Abstract
The prevalence of anxiety, depression, cognitive disorders, as well as conditions accompanied by pain syndromes, necessitate the search for appropriate corrective agents. The original remedy "Glucinkovit" capsules, manufactured by Leda LLC (Ukraine), containing glucosamine hydrochloride, ascorbic acid, rutin, riboflavin and zinc picolinate, is indicated for cold injuries, inflammatory joint diseases, and the prevention of respiratory viral infections. However, the combination of pharmacological properties of the components of "Glucinkovit" capsules gives reason to expect a range of central neurotropic effects and an influence on pain sensitivity. The aim of the study – to determine the effect of "Glucinkovit" capsules on the functional state of the central nervous system and pain sensitivity. In the experiments, outbred male white mice weighing approximately 40 g were administered contens of "Glucinkovit" capsules at a dose of 50 mg/kg (by glucosamine hydrochloride) intragastrically via a probe in the form of an aqueous solution in a volume of 0.1 ml/10 g 30–40 minutes before the start of testing. Control animals received an equivalent amount of water. The behaviour of mice under stress was assessed in the оpen field test. Movement coordination (rotarod test) and anxiety levels were evaluated in the light- dark box test, the dark compartment of which was equipped with an electrified floor. After the animal entered this compartment, it was subjected to a standard electric shock, which allowed testing of memory the next day for the formation of a conditioned avoidance reflex (CAR) based on changes in the latency period of entry. Pain sensitivity was assessed in the hot plate test, and the effect on depressive behaviour was assessed in the tail suspension test. The results were statistically processed (Mann–Whitney test, Fisher’s angular transformation). In the оpen field test, "Glucinkovit" capsules significantly reduced locomotor and exploratory activity and emotional reactions, indicating stress-protective and sedative properties. The sum of all activities was reduced by half (p < 0.05). In the light-dark box test "Glucinkovit" capsules had an anxiolytic effect, increasing the latency to enter the dark compartment of the apparatus by 4.7 times (p < 0.05). The nootropic properties of "Glucinkovit" capsules were indicated by an increase in the number of mice that, during the CAR test, met the criterion of learning – they did not enter the dark compartment of the apparatus, where they had previously received electrical stimulation, within 3 minutes (100% vs. 75% in the control group, p < 0.05). In the hot plate test, the analgesic effect of "Glucinkovit" capsules was shown by a 1.6-fold increase (p < 0.05) in the latency period of licking the hind paw. "Glucinkovit" capsules did not cause any disturbances in muscle tone or coordination of movements in the rotarod test; on the contrary, it tended to increase the fall latency of animals by an average of 1.8 times. "Glucinkovit" capsules had no effect on depressive behaviour in the tail suspension test: no significant changes were found in the latency period to first immobile suspension, nor in the number and duration of immobility episodes. Thus, original remedy "Glucinkovit" capsules has a favourable profile of central neurotropic effects: a combination of stress-protective, sedative, anxiolytic, nootropic and analgesic properties, with no side effects such as movement discoordination or depressogenic action.
References
2. Associations between mental health symptoms, trauma, quality of life and coping in adults living in Ukraine: a cross-sectional study a year after the 2022 Russian invasion. S. Wang, E. Barrett, M. H. Hicks et al. Psychiatry research. 2024. V. 339. https://doi.org/10.1016/j.psychres.2024.116056.
3. Демченко Н. О., Штриголь С. Ю. Фригопротекторна ефективність капсул «Глюцинковіт». Фундаментальні та прикладні дослідження у галузі фармацевтичної технології: матеріали ІI Міжнародної науково-практичної конференції (м. Харків, 13 жовтня 2022 р.). Харків : Вид-во НФаУ, 2022. С. 126–128.
4. Drug discovery and evaluation: pharmacological assays. Ed. by F . J. Hock. Berlin : Heidelberg, 2014. 2071 p.
5. Havrylov I., Shtrygol’ S. Investigation of the effect of a modified fragment of neuropeptide Y on memory phases and extrapolation escape task of animals. Česká a slovenská farmacie. 2021. V. 70 (3). P. 91–99.
