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Antiparkinsonian Action of the Prolyl Endopeptidase Inhibitor in Mice

  • A. P. KalininaEmail author
  • I. G. Kapitsa
  • E. A. Ivanova
  • T. A. Voronina
RESEARCH ARTICLE
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Abstract

Prolyl endopeptidase is involved in neurodegeneration, proliferation, neuroinflammation, and neuron differentiation. It has been observed that severity of the neurodegenerative process correlates with an increasing level of prolyl endopeptidase in the brain. According to recent research, prolyl endopeptidase might interact with prion-like proteins, which are believed to play the key role in the development of neurodegenerative diseases. Consequently, prolyl endopeptidase inhibitors might be a promising group of chemicals to study in neurodegenerative diseases, particularly Parkinson’s disease. The aim of this research was to determine the effects of benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine, a new inhibitor of prolyl endopeptidase, using haloperidol catalepsy test in SHK outbred mice and Parkinson-like syndrome induced by a single systemic injection of neurotoxic 1-methyl-4-phenyl-tetrahydropiridine at a dose of 30 mg/kg in C57Bl/6 inbred mice. As a result, the compound reduces the severity of the main extrapyramidal symptoms: rigidity and motor deficits. However, anticataleptic activity was not found. According to our results, the prolyl endopeptidase inhibitor does not affect the dopaminergic neurons directly but provides possible neuroprotection to the neurons.

Keywords:

prolyl endopeptidase prolyl endopeptidase inhibitors Parkinson-like syndrome mice Parkinson’s disease neurodegeneration. 

Notes

FUNDING

The study was conducted within the state task, project no. 0521–2019–0007.

COMPLIANCE WITH ETHICAL STANDARDS

Conflict of interests. The authors declare that they have no conflict of interest.

Statement on the welfare of animals. Animals were kept according to Sanitary Epidemiological Requirements to the Organization, Equipment, and Maintenance of Biological Experimental Clinics (Vivariums), sanitary regulation no. 2.2.1.3218–14, August 29, 2014, no 51. The work was organized and performed according to international and Russian legal documents: Order of the Ministry of Health of the Russian Federation no. 199n, January 1, 2016 “On Approval of the Rules of Good Laboratory Practice” and the Directive of the European Parliament and of the Council 2010/63/EU, September 22, 2010 “On Protection of Animals Used for Scientific Purposes.” Experiments were approved by the Biomedical Ethics Committee of Zakusov Research Institute of Pharmacology.

The study was conducted in accordance with the Preclinical Study Manual for Drugs (Methodological Recommendations on Preclinical Trial of Drugs with Antiparkinsonian Activity, 2012) [18].

