2025-2-54-64

УДК 615.015.1: 599.323.45
DOI: https://doi.org/10.52540/2074-9457.2025.2.54
Скачать статью

Е. В. Кравченко¹, О. Н. Саванец¹, Д. И. Макеева^2,1, Д. В. Сикита¹, К. В. Бородина¹, О. В. Грибовская¹, Р. Д. Зильберман¹, Н. А. Бизунок²

Действие тетрапептида, структурно родственного С-концевому фрагменту аргинин-вазопрессина, на модели обсессивно-компульсивного расстройства

¹ГНУ «Институт биоорганической химии НАН Беларуси», г. Минск, Республика Беларусь

²УО «Белорусский государственный медицинский университет», г. Минск, Республика Беларусь

Изучено корректорное влияние тетрапептида N-Ac-Trp-Pro-Arg-Gly-NH₂ на ориентировочно-исследовательскую активность мышей, нарушенную квинпиролом (животная модель обсессивно-компульсивного расстройства – ОКР).

Эксперименты проведены на аутбредных мышах ICR (n = 120). Особям группы I назначали две инъекции растворителя (Р; вода очищенная – интраназально (и/н) и внутрибрюшинно (в/б)); группы II – Р (и/н) и квинпирол (КВ) (0,5 мг/кг, в/б); группы III –
В-5 (N-Ac-Trp-Pro-Arg-Gly-NH₂) в дозе 1,0 мкг/кг, и/н и КВ (0,5 мг/кг, в/б); IV – В-5 (1,0 мкг/кг, и/н) и Р (в/б). Проводили групповую актометрию продолжительностью 70 мин с использованием актометра «Ugo Basile», Италия. Выявлено снижение вертикальной двигательной активности (ВДА) в группе мышей, которым вводили КВ (группа II) в сравнении с контролем (в 5 и 6 мин эксперимента, р < 0,05), а также с уровнем ВДА мышей, которым применяли В-5 (в 1 мин – р < 0,05). Введение В-5 накануне назначения КВ препятствовало патологической гипоактивности в период наиболее выраженного стресса «новизны». В последний 5-минутный интервал ВДА грызунов, получавших КВ, статистически значимо возрастала относительно среднего уровня ВДА за 70 мин; В-5 препятствовал соответствующим КВ-индуцированным нарушениям. Эффективность В-5 позволяет рассматривать его как перспективное фармакологическое вещество для терапии расстройств настроения.

Ключевые слова: мыши, актометрия, N-Ac-Trp-Pro-Arg-Gly-NH₂, квинпирол.

SUMMARY

V. Kravchenko, O. N. Savanets, D. I. Makeeva, D. I. Sikita, K. V. Borodina, О. V. Gribovskaya, R. D. Zilberman, N. A. Bizunok

TETRAPEPTIDE EFFECT STRUCTURALLY RELATED TO THE C-TERMINAL FRAGMENTOF ARGININE VASOPRESSIN ON A MODEL OF OBSESSIVE-COMPULSIVE DISORDER

The corrective effect of tetrapeptide N-Ac-Trp-Pro-Arg-Gly-NH₂ on exploratory and orienting behaviour of mice disrupted by quinpirole (an animal model of obsessive-compulsive disorder - OCD) was studied.

The experiments were conducted on outbred ICR mice (n = 120). Specimen of group I were prescribed two injections of solvent (S; distilled water – intranasally (i.n.) and intraperitoneally (i.p.)); group II – S (i.n.) and quinpirole (0.5 mg / kg, i.p.); group III – B-5 (N-Ac-Trp-Pro-Arg-Gly-NH₂) at a dose of 1.0 mcg / kg, i.n. and Q (0.5 mg / kg, i.p.); IV–V-5 (1.0 mcg / kg, i.n.) and S (i.p.). Group actimetry was performed for the session lasting for 70 minutes using an actimeter "Ugo Basile", Italy. A decrease in the vertical locomotor activity (VLA) was detected in the group of mice treated with Q (group II) compared with the control (in the 5^th and 6^th minutes of the experiment, p < 0.05), and also with the level of VLA in the mice treated with V–5 (in the 1^st minute, p < 0.05). Injection of V-5 before administering Q prevented pathological hypoactivity during the period of the most pronounced stress of "novelty". In the last 5-minute interval the VLA level of rodents treated with Q increased statistically significantly related to the average VLA level over 70 minutes; V-5 prevented corresponding Q-induced disorders. The effectiveness of V-5 allows us to consider it as a promising pharmacological substance for the treatment of mood disorders.

Keywords: mice, actimetry, N-Ac-Trp-Pro-Arg-Gly-NH₂, quinpirole.

