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

References

Al-Onaizi MA, Thériault P, Lecordier S, Prefontaine P, Rivest S, ElAli A (2022) Early monocyte modulation by the non-erythropoietic peptide ARA 290 decelerates AD-like pathology progression. Brain Behavior Immunity 99: 363–382. https://doi.org/10.1016/j.bbi.2021.07.016 [PuMed]

Antsiferov OV, Cherevatenko RF, Korokin MV, Gureev VV, Gureeva AV, Zatolokina MA, Avdeyeva EV, Zhilinkova LA, Kolesnik IM (2021) A new EPOR/CD131 heteroreceptor agonist EP-11-1: a neuroprotective effect in experimental traumatic brain injury. Research Results in Pharmacology7(4): 1–9. https://doi.org/10.3897/rrpharmacology.7.75301

Belyaeva VS, Stepenko YV, Lyubimov II, Kulikov AL, Tietze AA, Kochkarova IS, Martynova OV, Pokopeyko ON, Krupen’kina LA, Nagikh AS, Pokrovskiy VM, Patrakhanov EA, Belashova AV, Lebedev PR, Gureeva AV (2020) Non-hematopoietic erythropoietin-derived peptides for atheroprotection and treatment of cardiovascular diseases. Research Results in Pharmacology 6(3): 75–86. https://doi.org/10.3897/rrpharmacology.6.58891

Dinda B, Dinda M, Kulsi G, Chakraborty A, Dinda S (2019) Therapeutic potentials of plant iridoids in Alzheimer’s and Parkinson’s diseases: A review. European Journal of Medicinal Chemistry 169: 185–199. https://doi.org/10.1016/j.ejmech.2019.03.009 [PubMed]

El-Ganainy SO, Soliman OA, Ghazy AA, Allam M, Elbahnasi AI, Mansour AM, Gowayed MA (2022) Intranasal Oxytocin attenuates cognitive impairment, β-amyloid burden and Tau deposition in female rats with Alzheimer's disease: interplay of ERK1/2/GSK3β/Caspase-3. Neurochemical Research 47(8): 2345–2356. https://doi.org/10.1007/s11064-022-03624-x[PubMed] [PMC]

Ivanov IM, Nikiforov AS, Vengerovich NG, Perelygin VV, Proshina YuA (2020) Pathogenetic rationale for the use of modified forms and peptide analogues of erythropoietin as cytoprotectors. Pharmacy Formulas [Formuly Farmacii] 2(1): 70–81. https://doi.org/10.17816/phf21382 [in Russian]

Larson T, Khandelwal V, Weber MA, Leidinger MR, Meyerholz DK, Narayanan NS, Zhang Q (2022) Mice expressing P301S mutant human tau have deficits in interval timing. Behavioural Brain Research 432: 113967. https://doi.org/10.1016/j.bbr.2022.113967[PubMed] [PMC]

Lecordier S, Pons V, Rivest S, Еlali A (2021) Multifocal cerebral microinfarcts modulate early Alzheimer’s disease pathology in a sex-dependent manner.Frontiers in Immunology 12: 813536. https://doi.org/10.3389/fimmu.2021.813536 [PubMed] [PMC]

Limorenko G, Hilal A (2021) Neurobiology of disease review to target Tau pathologies, we must embrace and reconstruct their complexities. Neurobiology of Disease 161: 1–22. https://doi.org/10.1016/j.nbd.2021.105536 [PubMed]

Mahady LJ, Perez SE, Malek-Ahmadi M, Mufson EJ (2023) Oligomeric, phosphorylated, and truncated tau and spliceosome pathology within the entorhinal-hippocampal connectome across stages of Alzheimer’s disease.Journal of Comparative Neurology 531(18): 2080–2108. https://doi.org /10.1002/cne.25466 [PubMed]

Meyer JH, Cervenka S, Kim MJ, Kreisl WC, Henter ID, Innis RB (2020) Neuroinflammation in psychiatric disorders: PET imaging and promising new targets.Lancet Psychiatry 7(12): 1064–1074. https://doi.org/10.1016/S2215-0366(20)30255-8 [PubMed] [PMC]

O'Leary OE, Canning P, Reid E, Bertelli PM, McKeown S, Brines M, Cerami A, Du X, Xu H, Chen M, Dutton L, Brazil DP, Medina RJ, Stitt AW (2019) The vasoreparative potential of endothelial colony-forming cells in the ischemic retina is enhanced by cibinetide, a non-hematopoietic erythropoietin mimetic. Experimental Eye Research 182: 144–155. https://doi.org/10.1016/j.exer.2019.03.001 [PubMed]

Pinto L, Macedo J, Araújo B, Anjo S, Silveira-Rosa T, Patrício P, Teixeira F, Manadas B, Rodrigues AJ, Lepore A, Salgado A, Gomes E (2023) Glial-restricted precursors stimulate endogenous cytogenesis and effectively recover emotional deficits in a model of cytogenesis ablation.Research Square31:3.rs-2747462.https://doi.org/10.1038/s41380-024-02490-z [PubMed] [PMC]

Vogels T, Murgoci AN, Hromádka T (2019) Intersection of pathological tau and microglia at the synapse. Acta Neuropathologica Communications 7(1): 109. https://doi.org/10.1186/s40478-019-0754-y [PubMed] [PMC]

Wu A, Zhang J (2023) Neuroinflammation, memory, and depression: new approaches to hippocampal neurogenesis.Journal of Neuroinflammation 20(1): 283. https://doi.org/10.1186/s12974-023-02964-x [PubMed] [PMC]

Xu G, Zou T, Deng L, Yang G, Guo T, Wang Y, Niu C, Cheng Q, Yang X, Dong J, Zhang J (2022)Nonerythropoietic erythropoietin mimetic peptide ara290 ameliorates chronic stress-induced depression-like behavior and inflammation in mice.Frontiers in Pharmacology 13: 896601. https://doi.org/10.3389/fphar.2022.896601 [PubMed] [PMC]

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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