REFERENCES

  1. 1.
    Babkova, K., Korabecny, J., Soukup, O., Nepovimova, E., Jun, D., and Kuca, K., Prolyl oligopeptidase and its role in the organism: Attention to the most promising and clinically relevant inhibitors, Future Med. Chem., 2017, vol. 9, no. 10, pp. 1015–1038.CrossRefGoogle Scholar
  2. 2.
    Myohanen, T.T., Hannula, M.J., Van Elzen, R., Gerard, M., Van Der Veken, P., Garcia-Horsman, J.A., Baekelandt, V., Mannisto, P.T., and Lambeir, A.M., A prolyl oligopeptidase inhibitor, KYP-2047, reduces alpha-synuclein protein levels and aggregates in cellular and animal models of Parkinson’s disease, Br. J. Pharmacol., 2012, vol. 166, no. 3, pp. 1097–1113.CrossRefGoogle Scholar
  3. 3.
    Besedin, D.V. and Rudenskaya, G.N., Proline-specific endopeptidases, Bioorg. Khim., 2003, vol. 29, no. 1, pp. 3–20.Google Scholar
  4. 4.
    Myohanen, T.T., Venalainen, J.I., Tupala, E., Garcia-Horsman, J.A., Miettinen, R., and Mannisto, P.T., Distribution of immunoreactive prolyl oligopeptidase in human and rat brain, Neurochem. Res., 2007, vol. 32, no. 8, pp. 1365–1374.CrossRefGoogle Scholar
  5. 5.
    Tenorio-Laranga, J., Montoliu, C., Urios, A., Hernandez-Rabaza, V., Ahabrach, H., Garcia-Horsman, J.A., and Felipo, V., The expression levels of prolyl oligopeptidase responds not only to neuroinflammation but also to systemic inflammation upon liver failure in rat models and cirrhotic patients, J. Neuroinflamm., 2015, vol. 12, p. 183.CrossRefGoogle Scholar
  6. 6.
    Penttinen, A., Tenorio-Laranga, J., Siikanen, A., Morawski, M., Rossner, S., and Garcia-Horsman, J.A., Prolyl oligopeptidase: A rising star on the stage of neuroinflammation research, CNS Neurol. Disord. Drug Targets., 2011, vol. 10, no. 3, pp. 340–348.CrossRefGoogle Scholar
  7. 7.
    Natunen, T.A., Gynther, M., Rostalski, H., Jaako, K., and Jalkanen, A.J., Extracellular prolyl oligopeptidase derived from activated microglia is a potential neuroprotection target, Basic Clin. Pharmacol., 2019, vol. 124, no. 1, pp. 40–49.CrossRefGoogle Scholar
  8. 8.
    Hofling, C., Kulesskaya, N., Jaako, K., Peltonen, I., Mannisto, P.T., Nurmi, A., Vartiainen, N., Morawski, M., Zharkovsky, A., Voikar, V., Rossner, S., and Garcia-Horsman, J.A., Deficiency of prolyl oligopeptidase in mice disturbs synaptic plasticity and reduces anxiety-like behaviour, body weight, and brain volume, Eur. Neuropsychopharm., 2016, vol. 26, no. 6, pp. 1048–1061.CrossRefGoogle Scholar
  9. 9.
    Hannula, M.J., Myohanen, T.T., Tenorio-Laranga, J., Mannisto, P.T., and Garcia-Horsman, J.A., Prolyl oligopeptidase colocalizes with alpha-synuclein, beta-amyloid, tau protein and astroglia in the post-mortem brain samples with Parkinson’s and Alzheimer’s diseases, Neuroscience, 2013, vol. 242, pp. 140–150.CrossRefGoogle Scholar
  10. 10.
    Mannisto, P.T., Venalainen, J., Jalkanen, A., and Garcia-Horsman, J.A., Prolyl oligopeptidase: A potential target for the treatment of cognitive disorders, Drug News Perspect., 2007, vol. 20, no. 5, pp. 293–305.CrossRefGoogle Scholar
  11. 11.
    Dokleja, L., Hannula, M.J., and Myohanen, T.T., Inhibition of prolyl oligopeptidase increases the survival of alpha-synuclein overexpressing cells after rotenone exposure by reducing alpha-synuclein oligomers, Neurosci. Lett., 2014, vol. 583, pp. 37–42.CrossRefGoogle Scholar
  12. 12.
    Di Daniel, E., Glover, C.P., Grot, E., Chan, M.K., Sanderson, T.H., White, J.H., Ellis, C.L., Gallagher, K.T., Uney, J., Thomas, J., Maycox, P.R., and Mudge, A.W., Prolyl oligopeptidase binds to GAP-43 and functions without its peptidase activity, Mol. Cell Neurosci., 2009, vol. 41, no. 3, pp. 373–382.CrossRefGoogle Scholar
  13. 13.
    Myohanen, T.T., Norrbacka, S., and Savolainen, M.H., Prolyl oligopeptidase inhibition attenuates the toxicity of a proteasomal inhibitor, lactacystin, in the alpha-synuclein overexpressing cell culture, Neurosci. Lett., 2017, vol. 636, pp. 83–89.CrossRefGoogle Scholar
  14. 14.
    Lashuel, H.A., Overk, C.R., Oueslati, A., and Masliah, E., The many faces of alpha-synuclein: From structure and toxicity to therapeutic target, Nat. Rev. Neurosci., 2013, vol. 14, no. 1, pp. 38–48.CrossRefGoogle Scholar
  15. 15.
    Ivanova, E.A., Zolotov, N.N., Kapitsa, I.G., Pozdnev, V.F., Valdman, E.A., and Voronina, T.A., Proline-specific endopeptidase and adenosine deaminase activity in blood serum and cerebrospinal fluid in experimental Parkinson’s syndrome, Immunologiya, 2017, vol. 38, no. 4, pp. 213–218.Google Scholar
  16. 16.
    Khlebnikova, N.N., Krupina, N.A., Bogdanova, N.G., and Zolotov, N.N., Effect of prolyl endopeptidase inhibitor benzyloxycarbonyl-methionyl-2(s)-cyanopyrrolidine on activity of proline-specific peptidases in brain structures of rats with experimental MPTP-induced depressive syndrome, Bull. Exp. Biol. Med., 2013, vol. 155, no. 6, pp. 670–674.Google Scholar
  17. 17.
    Rocha, E.M., De Miranda, B., and Sanders, L.H., Alpha-synuclein: Pathology, mitochondrial dysfunction and neuroinflammation in Parkinson’s disease, Neurobiol. Dis., 2018, vol. 109, part B, pp. 249–257.Google Scholar
  18. 18.
    Rukovodstvo po provedeniyu doklinicheskikh issledovanii lekarstvennykh sredstv. Ch. 1 (Guidelines for Conducting Preclinical Studies of Drugs. Part 1), Mironov, A.N., Eds., Moscow: Grif i K, 2012.Google Scholar
  19. 19.
    Blandini, F. and Armentero, M.T., Animal models of Parkinson’s disease, FEBS J., 2012, vol. 279, no. 7, pp. 1156–1166.CrossRefGoogle Scholar

Copyright information

© Allerton Press, Inc. 2019

Authors and Affiliations

  • A. P. Kalinina
    • 1
    Email author
  • I. G. Kapitsa
    • 1
  • E. A. Ivanova
    • 1
  • T. A. Voronina
    • 1
  1. 1.Laboratory of Psychopharmacology, Zakusov Institute of PharmacologyMoscowRussia

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