The pro-depressive effect of levodopa in a 6-OHDA-induced hemiparkinsonism rat model

Cover Page


Cite item

Full Text

Abstract

Rationale: Treatment of Parkinson's disease has been by now symptomatic. The literature on the efficacy and side effects of levodopa has been contradictory. Some authors mention an anti-depressant effect of the agent, while others believe that it is exactly levodopa that eventually induces the occurrence of depressive symptoms. Aim: To reproduce the OHDA-hemiparkinsonism rat model with subsequent assessment of both external and structural manifestations of the disorder, as well as to study the efficacy of levodopa for motor and non-motor symptoms of parkinsonism. Materials and methods: The study was performed in 52 male Wistar rats. The disease model included stereotaxic administration of neurotoxic 6-OHDA into the pars compacta of the substantia nigra. At 2 months after the administration, the animals underwent test for motor (Rotarod, cylinder, ketamine-induced rotation in the rotometer) and non-motor abnormalities (open field, social interest, conditioned escape response). Results: In 18% of the animals no hemiparkinsonism symptoms were found. 32% of rats had only motor symptoms, whereas in 50% of the animals both motor and non-motor symptoms were noted. Levodopa could partially correct the motor abnormalities, with augmentation of depressive-like behavior. Conclusion: Levodopa has shown its partial efficacy in correction of the motor symptoms caused by administration of 6-OHDA neurotoxin; however, it caused such side effects as augmentation of depressive-like behavior and anxiety.

About the authors

O. S. Karimova

Serbsky Federal Medical Research Centre for Psychiatry and Narcology

Author for correspondence.
Email: karimovaos@yandex.ru
ORCID iD: 0000-0002-6377-3356

Olga S. Karimova – Laboratory Assistant Research Fellow, Laboratory of Immunochemistry, Department of Basic and Applied Neurobiology.

Tel.: +7 (985) 988 13 73
23 Kropotkinskiy pereulok, Moscow, 119034

Russian Federation

A. Yu. Morozova

Serbsky Federal Medical Research Centre for Psychiatry and Narcology

Email: hakurate77@gmail.com
ORCID iD: 0000-0002-8681-5299

Anna Yu. Morozova – MD, PhD, Senior Research Fellow, Laboratory of Neurochemistry,  Department of Basic and Applied Neurobiology.

23 Kropotkinskiy pereulok, Moscow, 119034

Russian Federation

Ya. A. Zorkina

Serbsky Federal Medical Research Centre for Psychiatry and Narcology

Email: zorkina.ya@serbsky.ru
ORCID iD: 0000-0003-0247-2717

Yana A. Zorkina – PhD (in Biol.), Research Fellow, Laboratory of Immunochemistry, Department of Basic and Applied Neurobiology.

23 Kropotkinskiy pereulok, Moscow, 119034

Russian Federation

E. A. Zubkov

Serbsky Federal Medical Research Centre for Psychiatry and Narcology

Email: zubkov@ngs.ru
ORCID iD: 0000-0001-6133-3421

Eugene A. Zubkov – PhD (in Biol.), Senior Research Fellow, Laboratory of Neurochemistry, Department of Basic and Applied Neurobiology

23 Kropotkinskiy pereulok, Moscow, 119034

Russian Federation

V. M. Ushakova

Serbsky Federal Medical Research Centre for Psychiatry and Narcology; Lomonosov Moscow State University

Email: ushakovavm@yandex.ru
ORCID iD: 0000-0003-3480-910X

Valeria M. Ushakova – PhD (in Biol.), Junior Research Fellow, Laboratory of  Immunochemistry, Department of Basic and Applied Neurobiology; Educational Master of the 1st category, Chair of Higher Nervous Activity, Biological Faculty

23 Kropotkinskiy pereulok, Moscow, 119034
1/2 Leninskie gory, Moscow, 119991

Russian Federation

O. V. Abramova

Serbsky Federal Medical Research Centre for Psychiatry and Narcology

Email: abramova1128@gmail.com
ORCID iD: 0000-0001-8793-1833

Olga V. Abramova – Junior Research Fellow, Laboratory of Neurochemistry, Department of Basic and Applied Neurobiology.