ЛИТЕРАТУРА

Phillips, K. A. Obsessive-Compulsive and Related Disorders / K. A. Phillips // Diagnostic and statistical manual of mental disorders : DSM-5-TR / American Psychiatric Association. – 5th ed. – Washington, DC : American Psychiatric Association Publishing. – 2022. – P. 264–272.
Диагностика и терапия расстройств обсессивно-компульсивного спектра в общемедицинской и неврологической практике / Д. С. Петелин, А. Н. Гамирова, О. Ю. Сорокина [и др.] // Неврология, нейропсихиатрия, психосоматика. – 2023. – Т. 15, № 2. – С. 98–105. – DOI: 10.14412/2074-2711-2023-2-98-105.
Clinical predictors of quality of life in a large sample of adult obsessive-compulsive disorder outpatients / P. Velloso, C. Piccinato, Y. Ferrão [et al.] // Comprehensive psychiatry. – 2018. – Vol. 86. – P. 82–90. – DOI: 10.1016/j.comppsych.2018.07.007.
Obsessive–compulsive disorder / D. J. Stein, D. L. Costa, C. Lochner [et al.] // Nature reviews. Disease primers. – 2019. – Vol. 5, N 1. – Art. 52. – DOI: 10.1038/s41572-019-0112-1.
Gender-related romantic attachment and serum oxytocin level difference in adult patients with obsessive compulsive disorder / H. H. Dessoki, M. N. Sadek, H. A. Abd Elrassol [et al.] // Middle East сurrent psychiatry. – 2021. – Vol. 28, N 1. – P. 1–11. – DOI: 10.1186/s43045-021-00159-9.
Soltan, M. R. Oxytocin and obsessive–compulsive disorder / M. R. Soltan // The Egyptian journal of psychiatry. – 2022. – Vol. 43, N 2. – P. 63–69. – DOI: 10.4103/ejpsy.ejpsy_28_21.
Hu, H. Arginine vasopressin in mood disorders: A potential biomarker of disease pathology and a target for pharmacologic intervention / H. Hu, C. A. Zarate Jr, J. Verbalis // Psychiatry and clinical neurosciences. – 2024. – Vol. 78, N 9. – P. 495–506. – DOI: 10.1111/pcn.13703.
Bowen, M. T. Oxytocin and vasopressin modulate the social response to threat: A preclinical study / M. T. Bowen, I. S. McGregor // The international journal of neuropsychopharmacology. – 2014. – Vol. 17, N 10. – P. 1621–1633. – DOI: 10.1017/S1461145714000388.
Синтез и исследование антидепрессивных свойств новых аналогов аргинин-вазопрессина / К. В. Бородина, О. Н. Саванец, Е. С. Пустюльга [и др.] // Биоорганическая химия. – 2022. – Т. 48, № 3. – С. 357–370. – DOI: 10.31857/S0132342322030058.
Антагонист V1AR SR49059 устраняет антидепрессантоподобное действие N-Ac-Trp-Pro-Arg-Gly-NH₂ в тесте принудительного плавания / О. Н. Саванец, Л. М. Ольгомец, К. В. Бородина, В. П. Голубович // Актуальные проблемы современной медицины и фармации-2023 : сб. материалов докладов LXXVII Междунар. науч.-практ. конф. студентов и молодых учёных, Минск, 19-20 апр. 2023 г. / Белорус. гос. мед. ун-т; под. ред. С. П. Рубниковича, В. А. Филонюка. – Минск : БГМУ, 2023. – С. 1332.
Changes of Locomotor Activity by Dopamine D2, D3 Agonist Quinpirole in Mice Using Home-cage Monitoring System / J. Park, E. Moon, H. J. Lim [et al.] // Clinical Psychopharmacology and neuroscience. – 2023. – Vol. 21, N 4. – P. 686–692. – DOI: 10.9758/cpn.22.1016.
