MOLECULAR MECHANISMS OF NEUROPROTECTION OF 3-[(E)-3-(3,5-DITRET-BUTYL-4-HYDROXYPHENYL)- 3-OXOPROP-1-ENYL]-6-METHOXY-CHROMENE-4-ONE IN EXPERIMENTAL TRAUMATIC BRAIN INJURY

DOI: https://doi.org/https://doi.org/10.29296/24999490-2022-03-08

D.I. Pozdnyakov
Pyatigorsk Medical and Pharmaceutical Institute, Kalinin Ave., 11, Pyatigorsk, 357532, Russian Federation

Introduction. Neuroprotection in traumatic brain injury is a promising area of therapy for cerebral disorders. Neuroprotective effect can be implemented by a action on variety molecular targets, a change in the activity of which leads to the elimination of pathogenetic reactions of secondary brain damage. Such targets can include the ultrastructures of the mitochondria of the cell. The aim of the study. To evaluate possible molecular mechanisms of neuroprotection of 3-[(E)-3-(3,5-ditret-butyl-4-hydroxyphenyl)-3-oxoprop-1-enyl]-6-methoxy-chromene-4-one in the context of changes in mitochondrial function under experimental traumatic brain injury. Material and methods. Traumatic brain injury was simulated in Wistar rats by free-falling of a load (150 g) from a height of 50 cm onto the parietal region of the animal's skull. The tested compound and the reference medication (ethylmethylhydroxypyridine succinate) were administered per os for 7 days after injury. After the specified time, the degree of development of neurological deficiency in animals was determined on the mNSS scale, the activity of enzymes in brain tissue was evaluated: succinate dehydrogenase, citrate synthase, cytochrome c oxidase and aconitase. The change in the concentration of annexin V was also evaluated. Results. It was found that the use of the tested compound and the reference significantly reduced the severity of neurological symptoms in rats by 31.6% (p
Keywords: 
traumatic brain injury, neuroprotection, mitochondrial dysfunction

Список литературы: 
  1. Khellaf A., Khan D.Z., Helmy A. Recent advances in traumatic brain injury. J. Neurol. 2019; 266 (11): 2878–89. https://doi.org/10.1007/s00415-019-09541-4
  2. Dixon K.J. Pathophysiology of Traumatic Brain Injury. Phys Med Rehabil Clin N Am. 2017; 28 (2): 215–25. https://doi.org/ 10.1016/j.pmr.2016.12.001.
  3. McGinn M.J., Povlishock J.T. Pathophysiology of Traumatic Brain Injury. Neurosurg Clin N Am. 2016; 27 (4): 397–407. https://doi.org/10.1016/j.nec.2016.06.002.
  4. Patel A., Malinovska L., Saha S., Wang J., Alberti S., Krishnan Y., Hyman A.A. ATP as a biological hydrotrope. Science. 2017; 356 (6339): 753–6. https://doi.org/10.1126/science.aaf6846.
  5. Поздняков Д.И., Руковицина В.М., Абаев В.Т., Оганесян Э.Т. Влияние 3-[(е)-3-(3,5-дитрет-бутил-4-гидроксифенил)-3-оксопроп-1-енил]-6-метокси-хромен-4-она на окислительный статус головного мозга крыс в условиях церебральной ишемии. Экспериментальная и клиническая фармакология. 2021; 84 (3): 3–7. https://doi.org/10.30906/0869-2092-2021-84-3-3-7 [Pozdnyakov D.I., Rukovitsina V.M., Abaev V.T., Oganesyan E.T. The effect of 3-[(e)-3-(3,5-ditret-butyl-4-hydroxyphenyl)-3-oxoprop-1-enyl]-6-methoxy-chromene-4-one on the oxidative status of the rat brain in conditions of cerebral ischemia. Experimental and clinical pharmacology. 2021; 84 (3): 3–7. https://doi.org/10.30906/0869-2092-2021-84-3-3-7 (in Russian)].
  6. Воронков А.В., Калашникова С.А., Хури Е.И., Поздняков Д.И. Моделирование черепно-мозговой травмы в условиях эксперимента у крыс. Современные проблемы науки и образования. 2016; 5: 75. [Voronkov A.V., Kalashnikova S. A., Khuri E. I., Pozdnyakov D. I. Modeling of traumatic brain injury in experimental conditions in rats. Modern problems of science and education. 2016; 5: 75 (in Russian)].
  7. Hong Y., Liu Q., Peng M. High-frequency repetitive transcranial magnetic stimulation improves functional recovery by inhibiting neurotoxic polarization of astrocytes in ischemic rats. J. Neuroinflammation. 2020; 17 (1): 150. https://doi.org/10.1186/s12974-020-01747-y
  8. Ternette N., Yang M., Laroyia M. Inhibition of mitochondrial aconitase by succination in fumarate hydratase deficiency.Cell Rep. 2013; 3 (3): 689–700. https://doi.org/10.1016/j.celrep.2013.02.013.
  9. Shepherd D., Garland P.B. The kinetic properties of citrate synthase from rat liver mitochondria. Biochem J. 1969; 114 (3): 597–610.
  10. Li Y., D'Aurelio M., Deng J.H. An assembled complex IV maintains the stability and activity of complex I in mammalian mitochondria.J Biol Chem. 2007; 282 (24): 17557–62. https://doi.org/10.1074/jbc.M701056200
  11. Wang H., Huwaimel B., Verma K. Synthesis and Antineoplastic Evaluation of Mitochondrial Complex II (Succinate Dehydrogenase) Inhibitors Derived from Atpenin A5. Chem. Med. Chem. 2017; 12 (13): 1033–44. https://doi.org/10.1002/cmdc.201700196
  12. Chakraborty S., Skolnick B., Narayan R.K. Neuroprotection Trials in Traumatic Brain Injury. Curr Neurol Neurosci Rep. 2016; 16 (4): 29. https://doi.org/10.1007/s11910-016-0625-x.
  13. Lerouet D., Marchand-Leroux C., Besson V.C. Neuropharmacology in traumatic brain injury: from preclinical to clinical neuroprotection? Fundam Clin. Pharmacol. 2021; 35 (3): 524–38. https://doi.org/ 10.1111/fcp.12656.
  14. Perez-Pinzon M.A., Stetler R.A., Fiskum G. Novel mitochondrial targets for neuroprotection. J. Cereb Blood Flow Metab. 2012; 32 (7): 1362–76. https://doi.org/10.1038/jcbfm.2012.32.
  15. Jornayvaz F.R., Shulman G.I. Regulation of mitochondrial biogenesis. Essays Biochem. 2010; 47: 69–84. https://doi.org/10.1042/bse0470069.
  16. Khodagholi F., Shaerzadeh F., Montazeri F. Mitochondrial Aconitase in Neurodegenerative Disorders: Role of a Metabolism-related Molecule in Neurodegeneration. Curr Drug Targets. 2018; 19 (8): 973–85. https://doi.org/10.2174/1389450118666170816124203.
  17. Sharma B., Kanwar S.S. Phosphatidylserine: A cancer cell targeting biomarker. Semin Cancer Biol. 2018; 52 (1): 17–25. https://doi.org/10.1016/j.semcancer.2017.08.012.