Comparison of the effects of three glyprolines after five days of intraperitoneal administration

To date, about 70 drugs based on regulatory peptides have been registered, including proline-containing ones, such as the nootropics Semax and Selank. Further study of the properties of glyproline peptide sequences is relevant in order to describe their neuroprotective properties and the possible development of new drugs based on them. The purpose of the study was to compare the effects of three glyproline peptides on the morphometric characteristics and proliferative activity of brain cells in albino rats. Material and methods. Sexually mature Wistar male rats were intraperitoneally injected with the peptides Thy-Lys-Pro-Arg-Pro-Gly-Pro (TKPRPGP), Arg-Pro-Gly-Pro (RPGP) and Pro-Gly-Pro-Leu (PGPL) at a dose of 0.1 mg/kg for 5 days. The intact animals that received 0.9 % sodium chloride solution in equivolume served as controls. Morphocytometry was performed on preparations of the right hemisphere of the brain after staining with hematoxylin and eosin. The dimensional (area of bodies, nuclei, and nucleoli) and numerical (number of nucleoli) characteristics of cells were assessed. We examined the parameters of neurons and gliocytes in five localizations (the second and fifth layers of the anterior parietal lobe, the second and fifth layers of the proprietal lobe, field CA1 of the hippocampus). Using immunohistochemical staining, the proliferation intensity was determined (marker Ki-67, clone MIB1). Results. The TKPRPGP peptide changed the morphometric parameters of nervous tissue cells and the gliocyte proliferation index to a greater extent than RPGP and PGPL. In our experiment, the proliferative activity of neurons is maximally influenced by glyproline PGPL. The arginine-containing compound RPGP activates the proliferative activity of gliocytes. Leucine-containing PGPL, to a greater extent, changes the morphometric parameters of neurons. Conclusions. Both studied tetrapeptides affect the morphometric characteristics and proliferative activity of nervous tissue cells when administered five times intraperitoneally at a dose of 0.1 mg/kg. When comparing glyprolines, a more pronounced effect was observed after the administration of PGPL.

1. Zhuikova S.E. Glyprolines: regulatory peptides with an integrative action. Integrativnaya fiziologiya = Integrative Physiology. 2020;1(4):303–316. [In Russian]. doi: 10.33910/2687-1270-2020-1-4-303-316

2. Krasnov I.B., Krasnikov G.V., Burtseva T.D., Chel’naya N.A. Reaction of the neuronal population of rat’’s l5 spinal ganglia to primary and repeated modeling of microgravity effects. Aviakosmicheskaya i ekologicheskaya meditsina = Aerospace and Environmental Medicine. 2009;43(2):21–26. [In Russian].

3. Khavinson V.Kh. Peptide medicines: past, present, future. Klinicheskaya meditsina = Clinical Medicine. 2020;98(3):165–177. [In Russian]. doi.org/10.30629/0023-2149-2020-98-3-165-177

4. Misiura M., Miltyk W. Proline-containing peptides – new insight and implications: A review. Biofactors. 2019;45(6):857–866. doi: 10.1002/biof.1554

5. Jariwala N., Ozols М., Bell М., Bradley Е., Gilmore А., Debelle L., Sherratt M.J. Matrikines as mediators of tissue remodeling: А Review. Adv. Drug Deliv. Rev. 2022;(185):114240. doi: 10.1016/j.addr.2022.114240

6. Stavchansky V.V., Filippenkov I.B., Remizova J.A., Denisova A.E., Mozgovoy I.V., Gubsky L.V., Myasoedov N.F., Andreeva L.A., Limborska S.A., Dergunova L.V. Insight into glyproline peptides’ activity through the modulation of the inflammatory and neurosignaling genetic response following cerebral ischemia-reperfusion. Genes (Basel). 2022;13(12):2380. doi: 10.3390/genes13122380

7. Akimov M.G., Fomina-Ageeva E.V., Dudina P.V., Andreeva L.A., Myasoyedov N.F., Bezuglov V.V. ACTH(6–9)PGP peptide protects SH-SY5Y cells from H2O2, tert-butyl hydroperoxide, and cyanide cytotoxicity via stimulation of proliferation and induction of prosurvival-related genes. Molecules. 2021;26(7):1878. doi: 10.3390/molecules26071878

8. Nikolaev S.V., Logvinov I.O., Koliasnikova K.N., Kuznetsova E.A., Antipov P.I., Antipova T.A. The neuroprotective properties of analogues of substituted glyproline gzk-111 at the с-terminus in vitro. Farmakokinetika i farmakodinamika = Pharmacokinetics and Pharmacodynamics. 2020;(2):4–10. [In Russian]. doi: 10.37489/2587-7836-2020-2-4-10

9. Dergunova L.V., Filippenkov I.B., Limborska S.A., Myasoedov N.F. Neuroprotective peptides and new strategies for ischemic stroke drug discoveries. А Review. Genes (Basel). 2023;14(5):953. doi: 10.3390/genes14050953

10. Korzhevskii D.E., Gilyarov A.V. Fundamentals of histological technique. Saint-Petersburg: SpetsLit, 2010. 95 p. [In Russian].

11. Medik V.A., Tolmachev M.S., Fishman B.B. Statistics in medicine and biology: Guide. In 2 volumes. Vol. 1. Ed. Yu.M. Komarov. Moscow: Meditsina, 2000. 412 p. [In Russian].

12. Barvina A.R. Modern rules for the use of parametric and nonparametric tools in the statistical analysis of biomedical data. Meditsinskiy al’manakh = Medical Almanac. 2021;(1):64–73. [In Russian].

13. Vasil’ev Yu.G., Berestov D.S. Homeostasis and brain plasticity: monography. Izhevsk: FGBOU VPO Izhevskaya GSKhA, 2011. 216 p. [In Russian].

14. Vidal Directory 2022: Medicines in Russia Red. E.A. Tolmacheva. Moscow: Vidal’ Rus, 2022. 1120 p. [In Russian].