Dofman, A. Social interaction modulates the intensity of compulsive checking in a rat model of obsessive-compulsive disorder (OCD) / A. Dorfman, H. Szechtman, D. Eilam // Behavioural brain research. – 2019. – Vol. 359. – P. 156–164. – DOI: 10.1016/j.bbr.2018.10.038.
Multistrain probiotic rescinds quinpirole-induced obsessive-compulsive disorder phenotypes by reshaping of microbiota gut-brain axis in rats / Sh. Ghuge, Z. Rahman, N. A. Bhale [et al.] // Pharmacology, Biochemistry and Behavior. – 2023. – Vol. 232. – Art. 173652. – DOI: 10.1016/j.pbb.2023.173652. – URL: https://pubmed.ncbi.nlm.nih.gov/37804865 (date of access: 12.05.2025).
Marked inbred mouse strain difference in the expression of quinpirole induced compulsive like behavior based on behavioral pattern analysis / R. de Haas, A. Seddik, H. Oppelaar [et al.] // European neuropsychopharmacology. – 2012. – Vol. 22, N 9. – P. 657–663. – DOI: 10.1016/j.euroneuro.2012.01.003.
Animal models of obsessive–compulsive disorder: utility and limitations / P. Alonso, C. López-Solà, E. Real [et al.] // Neuropsychiatric disease and treatment. – 2015. – Vol. 11. – P. 1939 – 1955. – DOI: 10.2147/NDT.S62785.
Validity of Quinpirole Sensitization Rat Model of OCD: Linking Evidence from Animal and Clinical Studies / A. Stuchlik, D. Radostová, H. Hatalova [et al.] // Frontiers in behavioral neuroscience. – 2016. – Vol. 10. – Art. 209. – DOI: 10.3389/fnbeh.2016.00209. – URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC5080285 (date of access: 16.05.2025).
Enhanced reward-facilitating effects of d-amphetamine in rats in the quinpirole model of obsessive-compulsive disorder / T. T. Schmidt, E. Rea, J. Shababi-Klein [et al.] // The International journal of neuropsychopharmacology. – 2013. – Vol. 16, N 5. – P. 1083–1091. – DOI: 10.1017/S1461145712000983.
Behavior Changes in Quinpirole Obsessive-Compulsive Disorder Rats Treated with 6-Hydroxydopamine and the Corresponding Dopaminergic Compulsive Loop Mechanism / H. Zheng, R. He, Y. Ming [et al.] // Journal of integrative neuroscience. – 2025. – Vol. 24, N 1. – Art. 25840. – DOI: 10.31083/JIN25840. – URL: https://pubmed.ncbi.nlm.nih.gov/39862015 (date of access: 19.05.2025).
Влияние пролинсодержащих олигопептидов на особенности оперантного обусловливания поведения аутбредных крыс / Е. В. Кравченко, О. Н. Саванец, Л. М. Ольгомец [и др.] // Весцi Нацыянальнай акадэмii навук Беларусі. Серыя iялагiчных навук. – 2024. – Т. 69, № 2. – C. 120–133. – DOI: 10.29235/1029-8940-2024-69-2-120-133.
Effects of L-Dopa, SKF-38393, and quinpirole on exploratory, anxiety- and depressive-like behaviors in pubertal female and male mice / M. A. Moraes, L. B. Árabe, B. L. Resende, B. C. Codo, A. L. Reis, B. R. Souza // Behavioural brain research. – 2024. – Vol. 459. – Art. 114805. – DOI: 10.1016/j.bbr.2023.114805. – URL: https://pubmed.ncbi.nlm.nih.gov/38096922 (date of access: 19.05.2025).