23 Kropotkinskiy pereulok, Moscow, 119034

Russian Federation

V. P. Chekhonin

Serbsky Federal Medical Research Centre for Psychiatry and Narcology; Pirogov Medical University

Email: checkhoninnew@yandex.ru
ORCID iD: 0000-0003-4386-7897

Vladimir P. Chekhonin – MD, PhD, Professor, Member of Russian Academy of Sciences, Head of the Department of Basic and Applied Neurobiology; Head of the Chair of Nanobiotechnology in Medicine, Faculty of Medicine and Biology

23 Kropotkinskiy pereulok, Moscow, 119034
1 Ostrovityanova ul., Moscow, 117997

Russian Federation

References

  1. Tysnes OB, Storstein A. Epidemiology of Parkinson's disease. J Neural Transm (Vienna). 2017;124(8):901–5. doi: 10.1007/s00702-0171686-y.
  2. Pringsheim T, Jette N, Frolkis A, Steeves TD. The prevalence of Parkinson's disease: a systematic review and meta-analysis. Mov Disord. 2014;29(13):1583–90. doi: 10.1002/mds.25945.
  3. Wright Willis A, Evanoff BA, Lian M, Criswell SR, Racette BA. Geographic and ethnic variation in Parkinson disease: a population-based study of US Medicare beneficiaries. Neuroepidemiology. 2010;34(3):143–51. doi: 10.1159/000275491.
  4. Левин ОС, Артемьев ДВ, Бриль ЕВ, Кулуа ТК. Болезнь Паркинсона: современные подходы к диагностике и лечению. Практическая медицина. 2017;(1):45–51.
  5. Swick TJ, Ondo WG. Parkinson's Disease and Sleep/Wake Disturbances. In: Monti MJ, PandiPerumal SR, Chokroverty S, editors. Dopamine and Sleep: Molecular, Functional, and Clinical Aspects. Springer, Cham; 2016. p. 115–46. doi: 10.1007/978-3-319-46437-4_7.
  6. Пастухов ЮФ. Изменения характеристик парадоксального сна – ранний признак БП. Журнал высшей нервной деятельности им. И.П. Павлова. 2013;63(1):75–85. doi: 10.7868/S0044467713010103.
  7. Wen MC, Chan LL, Tan LC, Tan EK. Depression, anxiety, and apathy in Parkinson's disease: insights from neuroimaging studies. Eur J Neurol. 2016;23(6):1001–19. doi: 10.1111/ene.13002.
  8. Жукова ИА, Жукова НГ, Алифирова ВМ, Никитина МА, Ижболдина ОП, Бразовская НГ. Депрессия и другие немоторные проявления болезни Паркинсона. Клиническая медицина. 2017;95(5):419–24. doi: 10.18821/00232149-2017-95-5-419-424.
  9. Ершова МВ, Иванова ЕО, Иллариошкин СН. Болезнь Паркинсона и нейротрофический гомеостаз. Нервные болезни. 2018;(1):3–9. doi: 10.24411/2071-5315-2018-11991.
  10. Lu B, Nagappan G, Guan X, Nathan PJ, Wren P. BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases. Nat Rev Neurosci. 2013;14(6):401–16. doi: 10.1038/nrn3505.
  11. Sun M, Kong L, Wang X, Lu XG, Gao Q, Geller AI. Comparison of the capability of GDNF, BDNF, or both, to protect nigrostriatal neurons in a rat model of Parkinson's disease. Brain Res. 2005;1052(2):119–29. doi: 10.1016/j.brainres.2005.05.072.
  12. Wang Y, Liu H, Du XD, Zhang Y, Yin G, Zhang BS, Soares JC, Zhang XY. Association of low serum BDNF with depression in patients with Parkinson's disease. Parkinsonism Relat Disord. 2017;41:73–8. doi: 10.1016/j.parkreldis.2017.05.012.
  13. Wang Y, Liu H, Zhang BS, Soares JC, Zhang XY. Low BDNF is associated with cognitive impairments in patients with Parkinson's disease. Parkinsonism Relat Disord. 2016;29:66–71. doi: 10.1016/j.parkreldis.2016.05.023.
  14. Jiang L, Zhang H, Wang C, Ming F, Shi X, Yang M. Serum level of brain-derived neurotrophic factor in Parkinson's disease: a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2019;88:168–74. doi: 10.1016/j.pnpbp.2018.07.010.
  15. Федорова НВ, Омарова СМ. Леводопаиндуцированные дискинезии при болезни Паркинсона: фармакотерапия и нейрохирургическое лечение. Нервные болезни. 2017;(1): 22–30.
  16. Раимова ММ. Спектр проявлений и принципы коррекции поздних двигательных осложнений дофаминергической терапии при болезни Паркинсона и сосудистом паркинсонизме. Медицинские новости. 2016;(4): 80–2.
  17. Kim SD, Allen NE, Canning CG, Fung VSC. Parkinson disease. Handb Clin Neurol. 2018;159:173–93. doi: 10.1016/B978-0-44463916-5.00011-2.
