Myeloperoxidase, Cathepsin D, and Plasminogen Activation Inhibitor Type 1 as Potential Biomarkers of Schizophrenia (pilot study)

Schizophrenia is a severe multifactorial mental disorder. Recently, there has been a significant increase in studies of potential peripheral biomarkers that can determine the development of a particular clinical form, type of course and the development of metabolic syndrome in patients with schizophrenia for the prognosis and effective treatment of this disease. The aim of this work was to study the concentrations of serum potential biomarkers myeloperoxidase (MPO), cathepsin D, plasminogen activator inhibitor type 1 (PAI-1) in schizophrenia, taking into account the clinical heterogeneity of the disease. A comprehensive clinical and biological examination of 212 patients (119 men and 93 women) of ethnic Russian patients with schizophrenia (F20), who had long-term use of antipsychotic therapy, was conducted. The control group consisted of 30 healthy donors, matched by gender and age to patients with schizophrenia. The concentration of cathepsin D, MPO and PAI-1 was measured in the blood serum using xMAP technology on Magpix and Luminex 200 analyzers (Luminex, USA). Statistical processing of the results was performed using the SPSS 23.0 program. It was shown that the concentration of MPO and PAI-1 is significantly higher in the group of patients with schizophrenia compared to the group of healthy individuals (p = 0.001 and p = 0.002, respectively). As a result of the study, correlation relationships between the concentrations of the studied serum biomarkers and the clinical heterogeneity of schizophrenia (duration of the disease, leading symptoms, type of course) were not found. The concentrations of cathepsin D and PAI-1 in the blood serum positively correlate with the body mass index (p = 0.0001 and p = 0.004, respectively). Thus, we have obtained pilot data that elevated serum MPO and PAI-1 concentrations can be used as biomarkers of schizophrenia, and elevated concentrations of cathepsin D and PAI-1 can be used as antipsychotic-induced increases in body mass index in schizophrenia.

1. Kornetova EG, Semke AV. Current issues and prospects for studying schizophrenia with leading negative symptoms. Byulleten' sibirskoj mediciny. 2014;13(1):5-13. (In Russ.).

2. Neznanov N.G. Psihiatriya. Uchebnik. M: GEOTAR-Media; 2016. (In Russ.).

3. Semke AV, Fedorenko OYu, Lobacheva OA, Rakhmazova LD, Kornetova EG, Smirnova LP, Shchigoreva YuG. Clinical, epidemiological and biological prerequisites for adaptation of patients with schizophrenia as a basis for a personalized approach to antipsychotic therapy. Sibirskij vestnik psihiatrii i narkologii. 2015;88(3):19-25. (In Russ.).

4. Al-Asmari AK, Khan MW. Inflammation and schizophrenia: alterations in cytokine levels and perturbation in antioxidative defense systems. Human & experimental toxicology. 2014;33(2):115-122. https://doi.org/10.1177/0960327113493305

5. Ansari Z, Pawar S, Seetharaman R. Neuroinflammation and oxidative stress in schizophrenia: are these opportunities for repurposing? Postgrad Med. 2022;134(2):187-199. https://doi.org/10.1080/00325481.2021.2006514

6. Balõtšev R, Haring L, Koido K, et al. Antipsychotic treatment is associated with inflammatory and metabolic biomarkers alterations among first-episode psychosis patients: A 7-month follow-up study. Early Interv Psychiatry. 2019;13(1):101-109. https://doi.org/10.1111/eip.12457

7. Bradshaw NJ, Korth C. Protein misassembly and aggregation as potential convergence points for non-genetic causes of chronic mental illness. Mol Psychiatry. 2019;24(7):936–51. https://doi.org/10.1038/s41380-018-0133-2

8. Carrizo E, Fernández V, Quintero J, et al. Coagulation and inflammation markers during atypical or typical antipsychotic treatment in schizophrenia patients and drug-free first-degree relatives . Schizophr Res. 2008;103(1-3):83-93. https://doi.org/10.1016/j.schres.2008.03.004

9. Chen S, Jiang H, Liu Y, et al. Combined serum levels of multiple proteins in tPA-BDNF pathway may aid the diagnosis of five mental disorders. Sci Rep. 2017;7(1):6871. https://doi.org/10.1038/s41598-017-06832-6

10. Davies MJ, Hawkins CL. The role of Myeloperoxidase in biomolecule modification, chronic inflammation, and disease. antioxid redox signal. Antioxid Redox Signal. 2020;32(13):957–81. https://doi.org/10.1089/ars.2020.8030

11. Elmi S, Sahu G, Malavade K, et al. Role of tissue plasminogen activator and plasminogen activator inhibitor as potential biomarkers in psychosis. Asian J Psychiatr. 2019;43:105-110. https://doi.org/10.1016/j.ajp.2019.05.021

12. Ermakov EA, Melamud MM, Buneva VN, et al. Immune System Abnormalities in Schizophrenia: An Integrative View and Translational Perspectives. Front Psychiatry. 2022;25;13:880568. https://doi.org/10.3389/fpsyt.2022.880568

13. Guler EM, Kurtulmus A, Gul AZ, et al. Oxidative stress and schizophrenia: A comparative cross-sectional study of multiple oxidative markers in patients and their first-degree relatives. Int J Clin Pract. 2021;75(11):e14711. https://doi.org/10.1111/ijcp.14711

14. Kimura T, Jia J, Kumar S, et al. Dedicated SNAREs and specialized TRIM cargo receptors mediate secretory autophagy. EMBO J. 2017;36(1):42–60. https://doi.org/10.15252/embj.201695081

15. Lasić D, Bevanda M, Bošnjak N, et al. Franić Metabolic syndrome and inflammation markers in patients with schizophrenia and recurrent depressive disorder. Psychiatr Danub. 2014;26(3):214-9.

16. Lasić D, Uglešić B, Vujnović Z, et al. PAI-1 as a component of the metabolic syndrome in depression and schizophrenia - Croatian experience. Psychiatr Danub. 2015;27(1):71-2.

17. Marder SR, Umbricht D. Negative symptoms in schizophrenia: Newly emerging measurements, pathways, and treatments. Schizophr Res. 2023;258:71-77. https://doi.org/10.1016/j.schres.2023.07.010

18. Nesvaderani M, Matsumoto I, Sivagnanasundaram S. Anterior hippocampus in schizophrenia pathogenesis: molecular evidence from a proteome study. Aust N Z J Psychiatry. 2009;43(4):310–22. https://doi.org/10.1080/00048670902721103

19. Pope A, Amelotte JA, Belfer H, et al. Protease activities in normal and schizophrenic human prefrontal cortex and white matter. Neurochem Res. 1981;6(10):1043-1052. https://doi.org/10.1007/BF00964411

20. Reponen EJ, Dieset I, Tesli M, et al. Atherogenic Lipid Ratios Related to Myeloperoxidase and C-Reactive Protein Levels in Psychotic Disorders. Front Psychiatry. 2020;11:672. https://doi.org/10.3389/fpsyt.2020.00672

21. Tsukuba T, Okamoto K, Yasuda Y, et al. New functional aspects of cathepsin D and cathepsin E. Mol Cells. 2000;10(6)601-611. https://doi.org/10.1007/s10059-000-0601-8

22. Vaughan DE. PAI-1 and atherothrombosis. J Thromb Haemost. 2005;3(8):1879-83. https://doi.org/10.1111/j.1538-7836.2005.01420.x

23. Vidak E, Javorsek U, Vizovisek M, et al. Cysteine Cathepsins and their Extracellular Roles: Shaping the Microenvironment. Cells. 2019;8(3). https://doi.org/10.3390/cells8030264

24. Yesilkaya UH, Gica S, Guney Tasdemir B, et al. A novel commentary: Investigation of the role of a balance between neurotrophic and apoptotic proteins in the pathogenesis of psychosis via the tPA-BDNF pathway. J Psychiatr Res. 2021;142:160-166. https://doi.org/10.1016/j.jpsychires.2021.07.056

25. Zheng C, Liu H, Tu W, et al. Hypercoagulable state in patients with schizophrenia: different effects of acute and chronic antipsychotic medications. Ther Adv Psychopharmacol. 2023;13:20451253231200257. https://doi.org/10.1177/20451253231200257

26. Zhilyaeva TV, Kasyanov ED, Rukavishnikov GV, et al. Pterin metabolism, inflammation and oxidative stress biochemical markers in schizophrenia: Factor analysis and assessment of clinical symptoms associations. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2023;127:110823. https://doi.org/10.1016/j.pnpbp.2023.110823.