Abstract
Introduction. Despite research into the pathogenesis of depression in PD, there is still no unified theory regarding its onset.
Objective: To evaluate the expression of tyrosine hydroxylase (TH) and 3-nitrotyrosine (3-NT) in brain structures using models of PD and ELMS.
Materials and Methods: A pilot study was conducted using immunohistochemistry, fluorescence microscopy, and image analysis.
Results. Due to study limitations, statistical analysis was not feasible. In the PD model, a decrease in TH expression was observed in the substantia nigra, along with varying 3-NT expression across structures. In the ELMS model, a decrease in TH and 3-NT expression was noted in the striatum, while 3-NT expression increased in the amygdala and hippocampus. Despite the differences observed between groups, the interpretation of the results is subject to certain limitations.
Conclusion. Despite the differences observed between the experimental and control groups, the interpretation of the results is subject to several limitations. The primary limitation is the relatively small sample size (n = 11), which reduces the study’s statistical power and limits the ability to extrapolate the findings to broader populations.
Authors and affiliations
https://elibrary.ru/sfafnm T.V. Potupchik(1), N.A. Malinovskaya(1), K.R. Torgaeva(1), V.V. Davidenko(1), A.G. Popkova(2)
1-Federal State Budgetary Educational Institution of Higher Education “Krasnoyarsk State Medical University named after Professor
V.F. Voino-Yasenetsky” of the Ministry of Health of the Russian Federation, Partizan Zheleznyak str., 1, Krasnoyarsk, 660022, Russian Federation;
2-Orenburg State Medical University, Ministry of Health of the Russian Federation, Sovetskaya St., 6, Orenburg, 460000, Russian Federation
References
1. Неврология: национальное руководство: в 2-х т. Под ред. Е.И. Гусева, А.Н. Коновалова, В.И. Скворцовой. Москва: ГЭОТАР-Медиа, 2022. [Neurology: a national guide: in 2 volumes. Еdited by E.I. Gusev, A.N. Konovalov, V.I. Skvortsova. Moscow: GEOTAR-Media, 2022. (In Russian)].
2. Болезнь Паркинсона [Электронный ресурс]. Режим доступа: https://www.who.int/ru/news-room/fact-sheets/detail/parkinson-disease [Parkinson’s disease [Electronic resource]. Access mode: https://www.who.int/ru/news-room/fact-sheets/detail/parkinson-disease (In Russian)].
3. Cong S., Xiang C., Zhang S., Zhang T., Wang H., Cong S. Prevalence and clinical aspects of depression in Parkinson’s disease: A systematic review and meta analysis of 129 studies. Neurosci Biobehav Rev. 2022; 141: 104749. DOI: 10.1016/j.neubiorev.2022.104749
4. Zhou Z.D., Yi L.X., Wang D.Q., Lim T.M., Tan E.K. Role of dopamine in the pathophysiology of Parkinson’s disease. TranslNeurodegener. 2023; 12 (1): 44. DOI: 10.1186/s40035-023-00378-6
5. Джалалов Р., Салиева М., Абдурахимов А., Нугманов О. Патофизиология болезни Паркинсона и эффективность ее лечения. Re-HealthJournal. 2020; 2–3 (6): 50–6. [Jalalov R., Salieva M., Abdurakhimov A., Nugmanov O. Pathophysiology of Parkinson’s disease andeffectiveness of itstreatment. Re-HealthJournal. 2020; 2–3 (6): 50–6. DOI 10.24411/2181-0443/2020-10083 (InRussian)].
