 109–125.CrossRefGoogle Scholar
  24. 24.
    Hutter-Saunders, J.A., Gendelman, H.E., and Mosley, R.L., J. Neuroimmune Pharmacol., 2012, vol. 7, pp. 279–288.CrossRefGoogle Scholar
  25. 25.
    Chia, L.G., Ni, D.R., Cheng, F.C., Ho, Y.P., and Kuo, J.S., Neurochem. Res., 1999, vol. 24. pp. 719–722.CrossRefGoogle Scholar
  26. 26.
    Amato, D., Behav. Brain. Res., 2015, vol. 277, pp. 125–135.CrossRefGoogle Scholar
  27. 27.
    Zhou, J., Bradford, H.F., and Stern, G.M., Brain Res. Dev. Brain Res., 1997, vol. 100, pp. 43–51.CrossRefGoogle Scholar
  28. 28.
    Riaz, S.S., Jauniaux, E., Stern, G.M., and Bradford, H.F., Brain Res. Dev. Brain Res., 2002, vol. 136, pp. 27–34.CrossRefGoogle Scholar
  29. 29.
    Narita, M., Aoki, K., Takagi, M., Yajima, Y., and Suzuki, T., Neuroscience, 2003, vol. 119, pp. 767–775.CrossRefGoogle Scholar
  30. 30.
    Goggi, J., Pullar, I.A., Carney, S.L., and Bradford, H.F., Brain Res., 2003, vol. 968, pp. 156–161.CrossRefGoogle Scholar
  31. 31.
    Bustos, G., Abarca, J., Campusano, J., Bustos, V., Noriega, V., and Aliaga, E., Brain Res. Brain Res. Rev., 2004, vol. 47, pp. 126–144.CrossRefGoogle Scholar
  32. 32.
    Cunha, M.P., Pazini, F.L., Lieberknecht, V., Budni, J., Oliveira, Á., Rosa, J.M., Mancini, G., Mazzardo, L., Colla, A.R., Leite, M.C., Santos, A.R.S., Martins, D.F., de Bem, A.F., Gonçalves, C.A.S., Farina, M., and Rodrigues, A.L.S., Mol. Neurobiol., 2017, vol, 54, pp. 6356–6377.CrossRefGoogle Scholar
  33. 33.
    Mocchetti, I., Bachis, A., Nosheny, R.L., and Tanda, G., Neurotox. Res., 2007, vol. 12, pp. 135–143.CrossRefGoogle Scholar
  34. 34.
    Lesemann, A., Reinel, C., Huhnchen, P., Pilhatsch, M., Hellweg, R., Klaissle, P., Winter, C., and Steiner, B., Brain Res., 2012, vol. 1457, pp. 51–69.CrossRefGoogle Scholar
  35. 35.
    Fumagalli, F., Molteni, R., Bedogni, F., Gennarelli, M., Perez, J., Racagni, G., and Riva, M.A., Neuroreport, 2004, vol. 15, pp. 2109–2112.CrossRefGoogle Scholar
  36. 36.
    Xu, H., Chen, Z., He, J., Haimanot, S., Li, X., Dyck, L., and Li, X.M., Hippocampus, 2006, vol. 16, pp. 551–559.CrossRefGoogle Scholar
  37. 37.
    Park, S.W., Lee, S.K., Kim, J.M., Yoon, J.S., and Kim, Y.H., Neurosci. Let., 2006, vol. 402, pp. 25–29.CrossRefGoogle Scholar
  38. 38.
    Kim, H.W., Cheon, Y., Modi, H.R., Rapoport, S.I., and Rao, J.S., Psychopharmacology (Berl.), 2012, vol. 222, pp. 663–674.CrossRefGoogle Scholar
  39. 39.
    Rizig, M.A., McQuillin, A., Ng, A., Robinson, M., Harrison, A., Zvelebil, M., Hunt, S.P., and Gurling, H.M., J. Psychopharmacol., 2012, vol. 26. pp. 1218–1230.CrossRefGoogle Scholar
  40. 40.
    Saavedra, A., Baltazar, G., and Duarte, E.P., Prog. Neurobiol., 2008, vol. 86, pp. 186–215.CrossRefGoogle Scholar
  41. 41.
    Saavedra, A., Baltazar, G., Santos, P., Carvalho, C.M., and Duarte, E.P., Neurobiol. D., 2006, vol. 23, pp. 533–542.CrossRefGoogle Scholar
  42. 42.
    Lindholm, P., Voutilainen, M.H., Laurén, J., Peränen, J., Leppänen, V.M., Andressoo, J.O., Lindahl, M., Janhunen, S., Kalkkinen, N., Timmusk, T., Tuominen, R.K., and Saarma, M., Nature, 2007, vol. 448, pp. 73–77.CrossRefGoogle Scholar
  43. 43.
    Voutilainen, M.H., Bäck, S., Peränen, J., Lindholm, P., Raasmaja, A., Männistö, P.T., Saarma, M., and Tuominen, R.K., Exp. Neurol., 2011, vol. 228, pp. 99–108.CrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2019

Authors and Affiliations

  • A. S. Tsybko
    • 1
    • 2
    Email author
  • T. V. Il’chibaeva
    • 1
  • N. V. Khotskin
    • 1
  • A. I. Kovetskaya
    • 1
  • V. S. Naumenko
    • 1
  • N. K. Popova
    • 1
  1. 1.The Federal Research Center Institute of Cytology and Genetics SB RASNovosibirskRussia
  2. 2.Novosibirsk State UniversityNovosibirskRussia

Personalised recommendations