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
- Institute of High Technologies, Taras Shevchenko National University of Kyiv, Ukraine
- Faculty of Chemistry, Taras Shevchenko National University of Kyiv, Ukraine
- 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
- Chen Ch, Turnbull D, Reeve A. mitochondrial dysfunction in parkinson's disease-cause or consequence? Biology (Basel). 2019;8(2):38.
CrossRef
PubMed PubMedCentral
- Jenner P. Parkinson's disease, pesticides and mitochondrial dysfunction. Trends Neurosci. 2001;24(5):245-7.
CrossRef
- 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
- 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
- Connolly B, Lang A. Pharmacological treatment of Parkinson disease: a review. JAMA. 2014;311:1670-83.
CrossRef
PubMed
- Xicoy H, Wieringa B, Martens G. The role of lipids in Parkinson's disease. Cells. 2019;8(1):27.
CrossRef
PubMed PubMedCentral
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Schapira A. Mitochondria in the aetiology and pathogenesis of Parkinson's disease. Lancet Neurol. 2008;7:97-109.
CrossRef
- 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
- 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
- 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
- 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
- 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
- Lamont J, Carey M. Cholesterol gallstone formation. 2. Pathobiology and pathomechanics. Prog Liver Dis. 1992;10:165-91.
- 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
- Cohen D. Hepatocellular transport and secretion of biliary lipids. Current Opin Lipid. 1999;10(4):295-302.
CrossRef
PubMed
- Zhang J, Liu Q. Cholesterol metabolism and homeostasis in the brain. Protein Cell Springer. 2015;6:254-64.
CrossRef
PubMed PubMedCentral
- 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
- 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
- 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
- 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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