REFERENCES

Phillips KA. Obsessive-Compulsive and Related Disorders. In: American Psychiatric Association. Diagnostic and statistical manual of mental disorders : DSM-5-TR. 5th ed. Washington, USA : American Psychiatric Association Publishing; 2022. p. 264–72
Petelin DS, Gamirova AN, Sorokina OIu, Troshina DV, Semin SA, Boltueva MSh, i dr. Diagnostics and therapy of obsessive-compulsive spectrum disorders in general medical and neurological practice. Nevrologiia, neiropsikhiatriia, psikhosomatika. 2023;15(2):98–105. doi: 10.14412/2074-2711-2023-2-98-105. (In Russ.)
Velloso P, Piccinato C, Ferrão Y, Perin EA, Cesar R, Fontenelle LF, et al. Clinical predictors of quality of life in a large sample of adult obsessive-compulsive disorder outpatients. Compr Psychiatry. 2018;86:82–90. doi: 10.1016/j.comppsych.2018.07.007
Stein DJ, Costa DL, Lochner C, Miguel EC, Reddy YC, Shavitt RG, et al. Obsessive–compulsive disorder. Nat Rev Dis Primers. 2019;5(1, Art. 52). doi: 10.1038/s41572-019-0112-1
Dessoki HH, Sadek MN, Abd Elrassol HA, El-Sayed SG, Soltan MR. Gender-related romantic attachment and serum oxytocin level difference in adult patients with obsessive compulsive disorder. Middle East Curr Psychiatry. 2021;28(1):1–11. doi: 10.1186/s43045-021-00159-9
Soltan MR. Oxytocin and obsessive–compulsive disorder. Egypt J Psychiatry. 2022;43(2):63–9. doi: 10.4103/ejpsy.ejpsy_28_21
Hu H, Zarate Jr CA, Verbalis J. Arginine vasopressin in mood disorders: A potential biomarker of disease pathology and a target for pharmacologic intervention. Psychiatry Clin Neurosci. 2024;78(9):495–506. doi: 10.1111/pcn.13703
Bowen MT, McGregor IS. Oxytocin and vasopressin modulate the social response to threat: A preclinical study. Int J Neuropsychopharmacol. 2014;17(10):1621–33. doi: 10.1017/S1461145714000388
Borodina KV, Savanets ON, Pustiul'ga ES, Martinovich VP, Kravchenko EV, Ol'gomets LM, i dr. Synthesis and study of antidepressant properties of new arginine vasopressin analogues. Bioorganicheskaia khimiia. 2022;48(3):357–70. doi: 10.31857/S0132342322030058. (In Russ.)
Savanets ON, Ol'gomets LM, Borodina KV, Golubovich VP. V1AR Antagonist SR49059 Abolishes Antidepressant-Like Effects of N-Ac-Trp-Pro-Arg-Gly-NH2 in Forced Swim Test. V: Belorusskii gosudarstvennyi meditsinskii universitet; Rubnikovich SP, Filoniuk VA, redaktory. Aktual'nye problemy sovremennoi meditsiny i farmatsii-2023 : sb materialov dokladov LXXVII Mezhdunar nauch-prakt konf studentov i molodykh uchenykh; 2023 Apr 19-20; Minsk. Minsk, RB: BGMU, 2023. s. 1332. (In Russ.)
Park J, Moon E, Lim HJ, Kim K, Hong YR, Lee JH. Changes of Locomotor Activity by Dopamine D2, D3 Agonist Quinpirole in Mice Using Home-cage Monitoring System. Clin Psychopharmacol Neurosci. 2023;21(4):686–92. doi: 10.9758/cpn.22.1016
Dofman A, Szechtman H, Eilam D. Social interaction modulates the intensity of compulsive checking in a rat model of obsessive-compulsive disorder (OCD). Behav Brain Res. 2019;359:156–64. doi: 10.1016/j.bbr.2018.10.038
Ghuge Sh, Rahman Z, Bhale NA, Dikundwar AG, Dandekar MP. Multistrain probiotic rescinds quinpirole-induced obsessive-compulsive disorder phenotypes by reshaping of microbiota gut-brain axis in rats. Pharmacol Biochem Behav. 2023;232(Art. 173652). DOI: 10.1016/j.pbb.2023.173652. URL: https://pubmed.ncbi.nlm.nih.gov/37804865 (date of access: 12.05.2025)
de Haas R, Seddik A, Oppelaar H, Westenberg HG, Kas MJ. Marked inbred mouse strain difference in the expression of quinpirole induced compulsive like behavior based on behavioral pattern analysis. Eur Neuropsychopharmacol. 2012; 22(9):657–63. doi: 10.1016/j.euroneuro.2012.01.003
Alonso P, López-Solà C, Real E, Segalàs C, Menchón JM. Animal models of obsessive–compulsive disorder: utility and limitations. Neuropsychiatr Dis Treat. 2015;11:1939–55. doi: 10.2147/NDT.S62785
Stuchlik A, Radostová D, Hatalova H, Vales K, Nekovarova T, Koprivova J. Validity of Quinpirole Sensitization Rat Model of OCD: Linking Evidence from Animal and Clinical Studies. Front Behav Neurosci. 2016;10(Art. 209). doi: 10.3389/fnbeh.2016.00209. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC5080285 (date of access: 16.05.2025)
Schmidt TT, Rea E, Shababi-Klein J, Panagis G, Winter C. Enhanced reward-facilitating effects of d-amphetamine in rats in the quinpirole model of obsessive-compulsive disorder. Int J Neuropsychopharmacol. 2013;16(5):1083–91. doi: 10.1017/S1461145712000983
Zheng H, He R, Ming Y, He H, Wang W, Chen L, et al. Behavior Changes in Quinpirole Obsessive-Compulsive Disorder Rats Treated with 6-Hydroxydopamine and the Corresponding Dopaminergic Compulsive Loop Mechanism. J Integr Neurosci. 2025;24(1, Art. 25840). doi: 10.31083/JIN25840. URL: https://pubmed.ncbi.nlm.nih.gov/39862015 (date of access: 19.05.2025)
Kravchenko EV, Savanets ON, Ol'gomets LM, Borodina KV, Golubovich VP, Zil'berman RD, i dr. The influence of proline-containing oligopeptides on the features of operant conditioning of behavior in outbred rats. Vestsi Natsyianal'nai akademii navuk Belarusі. Seryia biialagichnykh navuk. 2024;69(2):120–33. doi: 10.29235/1029-8940-2024-69-2-120-133. (In Russ.)
Moraes MA, Árabe LB, Resende BL, Codo BC, Reis AL, Souza BR. Effects of L-Dopa, SKF-38393, and quinpirole on exploratory, anxiety- and depressive-like behaviors in pubertal female and male mice. Behav Brain Res. 2024;459(Art. 114805). doi: 10.1016/j.bbr.2023.114805. URL: https://pubmed.ncbi.nlm.nih.gov/38096922 (date of access: 19.05.2025)