6. Ядловський О. Є., Суворова З. С., Науменко М. В. Особливості застосування методу «Гаряча пластина» у фармакологічних дослідженнях. Фармакологія та лікарська токсикологія. 2020. Т. 14, № 3. С. 177–184. https://doi.org/10.33250/14.03.177.
7. Effectiveness and safety of glucosamine in osteoarthritis: a systematic review. N. X. Vo, N. N. H. Le, T. D. P. Chu et al. Pharmacy (Basel). 2023. V. 11 (4). Р. 117. https://doi.org/10.3390/pharmacy11040117.
8. Vascular mechanisms in the formation of gender differences in the protective effect of glucosamine in experimental cold injury. A. V. Yuhimchuk, N. I. Voloshchuk, S. Yu. Shtrygol’ et al. World of Medicine and Biology. 2023. V. 4. P. 243–247. https://doi.org/10.26724/2079-8334-2023-4-86-243-24.
9. Acute heat trauma model in rats, gender-dependent thermoresistance, and screening of potential thermoprotectors. P. Chuykova, S. Shtrygol, A. Taran et al. ScienceRise: Pharmaceutical Science. 2024. V. 2 (48). P. 4–11. http://doi.org/10.15587/2519-4852.2024.301620.
10. Association between use of specialty dietary supplements and C-reactive protein concentrations. E. D. Kantor, J. W. Lampe, T. L. Vaughan et al. Am. J. Epidemiol. 2012. V. 176 (11). Р. 1002–1013. https://doi.org/10.1093/aje/kws186.
11. Effects of glucosamine on tooth pulpal nociceptive responses in the rat. K. Kaida, H. Yamashita, K. Toda, Y. Hayashi. Journal of Dental Sciences. 2013. V. 8. Р. 68–73. https://doi.org/10.1016/j.jds.2012.09.022.
12. Dalirfardouei R., Karimi G., Jamialahmadi K. Molecular mechanisms and biomedical applications of glucosamine as a potential multifunctional therapeutic agent. Life Sci. 2016. V. 152. Р. 21–29. https://doi.org/10.1016/j.lfs.2016.03.028.
13. Fox B. A., Stephens M. M. Glucosamine hydrochloride for the treatment of osteoarthritis symptoms. Clin. Interv. Aging. 2007. V. 2 (4). Р. 599–604. https://doi.org/10.2147/cia.s1632.
14. Antioxidant activity of glucosamine and its effects on ROS production, Nrf2, and O-GlcNAc expression in HMEC-1 cells. B. Fernández-Rojas, T. Gómez-Sierra, O. N. Medina-Campos et al. Current Research in Toxicology. 2023. V. 5 (2). Р. 100128. https://doi.org/10.1016/j.crtox.2023.100128.
15. Бондарєв Є. В. Експериментальне обґрунтування оптимізації профілактики та лікування холодової травми засобами метаболітотропної та протизапальної дії: автореф. дис. на здобуття наук. ступеня доктора фарм. наук: 14.03.05. Харків, 2020. 44 с.
16. Glucosamine facilitates cardiac ischemic recovery via recruiting Ly6Clow monocytes in a STAT1 and O-GlcNAcylation-dependent fashion. W. Zhou, X. Jiang, Q. Tang et al. Clin. Transl. Med. 2022. V. 12 (3). Р. e762. https://doi.org/10.1002/ctm2.762.
17. Вплив глюкозаміну гідрохлориду на репродуктивну функцію статевозрілих самців щурів. Г. В. Зайченко, Є. М. Коренєва, Н. М. Бречка, Л. А. Сиротенко. Ендокринологія. 2008. Т. 13. № 2. С. 257–261.
18. Зупанець І. А., Грінцова О. Є. Церебропротекторна дія похідних глюкозаміну в умовах експериментальної гіпоксії у щурів. Український біофармацевтичний журнал. 2010. № 1 (6). С. 26–29.
