PARTICIPATION OF NITROID OXIDE AND URIC ACID IN THE FORMATION OF IMPAIRMENTS OF THE FUNCTIONAL ACTIVITY OF THE CENTRAL NERVOUS SYSTEM IN THE MODELING OF POST TRAUMATIC STRESS DISORDER

Nasibullin B. A., Gushcha S. G., Polshchakova T. V.

CLINICAL AND EXPERIMENTAL MEDICINE

Scentific article

Recently, in the pathogenesis of post-traumatic stress disorder (PTSD), along with psychophysiological factors, much attention is paid to repeated light closed craniocerebral injuries, and attention is paid to changes in the metabolism of regulatory molecules – the nitric oxide cycle and glutamate metabolism. The metabolism of uric acid is closely related to the functioning of the nitric oxide cycle. However, in the available scientific literature, we did not find studies on the mutual changes of these regulatory molecules in persons with PTSD. The study aimed to determine the effect of changes in the indicators of the cycle of nitric oxide and uric acid on the state of the functional activity of the central nervous system in modeling PTSD in rats. Materials and methods. The work was performed on white rats of the Wistar line of outbred breeding. PTSD was modeled in rats by a combination of mild traumatic brain injury and immobilization-cold stress. The state of the functional activity of the central nervous system was assessed by the “open field” method, structural changes in the cerebral cortex were studied using histological preparations. Biochemical methods were used to determine the content of NOx, uric acid, total blood protein; the activity of Ca/Mg-ATP-ase and Na/K-ATP-ase was selected in the liver tissue homogenate. Results. The applied model of PTSD causes disturbance of cognitive and psycho-emotional indicators in experimental animals, similar to those described in persons with PTSD. Microscopically, in the cerebral cortex, focal disorders characteristic of traumatic brain injury were not revealed; however, there are diffuse changes of a hypoxic nature and various modifications in intracerebral vessels (spasm, paresis, perivascular edema). These changes are observed against the background of an increase in the content of NO x and uric acid in the blood and a decrease in the activity of Ca/Mg- and Na/K-ATP-ases. Conclusions. Since NOx affects behavioral reactions associated with anxiety, and an increase in the uric acid content promotes prooxidant urate radicals (precisely in the presence of an increased amount of NOx), an increase in NOx negatively affects the amino acid transport system. This is facilitated by the inactivation of both Ca/Mg- and Na/K-ATP-ases. In general, this creates conditions for the death of endothelial cells and, accordingly, to a violation of intracerebral hemodynamics, contributes to hypoxic changes in the neuronal pool of the cortex. Conclusions. Obviously, impaired metabolism of regulatory molecules can be considered a mechanism of CNS damage pathogenesis in PTSD.

post-traumatic stress disorder, nitric oxide cycle, uric acid, central nervous system dysfunction