6. Ramesh S., Arachchige A. Depletion of dopamine in Parkinson’s disease and relevant therapeutic options: A review of the literature. AIMS Neurosci. 2023; 10 (3): 200–31. DOI: 10.3934/Neuroscience.2023017
7. Schapira A.H., Jenner P. Etiology and pathogenesis of Parkinson’s disease. Mov Disord. 2011; 26 (6): 1049–55. DOI: 10.1002/mds.23732
8. Борозденко Д.А., Богородова В.И., Киселева Н.М., Негребецкий В.В. Болезнь Паркинсона: эпидемиология и патогенез. Российский медицинский журнал. 2021; 27 (2): 183–94. [Borozdenko D.A., Bogorodova V.I., Kiseleva N.M., Negrebetsky V.V. Parkinson’s disease: epidemiology and pathogenesis. Russian Medical J. 2021; 27 (2): 183–94. DOI: 10.17816/0869-2106-2021-27-2-183-194 (In Russian)].
9. Rocha N.P., de Miranda A.S., Teixeira A.L. Insights into Neuroinflammation in Parkinson’s Disease: From Biomarkers to Anti-Inflammatory Based Therapies. Biomed Res Int. 2015; 2015: 628192. DOI: 10.1155/2015/628192
10. Isik S., Yeman Kiyak B., Akbayir R., Seyhali R., Arpaci T. Microglia Mediated Neuroinflammation in Parkinson’s Disease. Cells. 2023; 12 (7): 1012. DOI: 10.3390/cells12071012
11. Du X.Y., Xie X.X., Liu R.T. The Role of α-Synuclein Oligomers in Parkinson’s Disease. Int. J. Mol. Sci. 2020; 21 (22): 8645. DOI: 10.3390/ijms21228645
12. Klemmensen M.M., Borrowman S.H., Pearce C., Pyles B., Chandra B. Mitochondrial dysfunction in neurodegenerative disorders. Neurotherapeutics. 2024; 21 (1): e00292. DOI: 10.1016/j.neurot.2023.10.002
13. Costello H., Schrag A.E., Howard R., Roiser J.P. Dissociable effects of dopaminergic medications on depression symptom dimensions in Parkinson disease. Nat. Mental Health. 2024; 2: 916–23. DOI: 10.1038/s44220-024-00256-8
14. Гончарова З.А., Гельпей М.А., Муталиева Х.М. Немоторные проявления у пациентов с болезнью Паркинсона. Южно-Российский журнал терапевтической практики. 2021; 2 (4): 73–8. [Goncharova Z.A., Gelpey M.A., Mutalieva Kh.M. Non‑motor manifestations in patients with Parkinson’s disease. South Russian J. of Therapeutic Practice. 2021; 2 (4): 73–8. DOI: 10.21886/2712-8156-2021-2-4-73-78 (In Russian)].
15. Ossowska K., Lorenc-Koci E. Depression in Parkinson’s disease. Pharmacol Rep. 2013; 65 (6): 1545–57. DOI: 10.1016/s1734-1140(13)71516-0
16. Lee M., Ryu Y.H., Cho W.G., Kang Y.W., Lee S.J., Jeon T.J., Lyoo C.H. et al. Relationship between dopamine deficit and the expression of depressive behavior resulted from alteration of serotonin system. Synapse. 2015; 69 (9): 453–60. DOI: 10.1002/syn.21834
17. Li Y., Yang H., Zhao P., Yang J., Yao C., Zhou C., Yang C. et al. Autophagy markers, cognitive deficits and depressive symptoms in Parkinson’s disease. J. Neural Transm (Vienna). 2024; 131 (1): 73–81. DOI: 10.1007/s00702-023-02702-w
18. Zhao Q., Zhang X., Zhang J., Zhang Y., Jia L., Guo S., Zhang M. et al. Reduction of D2 receptors on microglia leads to ZBP1-mediated PANoptosis of mPFC in Parkinson’s disease depression mice. Int Immunopharmacol. 2025; 158: 114809. DOI: 10.1016/j.intimp.2025.114809