19. Бондарєв Є. В. Експериментальне обґрунтування застосування глюкозаміну гідрохлориду як засобу ноотропної дії. Фармакологія та лікарська токсикологія. 2014. № 1 (37). С. 22–25.
20. Glucosamine enhancement of learning and memory functions by promoting fibroblast growth factor 21 production. Y. M. Chao, H. Y. Wu, S. H. Yeh et al. Int. J. Mol. Sci. 2024. V. 25 (8). Р. 4211. https://doi.org/10.3390/ijms25084211.
21. Glucosamine enhancement of BDNF expression and animal cognitive function. L.-Y. Chou, Y.-M. Chao, Y.-C. Peng et al. Molecules. 2020. V. 25 (16). Р. 3667. https://doi.org/10.3390/molecules2516366.
22. Antinociceptive effect of N-acetyl glucosamine in a rat model of neuropathic pain. E. Mohebbi, M. Molavi, M. Amin et al. Acta Neuropsychiatr. 2022. V. 34 (5). Р. 260–268. https://doi.org/10.1017/neu.2022.3.
23. Effects of glucosamine against morphine-induced antinociceptive tolerance and dependence in mice. F. Basiri, A. Rad, D. Mahdian et al. J. Biomed. Sci. 2019. V. 26 (1). Р. 21. https://doi.org/10.1186/s12929-019-0513-1.
24. The role of oxidative stress in hypertension: the insight into antihypertensive properties of vitamins A, C and E. E. Młynarska, L. Biskup, M. Możdżan et al. Antioxidants (Basel). 2024. V. 13 (7). Р. 848. https://doi.org/10.3390/antiox13070848.
25. Mititelu-Tartau L., Bogdan M., Ciocoiu M. Editorial: Vitamin C from bench to bedside. Front. Nutr. 2024. V. 11. Р. 1406342. https://doi.org/10.3389/fnut.2024.1406342.
26. Vitamin C status and cognitive function: a systematic review. N. Travica, K. Ried, A. Sali et al. Nutrients. 2017. V. 9 (9). Р. 960. https://doi.org/10.3390/nu9090960.
27. Parle M., Dhingra D. Ascorbic acid: a promising memory-enhancer in mice. J. Pharmacol. Sci. 2003. V. 93 (2). Р. 129–135. https://doi.org/10.1254/jphs.93.129.
28. Ganeshpurkar A., Saluja A. K. The pharmacological potential of rutin. Saudi Pharm. J. 2017. V. 25 (2). Р. 149–164. https://doi.org/10.1016/j.jsps.2016.04.025.
29. Rutin as a potent antioxidant: implications for neurodegenerative disorders. A. B. Enogieru, W. Haylett, D. C. Hiss et al. Oxid. Med. Cell. Longev. 2018. V. 2018. Р. 6241017. https://doi.org/10.1155/2018/6241017.
30. An up-to-date review of rutin and its biological and pharmacological activities. N. A. Al-Dhabi, M. V. Arasu, C. H. Park, S. U. Park. EXCLI J. 2015. V. 14. Р. 59–63. https://doi.org/10.17179/excli2014-663.
31. Rutin improves anxiety and reserpine-induced depression in rats. A. I. Foudah, M. H. Alqarni, A. Alam et al. Molecules. 2022. V. 27 (21). Р. 7313. https://doi.org/10.3390/molecules27217313.
32. Antidepressant-like effect of rutin isolated from the ethanolic extract from Schinus molle L. in mice: evidence for the involvement of the serotonergic and noradrenergic systems. D. G. Machado, L. E. Bettio, M. P. Cunha et al. Eur. J. Pharmacol. 2008. V. 587 (1–3). Р. 163–168. https://doi.org/10.1016/j.ejphar.2008.03.021.
33. Hernandez-Leon A., González-Trujano M. E., Fernández-Guasti A. The anxiolytic-like effect of rutin in rats involves GABA A receptors in the basolateral amygdala. Behav. Pharmacol. 2017. V. 28 (4). Р. 303–312. https://doi.org/10.1097/FBP.0000000000000290.
34. Rutin prevents cognitive impairments by ameliorating oxidative stress and neuroinflammation in rat model of sporadic dementia of Alzheimer type. H. Javed, M. M. Khan, A. Ahmad et al. Neuroscience. 2012. V. 210. Р. 340–352. https://doi.org/10.1016/j.neuroscience.2012.02.046.
35. Rylski M., Duriasz-Rowińska H., Rewerski W. The analgesic action of some flavonoids in the hot plate test. Acta Physiol. Pol. 1979. V. 30 (3). Р. 385–388. https://doi.org/10.103/00006450-01000-0000.
36. Anti-nociceptive effect in mice of thillai flavonoid rutin. G. Selvaraj, S. Kaliamurthi, R. Thirungnasam- bandam et al. Biomed. Environ. Sci. 2014. V. 27 (4). Р. 295–299. https://doi.org/10.3967/bes2014.052.
37. Olfat N., Ashoori M., Saedisomeolia A. Riboflavin is an antioxidant: a review update. British Journal of Nutrition. 2022. V. 128 (10). Р. 1887–1895. https://doi.org/10.1017/S0007114521005031.
38. Plantone D., Pardini M., Rinaldi G. Riboflavin in neurological diseases: a narrative review. Clin. Drug Investig. 2021. V. 41. Р. 513–527. https://doi.org/10.1007/s40261-021-01038-1.
39. Association between vitamin B2 intake and cognitive performance among older adults: a cross-sectional study from NHANES. K. Ji, M. Sun, L. Li et al. Sci Rep. 2024. V. 14 (1). Р. 21930. https://doi.org/10.1038/s41598-024-72949-0.
40. Zhou L. Association of vitamin B2 intake with cognitive performance in older adults: a cross-sectional study. J. Transl. Med. 2023. V. 21 (1). Р. 870. https://doi.org/10.1186/s12967-023-04749-5.
41. Riboflavin and pyridoxine restore dopamine levels and reduce oxidative stress in brain of rats. A. V. Peraza, D. C. Guzmán, N. O. Brizuela et al. BMC Neurosci. 2018. V. 19 (1). Р. 71. https://doi.org/10.1186/s12868-018-0474-4.
42. Huang L., Drake V. J., Ho E. Zinc. Adv. Nutr. 2015. V. 6 (2). Р. 224–226. https://doi.org/10.3945/an.114.006874.
43. Stiles L. I., Ferrao K., Mehta K. J. Role of zinc in health and disease. Clin. Exp. Med. 2024. V. 24 (1). Р. 38. https://doi.org/10.1007/s10238-024-01302-6.
44. Zinc and oxidative stress: current mechanisms. D. D. Marreiro, K. J. Cruz, J. B. Morais et al. Antioxidants (Basel). 2017. V. 6 (2). Р. 24. https://doi.org/10.3390/antiox6020024.
45. The involvement of serotonergic system in the antidepressant effect of zinc in the forced swim test. B. Szewczyk, E. Poleszak, P. Wlaź et al. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2009. V. 33 (2). Р. 323–329. https://doi.org/10.1016/j.pnpbp.2008.12.011.
46. Interaction of zinc with antidepressants in the tail suspension test. M. P. Cunha, D. G. Machado, L. E. Bettio et al. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2008. V. 32 (8). Р. 1913–1920. https://doi.org/10.1016/j.pnpbp.2008.09.006.
47. Antidepressant-like properties of zinc in rodent forced swim test. B. Kroczka, P. Branski, A. Palucha et al. Brain Res. Bull. 2001. V. 55(2). Р. 297–300. https://doi.org/10.1016/s0361-9230(01)00473-7.
48. Anxiolytic and antidepressant effect of zinc on rats and its impact on general behavioural parameters. J. Samardzić, K. Savić, N. Stefanović et al. Vojnosanit. Pregl. 2013. V. 70 (4). Р. 391–395. https://doi.org/10.2298/vsp111129036s.