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ISSN 2522-9028 (Print)
ISSN 2522-9036 (Online)
DOI: https://doi.org/10.15407/fz

Fiziologichnyi Zhurnal

is a scientific journal issued by the

Bogomoletz Institute of Physiology
National Academy of Sciences of Ukraine

Editor-in-chief: V.F. Sagach

The journal was founded in 1955 as
1955 – 1977 "Fiziolohichnyi zhurnal" (ISSN 0015 – 3311)
1978 – 1993 "Fiziologicheskii zhurnal" (ISSN 0201 – 8489)
1994 – 2016 "Fiziolohichnyi zhurnal" (ISSN 0201 – 8489)
2017 – "Fiziolohichnyi zhurnal" (ISSN 2522-9028)

Fiziol. Zh. 2021; 67(4): 64-75


Corrective effects of benzodiazepine derivative – diazepinone on purine and lipid metabolism in the liver of rats with Parkinson’s disease

l.Ya. Shtanova1,2, P.I. Yanchuk1, S.P. Vesеlsky1, O.V. Tsymbalyuk1, T.V. Vovkun2, V.S. Moskvina2, O.V. Shablykina2, A.A. Kravchenko3, V.N. Baban1, V.P. Khilya2

  1. Institute of High Technologies, Taras Shevchenko National University of Kyiv, Ukraine
  2. Faculty of Chemistry, Taras Shevchenko National University of Kyiv, Ukraine
  3. Chuiko Institute of Surface Chemistry, National Academy of Sciences, Ukraine
DOI: https://doi.org/10.15407/fz67.04.064


Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. The cause of PD is not fully understood, and effective treatments still do not exist. It is believed that oxidative stress, mitochondrial dysfunction, and impaired lipid metabolism may underlie the pathogenesis of PD. Bile contains the breakdown products of various compounds that form in hepatocytes. This study aimed to evaluate the effect of a new benzodiazepine derivative - diazepinone (DP) on purine and lipid metabolism in the liver of rats with PD caused by rotenone (ROT) by studying the composition of bile. The concentration of ATP, ADP, AMP, xanthine, hypoxanthine, phospholipids (PL), cholesterol (CHOL), cholesterol esters (ECHOL), free fatty acids (FFA), and triglycerides (TG) was quantified in bile samples by thin-layer chromatography. Our findings suggested that the ratio of AMP/ ATP in bile increased almost threefold under the influence of ROT, and with DP, it exceeded the norm by only 1.6 times. ROT also increased the content of xanthine and hypoxanthine by 28.6% and 66.7%, respectively. DP did not affect the increased xanthine content relative to control but significantly reduced the level of hypoxanthine (up to 22.2%, above normal). In addition, ROT reduced the content of bile PL, CHOL, ECHOL, TG by 23.9%, 38.6%, 47.5%, 39.2 %, respectively. Under the influence of the DP, all the above indicators returned to the level of control. Thus, diazepinone improves both the metabolism of purines and lipids in the liver of rats with ROT-simulated PD. This drug may become a therapeutic agent for treating PD and possibly other neurodegenerative diseases in the future.

Keywords: rotenone; Parkinson’s disease; liver; purine metabolism; lipid metabolis; bile.

References

  1. Chen Ch, Turnbull D, Reeve A. mitochondrial dysfunction in parkinson's disease-cause or consequence? Biology (Basel). 2019;8(2):38. CrossRef PubMed PubMedCentral
  2. Jenner P. Parkinson's disease, pesticides and mitochondrial dysfunction. Trends Neurosci. 2001;24(5):245-7. CrossRef
  3. Betarbet R, Sherer T, MacKenzie G, Garcia-Osuna M, Panov A, Greenamyre J. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci. 2000;3:1301-6. CrossRef PubMed
  4. Cabreira V, Massano J. Parkinson's Disease: Clinical Review and Update. Acta Med Port. 2019 Oct;32(10):661-670. CrossRef." id="ref_href_id" target="blank"">CrossRef CrossRef PubMed
  5. Connolly B, Lang A. Pharmacological treatment of Parkinson disease: a review. JAMA. 2014;311:1670-83. CrossRef PubMed
  6. Xicoy H, Wieringa B, Martens G. The role of lipids in Parkinson's disease. Cells. 2019;8(1):27. CrossRef PubMed PubMedCentral
  7. Lei S, Zavala-Flores L, Garcia-Garcia A, Nandakumar R, Huang Y, Madayiputhiya N, Stanton R, Dodds E, Powers R, Franco R. Alterations in energy/redox metabolism induced by mitochondrial and environmental toxins: a specific role for glucose-6-phosphatedehydrogenase and the pentose phosphate pathway in paraquat toxicity. AC S Chem Biol. 2014;9(9):2032-2048. CrossRef PubMed PubMedCentral
  8. Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F. Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. Neurol Sci. 1973;20(4):415-55. doi:10.1016/0022-510x(73)90175-5. CrossRef
  9. Fonseca-Fonseca L, Wong-Guerra M, Ramírez-Sánchez J, Montano-Peguero Y, Padrón Yaquis A, Rodríguez A, da Silva V, Costa S, Pardo-Andreu Y. JM-20, a novel hybrid molecule, protects against rotenone-induced neurotoxicity in experimental model of Parkinson's disease. Neurosci Lett. 2019;690:29-35. CrossRef PubMed
  10. Shablykina O, Krekhova O, Konovalenko A, Moskvina V, Khilya V. Interaction of 3-pyridyland 3-(imidazo[1,2-a] pyridin-2-yl) isocoumarins with hydrazine. Dopov Nac Akad Nauk Ukr. 2018;(12):71-8. CrossRef
  11. Zeng X, Geng W, Jia J. Neurotoxin induced animal models of Parkinson disease: Pathogenic mechanism and assessment. ASN Neuro. 2018;10:1759091418777438. CrossRef PubMed PubMedCentral
  12. Vovkun T, Yanchuk P, Shtanova L, Veselsky S, Filimonova N, Komarov I. Corvitin modulates the content of lipids in rat liver bile. Ukr Biochem J. 2019;91(6):112-121. CrossRef
  13. Bonora M, Patergnani S, Rimessi A, De Marchi E, Suski J, Bononi A, Giorgi C, ATP synthesis and storage. Purinergic Signal. 2012;8(3):343-357. CrossRef PubMed PubMedCentral
  14. Higgins D, Greenamyre J. [3H]dihydrorotenone binding to NADH: ubiquinone reductase (complex I) of the electron transport chain: an autoradiographic study. J Neurosci. 1996 June 15;16(12):3807-16. CrossRef PubMedCentral
  15. Palmer G, Horgan D, Tisdale H, Singer T, Beinert H. Studies on the respiratory chain-linked reduced nicotinamide adenine dinucleotide dehydrogenase. XIV. Location of the sites of inhibition of rotenone, barbiturates, and piericidin by means of electron paramagnetic resonance spectroscopy. J Biol Chem. 1968;243(4):844-7. CrossRef
  16. Schapira A. Mitochondria in the aetiology and pathogenesis of Parkinson's disease. Lancet Neurol. 2008;7:97-109. CrossRef
  17. Hernández-MuñozR, Glender W, Díaz-Muñoz M, Suárez J, Lozano J, Chagoya de Sánchez V. Alterations of ATP levels and of energy parameters in the blood of alcoholic and nonalcoholic patients with liver damage. Alcohol Clin Exp Res. 1991;15(3):500-3. CrossRef PubMed
  18. Sherer T, Betarbet R, Testa C, Seo B, Richardson J, Kim J, Miller G, Yagi T, Matsuno-Yagi A, Greenamyre J. Mechanism of toxicity in rotenone models of Parkinson's disease. J Neurosci. 2003 Nov 26;23(34):10756-64. CrossRef PubMed PubMedCentral
  19. Yakhine-Diop S, Morales-García J, Niso-Santano M, González-Polo R, Uribe-Carretero E, Martinez-Chacon G, Durand S, Maiuri M, Aiastui A, Zulaica M, RuízMartínez J, de Munain A, Pérez-Tur J, Pérez-Castillo A, Kroemer G, Bravo-San Pedro J, Fuentes J. Metabolic alterations in plasma from patients with familial and idiopathic Parkinson's disease. Aging (Albany NY). 2020;12(17):16690-708. CrossRef PubMed PubMedCentral
  20. El Ridi R., Tallima H. Physiological functions and pathogenic potential of uric acid: A review. J Adv Res. 2017;8:487-93. CrossRef PubMed PubMedCentral
  21. Morita S, Ikeda Y, Tsuji T, Terada T. Molecular mechanisms for protection of hepatocytes against bile salt cytotoxicity. Chem Pharm Bull (Tokyo). 2019;67(4):333-340. CrossRef PubMed
  22. Lamont J, Carey M. Cholesterol gallstone formation. 2. Pathobiology and pathomechanics. Prog Liver Dis. 1992;10:165-91.
  23. Rossmeisl M, Medrikova D, van Schothorst E, Pavlisova J, Kuda O, Hensler M, Bardova K, Flachs P, Stankova B, Vecka M, Tvrzicka E, Zak A, Keijer J, Kopecky J. Omega-3 phospholipids from fish suppress hepatic steatosis by integrated inhibition of biosynthetic pathways in dietary obese mice. Biochim Biophys Acta. 2014;1841(2):267-78. CrossRef PubMed
  24. Cohen D. Hepatocellular transport and secretion of biliary lipids. Current Opin Lipid. 1999;10(4):295-302. CrossRef PubMed
  25. Zhang J, Liu Q. Cholesterol metabolism and homeostasis in the brain. Protein Cell Springer. 2015;6:254-64. CrossRef PubMed PubMedCentral
  26. Gudala K, Bansal D, Muthyala H. Role of serum cholesterol in Parkinson's disease: a meta-analysis of evidence. J Parkinsons Dis. 2013;3:363-70. CrossRef PubMed
  27. Shtanova L, Yanchuk P, Veselsky S, Tsymbalyuk O, Vovkun T, Moskvina V, Shablykina O, Bogza S, Baban V, Kravchenko A, Khily V. Diazepinone effect on liver tissue respiration and serum lipid content in rats with a rotenone model of Parkinson's disease. ISSN 2409-4943. Ukr Biochem J. 2020;92(6):85-94. CrossRef
  28. Fang F, Zhan Y, Hammar N, Shen X, Wirdefeldt K, Walldius G, Mariosa D. Lipids, apolipoproteins, and the risk of Parkinson's disease. Circ Res. 2019;125(6):643-52. CrossRef PubMed
  29. Alves-Bezerra M, Cohen D. Triglyceride Metabolism in the Liver. Compr Physiol. 2017 Dec 12;8(1):1-8. CrossRef PubMed PubMedCentral

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