19. Wang J., Zhang H. Serotonin mitigates depression in a rotenone-induced mouse Parkinson’s disease model by inhibiting hippocampal neuronal pyroptosis and neuroinflammation. Behav Brain Res. 2025; 490: 115620. DOI: 10.1016/j.bbr.2025.115620
20. Riederer P., Strobel S., Nagatsu T. Watanabe H., Chen X., Löschmann P.A., Sian-Hulsmann J. et al. Levodopa treatment: impacts and mechanisms throughout Parkinson’s disease progression. J Neural Transm. 2025; 132 (6): 743–79. DOI: 10.1007/s00702-025-02893-4
21. Nagatsu T., Nakashima A., Watanabe H., Ito S., Wakamatsu K., Zucca F.A., Zecca L.et al. The role of tyrosine hydroxylase as a key player in neuromelanin synthesis and the association of neuromelanin with Parkinson’s disease. J. Neural Transm. 2023; 130: 611–25. DOI: 10.1007/s00702-023-02617-6
22. Muñoz A., Lopez-Lopez A., Labandeira C.M., Labandeira-Garcia JL. Interactions between the serotonergic and other neurotransmitter systems in the basal ganglia: role in Parkinson’s disease and adverse effects of L-DOPA. Front Neuroanat. 2020; 14: 26. DOI: 10.3389/fnana.2020.00026
23. Ушакова В.М., Горлова А.В., Зубков Е.А., Морозова А.Ю., Зоркина Я.А., Павлов Д.А., Иноземцев А.Н. и др. Экспериментальные модели депрессивного состояния. Журнал высшей нервной деятельности. 2019; 69 (2): 230–47. [Ushakova V.M., Gorlova A.V., Zubkov E.A., Morozova A.Yu., Zorkina Ya.A., Pavlov D.A., Inozemtsev A.N. et al. Experimental models of depressive state. Zhurnal Vysshei Nervnoi Deyatelnosti. 2019; 69 (2): 230–47. DOI: 10.1134/S0044467719020114 (In Russian)].
24. Lehrer S., Rheinstein P.H. α-synuclein enfolds tyrosine hydroxylase and dopamine ß-hydroxylase, potentially reducing dopamine and norepinephrine synthesis. J Proteins Proteom. 2022; 13: 109–15. DOI: 10.1007/s42485-022-00088-z
25. Gupta M., Paliwal V.K., Babu G.N. Serum fractalkine and 3-nitrotyrosine levels correlate with disease severity in Parkinson’s disease: a pilot study. Metab Brain Dis. 2022; 37: 209–17. DOI: 10.1007/s11011-021-00801-9
26. Cruces-Sande A., Garrido-Gil P., Sierra-Paredes G., Vázquez-Agra N., Hermida-Ameijeiras Á., Pose-Reino A., Méndez-Álvarez E., Soto-Otero R. Copper overload increased rat striatal levels of both dopamine and its main metabolite homovanillic acid in extracellular fluid. Int. J. Mol. Sci. 2024; 25 (15): 8309. DOI: 10.3390/ijms25158309
27. Feng Y., Ma J., Yuan L. β-Methylphenylalanine exerts neuroprotective effects in a Parkinson’s disease model by protecting against tyrosine hydroxylase depletion. J. Cell. Mol. Med. 2020; 24 (17): 9871–80. DOI: 10.1111/jcmm.15571
28. Zhang S.J., Ye J., Couey J.J., Witter M., Moser E.I., Moser M.B. Functional connectivity of the entorhinal‑hippocampal space circuit. Philosophical Transactions of the Royal Society B: Biological Sciences. 2013; 369. DOI: 10.1098/rstb.2012.0516
29. Phelps E.A. Human emotion and memory: interactions of the amygdala and hippocampal complex. Current Opinion in Neurobiology. 2004; 14: 198–202. DOI: 10.1016/j.conb.2004.03.015