  18. Росинская АВ, Васенина ЕЕ, Хайбуллин ТН, Левин ОС. Темп прогрессирования болезни Паркинсона при раннем и отсроченном назначении препаратов леводопы. Журнал неврологии и психиатрии им. С.С. Корсакова. 2018;118(6 Вып. 2):77–81. doi: 10.17116/jnevro201811806277.
  19. Carvalho MM, Campos FL, Coimbra B, Pêgo JM, Rodrigues C, Lima R, Rodrigues AJ, Sousa N, Salgado AJ. Behavioral characterization of the 6-hydroxidopamine model of Parkinson's disease and pharmacological rescuing of nonmotor deficits. Mol Neurodegener. 2013;8:14. doi: 10.1186/1750-1326-8-14.
  20. Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. 7 th Edition. Academic Press; 2013. 388 p.
  21. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402–8. doi: 10.1006/meth.2001.1262.
  22. Molinoff PB, Axelrod J. Biochemistry of catecholamines. Annu Rev Biochem. 1971;40:465–500. doi: 10.1146/annurev.bi.40.070171.002341.
  23. Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, Obeso J, Marek K, Litvan I, Lang AE, Halliday G, Goetz CG, Gasser T, Dubois B, Chan P, Bloem BR, Adler CH, Deuschl G. MDS clinical diagnostic criteria for Parkinson's disease. Mov Disord. 2015;30(12): 1591–601. doi: 10.1002/mds.26424.
  24. Deumens R, Blokland A, Prickaerts J. Modeling Parkinson's disease in rats: an evaluation of 6-OHDA lesions of the nigrostriatal pathway. Exp Neurol. 2002;175(2):303–17. doi: 10.1006/exnr.2002.7891.
  25. Ставровская АВ, Ямщикова НГ, Ольшанский АС, Гущина АС. Опыт моделирования болезни Паркинсона: анализ поведенческих нарушений. Нервные болезни. 2018;(2): 44–50. doi: 10.24411/2071-5315-2018-12022.
  26. Xu JT, Qian Y, Wang W, Chen XX, Li Y, Li Y, Yang ZY, Song XB, Lu D, Deng XL. Effect of stromal cell-derived factor-1/CXCR4 axis in neural stem cell transplantation for Parkinson's disease. Neural Regen Res. 2020;15(1):112–9. doi: 10.4103/1673-5374.264470.
  27. Branchi I, D'Andrea I, Armida M, Cassano T, Pèzzola A, Potenza RL, Morgese MG, Popoli P, Alleva E. Nonmotor symptoms in Parkinson's disease: investigating earlyphase onset of behavioral dysfunction in the 6-hydroxydopamine-lesioned rat model. J Neurosci Res. 2008;86(9):2050–61. doi: 10.1002/jnr.21642.
  28. Tadaiesky MT, Dombrowski PA, Figueiredo CP, Cargnin-Ferreira E, Da Cunha C, Takahashi RN. Emotional, cognitive and neurochemical alterations in a premotor stage model of Parkinson's disease. Neuroscience. 2008;156(4):830–40. doi: 10.1016/j.neuroscience.2008.08.035.
  29. Hanganu A, Degroot C, Monchi O, Bedetti C, Mejia-Constain B, Lafontaine AL, Chouinard S, Bruneau MA. Influence of depressive symptoms on dopaminergic treatment of Parkinson's disease. Front Neurol. 2014;5:188. doi: 10.3389/fneur.2014.00188.
  30. Eskow Jaunarajs KL, Dupre KB, Ostock CY, Button T, Deak T, Bishop C. Behavioral and neurochemical effects of chronic L-DOPA treatment on nonmotor sequelae in the hemiparkinsonian rat. Behav Pharmacol. 2010;21(7):627–37. doi: 10.1097/FBP.0b013e32833e7e80.
  31. Hernández VS, Luquín S, Jáuregui-Huerta F, Corona-Morales AA, Medina MP, RuízVelasco S, Zhang L. Dopamine receptor dysregulation in hippocampus of aged rats underlies chronic pulsatile L-Dopa treatment induced cognitive and emotional alterations. Neuropharmacology. 2014;82:88–100. doi: 10.1016/j.neuropharm.2013.11.013.
  32. Winter C, von Rumohr A, Mundt A, Petrus D, Klein J, Lee T, Morgenstern R, Kupsch A, Juckel G. Lesions of dopaminergic neurons in the substantia nigra pars compacta and in the ventral tegmental area enhance depressive-like behavior in rats. Behav Brain Res. 2007;184(2):133–41. doi: 10.1016/j.bbr.2007.07.002.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2020 Karimova O.S., Morozova A.Y., Zorkina Y.A., Zubkov E.A., Ushakova V.M., Abramova O.V., Chekhonin V.P.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies