Study of the neuroprotective properties of the heteroreceptor EPOR/CD131 agonist of peptide structure in tau-proteinopathy modeling

Authors

DOI:

https://doi.org/10.18413/rrpharmacology.10.492

Abstract

Introduction: Tau proteinopathy is a pathology associated with the activation of post-translational modifications and interactions of pathophysiological cascades of neuroinflammation with hyperphosphorylation of Tau aggregates. Therefore, preference is given to agents that have properties in reducing or slowing down the processes of neuroinflammation and post-translational modifications in the brain.

Materials and Methods: The study was conducted on male and female homozygous individuals of a transgenic murine line with overexpression of mutant human Tau gene (P301S) and a background wild mouse line C57Bl/6J. To assess the progression of Tau proteinopathy, behavioral tests were used at two control time points, and the last one measured the level of neuroinflammation markers and tau-proteinopathy.

Results and Discussion: In the group of P301S mice treated with ARA-290, an improvement in the phenotypic picture of Tau proteinopathy was demonstrated compared with intact animals. In the Barnes circular maze test, mice showed a decrease in the total distance traveled and the latent time spent on the platform, which indicates a rapid entry into the shelter. In the O-shaped maze test, the group maintained a fairly high level of spontaneous exploratory behavior. In the vertical rod test, the animals recorded the best time indicators that they needed to turn and maintain balance compared to the intact group. A statistically significant decrease in the level of GSK-3β and an increase in CDK5 and PP2A were revealed, which indicates a dephosphorylating effect on Tau protein, as well as markers of neuroinflammation. NF-KB and TNF-α were significantly reduced by 57% and 32%, respectively, compared to the intact group.

Conclusion: In the model of transgenic P301S murine line with overexpression of the mutant human Tau gene, the peptide agonist of the EPOR/CD 131 heteroreceptor demonstrated neuroprotective properties, which were confirmed by indicators of behavioral tests and markers of neuroinflammation and tau-proteinopathy.

Graphical Abstract

Keywords:

tau-proteinopathy, neuroinflammation, post-translational modifications, frontotemporal dementia, parkinsonism, ARA-290

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Author Contribution

Yulia V. Stepenko, Belgorod State National Research University

Assistant of the Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, Belgorod, Russia; e-mail: stepenko@bsu.edu.ru; ORCID ID https://orcid.org/0000-0002-7414-7326. The author took part in the design of the study, in conducting experimental work and analyzing the material.

Veronika S. Shmigerova, Belgorod State National Research University

Assistant Professor of the Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, Belgorod, Russia; e-mail: nika.beliaeva@yandex.ru; ORCID ID https://orcid.org/0000-0003-2941-0241. The author analyzed the results and edited the text of the article.

Darya A. Kostina, Belgorod State National Research University

Candidate of Medical Sciences, Associate Professor of the Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, Belgorod, Russia; e-mail: daria-f13@mail.ru; ORCID IDhttps://orcid.org/0000-0002-4505-3988. The author edited the text of the article.

Olesya V. Shcheblykina, Belgorod State National Research University

Candidate of Medical Sciences, Associate Professor of the Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, Belgorod, Russia; e-mail: sheolvi31@gmail.com; ORCID ID https://orcid.org/0000-0003-0346-9835. The author edited the text of the article

Nina I. Zhernakova, Belgorod State National Research University

Doctor Habil. of Medicine, Full Professor, Deputy Director of the Medical Institute for Research, Belgorod State National Research University, Russia, Belgorod; e-mail: zhernakova@bsu.edu.ru; ORCID ID https://orcid.org/0000-0001-7648-0774. The author analyzed the results and edited the text of the article.

Alexey V. Solin, Belgorod State National Research University

Doctor Habil. of Medical Sciences, Full Professor of the Department of Human Anatomy and Histology, Belgorod State National Research University, Belgorod, Russia; e-mail: solin@bsu.edu.ru; ORCID ID https://orcid.org/0000-0002-6277-3506. The author took part in the experimental work.

Natalia V. Koroleva, Belgorod State National Research University

Research Associate of the Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, Belgorod, Russia; e-mail: nkoroleva@gmail.com; ORCID ID https://orcid.org/0009-0006-3660-3438. The author edited the text of the article.

Vera A. Markovskaya, Belgorod State National Research University

PhD in Biology, Head of the Department of Pathology, Belgorod State National Research University, Belgorod, Russia; e-mail: markovskaya@bsu.edu.ru; ORCID ID https://orcid.org/0000-0003-4410-9318. The author analyzed the results and edited the text of the article.

Olga V. Dudnikova, Belgorod State National Research University

Forensic medical expert, Belgorod Bureau of Forensic Medicine, Belgorod State National Research University, Belgorod, Russia; e-mail: Olenka_normanskikh@mail.ru; ORCID ID https://orcid.org/0009-0005-8949-5058. The author analyzed the results and edited the text of the article.

Anton A. Bolgov, Belgorod State National Research University

Post-graduate student, Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, Belgorod, Russia; e-mail: toxabolgovv@mail.ru; ORCID ID https://orcid.org/0000-0001-9708-8181. The author participated in the review and analysis of literary sources.

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Published

17-06-2024

How to Cite

Stepenko YV, Shmigerova VS, Kostina DA, Shcheblykina OV, Zhernakova NI, Solin AV, Koroleva NV, Markovskaya VA, Dudnikova OV, Bolgov AA (2024) Study of the neuroprotective properties of the heteroreceptor EPOR/CD131 agonist of peptide structure in tau-proteinopathy modeling. Research Results in Pharmacology 10(2): 41–47. https://doi.org/10.18413/rrpharmacology.10.492

Issue

Vol. 10 No. 2 (2024)

Section

Experimental Pharmacology

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Copyright (c) 2024 Yulia V. Stepenko, Veronika S. Shmigerova, Darya A. Kostina, Olesya V. Shcheblykina, Nina I. Zhernakova, Alexey V. Solin, Natalia V. Koroleva, Vera A. Markovskaya, Olga V. Dudnikova, Anton A. Bolgov

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