30. Beheshti F., Gholami M., Ghane Z., Nazari S.E., Salari M., Shabab S., Hosseini M. PPARγ activation improved learning and memory and attenuated oxidative stress in the hippocampus and cortex of aged rats. Physiol Rep. 2022; 10 (24): e15538. DOI: 10.14814/phy2.15538
31. Lomeli-Lepe A.K., López-Pérez S.J., Castañeda-Cabral J.L., Ureña-Guerrero M.E. Early expression of monomeric and oligomeric alpha-synuclein and reduction of tyrosine hydroxylase following intranigral injection of lipopolysaccharide. Mol. Biol Rep. 2024; 51: 996. DOI: 10.21203/rs.3.rs-4253562/v1
32. Cecilia C., Rodrigo I., Ari Z. Revisiting the role of 3-nitrotyrosine residues in the formation of alpha-synuclein oligomers and fibrils. Archives of Biochemistry and Biophysics. 2024; 752: 109858. DOI: 10.1016/j.abb.2023.1098581. Неврология: национальное руководство: в 2-х т. Под ред. Е.И. Гусева, А.Н. Коновалова, В.И. Скворцовой. Москва: ГЭОТАР-Медиа, 2022. [Neurology: a national guide: in 2 volumes. Еdited by E.I. Gusev, A.N. Konovalov, V.I. Skvortsova. Moscow: GEOTAR-Media, 2022. (In Russian)].
2. Болезнь Паркинсона [Электронный ресурс]. Режим доступа: https://www.who.int/ru/news-room/fact-sheets/detail/parkinson-disease [Parkinson’s disease [Electronic resource]. Access mode: https://www.who.int/ru/news-room/fact-sheets/detail/parkinson-disease (In Russian)].
3. Cong S., Xiang C., Zhang S., Zhang T., Wang H., Cong S. Prevalence and clinical aspects of depression in Parkinson’s disease: A systematic review and meta analysis of 129 studies. Neurosci Biobehav Rev. 2022; 141: 104749. DOI: 10.1016/j.neubiorev.2022.104749
4. Zhou Z.D., Yi L.X., Wang D.Q., Lim T.M., Tan E.K. Role of dopamine in the pathophysiology of Parkinson’s disease. TranslNeurodegener. 2023; 12 (1): 44. DOI: 10.1186/s40035-023-00378-6
5. Джалалов Р., Салиева М., Абдурахимов А., Нугманов О. Патофизиология болезни Паркинсона и эффективность ее лечения. Re-HealthJournal. 2020; 2–3 (6): 50–6. [Jalalov R., Salieva M., Abdurakhimov A., Nugmanov O. Pathophysiology of Parkinson’s disease andeffectiveness of itstreatment. Re-HealthJournal. 2020; 2–3 (6): 50–6. DOI 10.24411/2181-0443/2020-10083 (InRussian)].
6. Ramesh S., Arachchige A. Depletion of dopamine in Parkinson’s disease and relevant therapeutic options: A review of the literature. AIMS Neurosci. 2023; 10 (3): 200–31. DOI: 10.3934/Neuroscience.2023017
7. Schapira A.H., Jenner P. Etiology and pathogenesis of Parkinson’s disease. Mov Disord. 2011; 26 (6): 1049–55. DOI: 10.1002/mds.23732
8. Борозденко Д.А., Богородова В.И., Киселева Н.М., Негребецкий В.В. Болезнь Паркинсона: эпидемиология и патогенез. Российский медицинский журнал. 2021; 27 (2): 183–94. [Borozdenko D.A., Bogorodova V.I., Kiseleva N.M., Negrebetsky V.V. Parkinson’s disease: epidemiology and pathogenesis. Russian Medical J. 2021; 27 (2): 183–94. DOI: 10.17816/0869-2106-2021-27-2-183-194 (In Russian)].
9. Rocha N.P., de Miranda A.S., Teixeira A.L. Insights into Neuroinflammation in Parkinson’s Disease: From Biomarkers to Anti-Inflammatory Based Therapies. Biomed Res Int. 2015; 2015: 628192. DOI: 10.1155/2015/628192
10. Isik S., Yeman Kiyak B., Akbayir R., Seyhali R., Arpaci T. Microglia Mediated Neuroinflammation in Parkinson’s Disease. Cells. 2023; 12 (7): 1012. DOI: 10.3390/cells12071012
11. Du X.Y., Xie X.X., Liu R.T. The Role of α-Synuclein Oligomers in Parkinson’s Disease. Int. J. Mol. Sci. 2020; 21 (22): 8645. DOI: 10.3390/ijms21228645
12. Klemmensen M.M., Borrowman S.H., Pearce C., Pyles B., Chandra B. Mitochondrial dysfunction in neurodegenerative disorders. Neurotherapeutics. 2024; 21 (1): e00292. DOI: 10.1016/j.neurot.2023.10.002
13. Costello H., Schrag A.E., Howard R., Roiser J.P. Dissociable effects of dopaminergic medications on depression symptom dimensions in Parkinson disease. Nat. Mental Health. 2024; 2: 916–23. DOI: 10.1038/s44220-024-00256-8
14. Гончарова З.А., Гельпей М.А., Муталиева Х.М. Немоторные проявления у пациентов с болезнью Паркинсона. Южно-Российский журнал терапевтической практики. 2021; 2 (4): 73–8. [Goncharova Z.A., Gelpey M.A., Mutalieva Kh.M. Non‑motor manifestations in patients with Parkinson’s disease. South Russian J. of Therapeutic Practice. 2021; 2 (4): 73–8. DOI: 10.21886/2712-8156-2021-2-4-73-78 (In Russian)].
15. Ossowska K., Lorenc-Koci E. Depression in Parkinson’s disease. Pharmacol Rep. 2013; 65 (6): 1545–57. DOI: 10.1016/s1734-1140(13)71516-0
16. Lee M., Ryu Y.H., Cho W.G., Kang Y.W., Lee S.J., Jeon T.J., Lyoo C.H. et al. Relationship between dopamine deficit and the expression of depressive behavior resulted from alteration of serotonin system. Synapse. 2015; 69 (9): 453–60. DOI: 10.1002/syn.21834
17. Li Y., Yang H., Zhao P., Yang J., Yao C., Zhou C., Yang C. et al. Autophagy markers, cognitive deficits and depressive symptoms in Parkinson’s disease. J. Neural Transm (Vienna). 2024; 131 (1): 73–81. DOI: 10.1007/s00702-023-02702-w
18. Zhao Q., Zhang X., Zhang J., Zhang Y., Jia L., Guo S., Zhang M. et al. Reduction of D2 receptors on microglia leads to ZBP1-mediated PANoptosis of mPFC in Parkinson’s disease depression mice. Int Immunopharmacol. 2025; 158: 114809. DOI: 10.1016/j.intimp.2025.114809
19. Wang J., Zhang H. Serotonin mitigates depression in a rotenone-induced mouse Parkinson’s disease model by inhibiting hippocampal neuronal pyroptosis and neuroinflammation. Behav Brain Res. 2025; 490: 115620. DOI: 10.1016/j.bbr.2025.115620
20. Riederer P., Strobel S., Nagatsu T. Watanabe H., Chen X., Löschmann P.A., Sian-Hulsmann J. et al. Levodopa treatment: impacts and mechanisms throughout Parkinson’s disease progression. J Neural Transm. 2025; 132 (6): 743–79. DOI: 10.1007/s00702-025-02893-4
21. Nagatsu T., Nakashima A., Watanabe H., Ito S., Wakamatsu K., Zucca F.A., Zecca L.et al. The role of tyrosine hydroxylase as a key player in neuromelanin synthesis and the association of neuromelanin with Parkinson’s disease. J. Neural Transm. 2023; 130: 611–25. DOI: 10.1007/s00702-023-02617-6
22. Muñoz A., Lopez-Lopez A., Labandeira C.M., Labandeira-Garcia JL. Interactions between the serotonergic and other neurotransmitter systems in the basal ganglia: role in Parkinson’s disease and adverse effects of L-DOPA. Front Neuroanat. 2020; 14: 26. DOI: 10.3389/fnana.2020.00026
23. Ушакова В.М., Горлова А.В., Зубков Е.А., Морозова А.Ю., Зоркина Я.А., Павлов Д.А., Иноземцев А.Н. и др. Экспериментальные модели депрессивного состояния. Журнал высшей нервной деятельности. 2019; 69 (2): 230–47. [Ushakova V.M., Gorlova A.V., Zubkov E.A., Morozova A.Yu., Zorkina Ya.A., Pavlov D.A., Inozemtsev A.N. et al. Experimental models of depressive state. Zhurnal Vysshei Nervnoi Deyatelnosti. 2019; 69 (2): 230–47. DOI: 10.1134/S0044467719020114 (In Russian)].
24. Lehrer S., Rheinstein P.H. α-synuclein enfolds tyrosine hydroxylase and dopamine ß-hydroxylase, potentially reducing dopamine and norepinephrine synthesis. J Proteins Proteom. 2022; 13: 109–15. DOI: 10.1007/s42485-022-00088-z
25. Gupta M., Paliwal V.K., Babu G.N. Serum fractalkine and 3-nitrotyrosine levels correlate with disease severity in Parkinson’s disease: a pilot study. Metab Brain Dis. 2022; 37: 209–17. DOI: 10.1007/s11011-021-00801-9
26. Cruces-Sande A., Garrido-Gil P., Sierra-Paredes G., Vázquez-Agra N., Hermida-Ameijeiras Á., Pose-Reino A., Méndez-Álvarez E., Soto-Otero R. Copper overload increased rat striatal levels of both dopamine and its main metabolite homovanillic acid in extracellular fluid. Int. J. Mol. Sci. 2024; 25 (15): 8309. DOI: 10.3390/ijms25158309
27. Feng Y., Ma J., Yuan L. β-Methylphenylalanine exerts neuroprotective effects in a Parkinson’s disease model by protecting against tyrosine hydroxylase depletion. J. Cell. Mol. Med. 2020; 24 (17): 9871–80. DOI: 10.1111/jcmm.15571
28. Zhang S.J., Ye J., Couey J.J., Witter M., Moser E.I., Moser M.B. Functional connectivity of the entorhinal‑hippocampal space circuit. Philosophical Transactions of the Royal Society B: Biological Sciences. 2013; 369. DOI: 10.1098/rstb.2012.0516
29. Phelps E.A. Human emotion and memory: interactions of the amygdala and hippocampal complex. Current Opinion in Neurobiology. 2004; 14: 198–202. DOI: 10.1016/j.conb.2004.03.015
30. Beheshti F., Gholami M., Ghane Z., Nazari S.E., Salari M., Shabab S., Hosseini M. PPARγ activation improved learning and memory and attenuated oxidative stress in the hippocampus and cortex of aged rats. Physiol Rep. 2022; 10 (24): e15538. DOI: 10.14814/phy2.15538
31. Lomeli-Lepe A.K., López-Pérez S.J., Castañeda-Cabral J.L., Ureña-Guerrero M.E. Early expression of monomeric and oligomeric alpha-synuclein and reduction of tyrosine hydroxylase following intranigral injection of lipopolysaccharide. Mol. Biol Rep. 2024; 51: 996. DOI: 10.21203/rs.3.rs-4253562/v1
32. Cecilia C., Rodrigo I., Ari Z. Revisiting the role of 3-nitrotyrosine residues in the formation of alpha-synuclein oligomers and fibrils. Archives of Biochemistry and Biophysics. 2024; 752: 109858. DOI: 10.1016/j.abb.2023.109858