1. Hoppen TH, Morina N. The prevalence of PTSD and major depression in the global population of adult war survivors: a meta-analytically informed estimate in absolute numbers. Eur J Psychotraumatol. 2019;10(1):1578637. DOI: 10.1080/20008198.2019.1578637.
2. Abu-El-Noor NI, Abu-El-Noor MK. Four Years After the 2014 War Against Gaza Strip, Post-Traumatic Stress Disorder Among People Who were Forced to Leave their Homes During the War: A Cross-Sectional Study. Biomedical Journal of Scientific & Technical Research. 2020;26(3):19905. DOI: 10.26717/BJSTR.2020.26.004342.
3. Kut’ko II, Panchenko OA, Linev AN. Posttravmaticheskoye stressovoye rasstroystvo u perenesshikh vooruzhennyy konflikt. Klinicheskaya dinamika, diagnostika, lecheniye i reabilitatsiya. Ukraí̈ns’kiy medichniy chasopis. 2016;1(111):24-27. Dostupno: http://nbuv.gov.ua/UJRN/ UMCh _2016_1_7. [in Russian].
4. Zlyvkov VL, Lukomska SO, Fedan OV. Psykhodiahnostyka osobystosti u kryzovykh zhyttievykh sytuatsiiakh. Kyiv: Pedahohichna dumka; 2016. 219 s. [in Ukrainian].
5. Jone Е, Wessely S. Battle for the mind: World War 1 and the birth of military psychiatry. The Lancet. 2014;38(9955):1708-1714. DOI: https://doi.org/10.1016/S0140-6736(14)61260-5.
6. Fernández АA, Martín ÁР, Martínez MI, Bustillo МА, Hernández FJB, Cruz Labrado J, et al. Chronic fatigue syndrome: aetiology, diagnosis and treatment. BMC Psychiatry. 2009;9:1. DOI: https://doi.org/10.1186/1471-244X-9-S1-S1.
7. Pols H, Oak S. War & military mental health: the US psychiatric response in the 20th century. Am J Public Health. 2007;97(12):2132-2142. DOI: 10.2105/AJPH.2006.090910.
8. Dieter JN, Engel SD. Traumatic Brain Injury and Posttraumatic Stress Disorder: Comorbid Consequences of War. Neurosci Insights. 2019;14:1179069519892933. DOI: 10.1177/1179069519892933.
9. Glaesser J, Neuner F, Lütgehetmann R, Schmidt, Elbert Т. Posttraumatic Stress Disorder in patients with traumatic brain injury. BMC Psychiatry. 2004;4:5. DOI: https://doi.org/10.1186/1471-244X-4-5. 10.
10. Petrie EC, Cross DJ, Yarnykh VL, Richards Т, Martin NM, Pagulayan К, et al. Neuroimaging, behavioral, and psychological sequelae of repetitive combined blast/impact mild traumatic brain injury in Iraq and Afghanistan war veterans. J. Neurotrauma. 2014;31(5):425-436. DOI: https://doi.org/10. 1089/neu.2013.2952.
11. Logsdon AF, Schindler AG, Meabon JS, Yagi М, Herbert MJ, Banks WA, et al. Nitric oxide synthase mediates cerebellar dysfunction in mice exposed to repetitive blast-induced mild traumatic brain injury. Sci Rep. 2020;10:9420. DOI: https://doi.org/10.1038/s41598-020-66113-7.
12. Oosthuizen F, Wegener G, Harvey BH. Nitric oxide as inflammatory mediator in post-traumatic stress disorder (PTSD): evidence from an animal model. Neuropsychiatr Dis Treat. 2005;1(2):109-123. DOI: 10.2147/nedt.1. 2.109.61049.
13. Zhu X, Dong J, Han B, Нuang R, Zhang A, Xia Z, et al. Neuronal Nitric Oxide Synthase Contributes to PTZ Kindling-Induced Cognitive Impairment and Depressive-Like Behavior. Frontiers in Behavioral Neuroscience. 2017;11:203. DOI: https://doi.org/10.3389/ fnbeh.2017.00203.
14. El Ridi R, Tallima H. Physiological functions and pathogenic potential of uric acid: A review. J Adv Res. 2017;8(5):487-493. DOI: 10.1016/j. jare. 2017.03.003.
15. Fang P, Li X, Luo JJ, Wang H, Yang XF. A Double-edged Sword: Uric Acid and Neurological Disorders. Brain Disord Ther. 2013;2(2):109. DOI: 10.4172/2168-975X.1000109.
16. Shao X, Lu W, Gao F, Li D, Hu J, Li Y, et al. Uric Acid Induces Cognitive Dysfunction through Hippocampal Inflammation in Rodents and Humans. J of Neuroscience. 2016;36(43):10990-11005. DOI: 10.1523/JNEUROSCI. 1480-16.2016.
17. European Communities. Council Directive 2010/63/EU of 22 September 2010 on the protection of animals used for scientific purposes. Official Journal of the European Communities. 2010;276:33-79.
18. Normatyvno-dyrektyvni dokumenty Mіnіsterstva osvіti і nauki, molodі ta sportu Ukrayiny [Internet]. Nakaz Mіnіsterstva osvіti і nauki, molodі ta sportu Ukrayiny vіd 01.03.2012 № 249 «Pro zatverdzhennja Porjadku provedennja naukovimi ustanovami doslіdіv, eksperimentіv na tvarinah». Dostupno: https://zakon.rada.gov.ua/laws/show/z0416-12#Text. [in Ukrainian].
19. Aleksyeyenko NО, Pavlova ОS, Nasibullin BA, Ruchkina AS. Posibnyk z metodiv doslidzhen’ pryrodnykh ta preformovanykh likuval’nykh zasobiv: mineral’ni pryrodni likuval’no-stolovi ta likuval’ni vody, napoyi na yikh osnovi; shtuchno-mineralizovani vody; peloyidy, rozsoly, hlyny, vosky ta preparaty na yikhniy osnovi. Ch. 3. Eksperymental’ni ta klinichni doslidzhennya. Odesa; 2002. 120 s. [in Ukrainian].
20. Normatyvno-dyrektyvni dokumenty MOZ Ukrayiny [Internet]. Nakaz MOZ Ukrayni vіd 28.09.2009 № 692 «Pro zatverdzhennja metodichnih rekomendacіj z metodіv doslіdzhen’ bіologіchnoi dіi prirodnih lіkuval’nih resursіv ta preformovanih lіkuval’nih zasobіv». Dostupno: . [in Ukrainian].
21. Walsh RN, Cummings RA. The open-field test: A critical Review. Psychological Bulletin. 1976;83(3):482-504.
22. Daniel FD, Yogesh AD, Ephrem E, Harald H, Gert L, Volker K. Individual Differences in Male Rats in a Behavioral Test Battery: A Multivariate Statistical Approach. Frontiers in Behavioral Neuroscience. 2017;11:26. DOI: 10.3389/fnbeh.2017.00026.
23. Zolotukhyn PV, Chmиkhalo VK, Makarenko MS, Korinfskaya SA, Lebedeva YUA, Kuz’minova ON, et al. Polozhytelnyi kontur mochevoi kysloty, homotsysteyna, NOkh y khor: nefrolohycheskye aspekty. Nefrolohyia. 2014;18(6):16-22. Dostupno: https://cyberleninka.ru/ article/n/ polozhitelnyy-kontur-mochevoy-kisloty-gomotsisteina-nox-i-xor-nefrologicheskie-aspekty. [in Russian].

«Bulletin of problems biology and medicine» Issue 3 (161), 2021 year, 126-131 pages, index UDK 616.831+616.89]-001.-008.9-092

10.29254/2077-4214-2021-3-161-126-131