Biopolym. Cell. 2019; 35(5):356-370.
Bioorganic Chemistry
The evaluation of 2.3-diazepine influence on tissue respiration of the liver and its exocrine function in rats with a rotenone model of Parkinson’s disease
2Khilya V. P., 1Yanchuk I. P., 1, 2Shtanova L. Ya., 1Veselsky S. P., 2Vovkun T. V., 1Tsymbalyuk O. V., 2Moskvina V. S., 2Shablykina O. V., 2Bogza S. L.
  1. Institute of High Technologies,
    Taras Shevchenko National University of Kyiv
    2, korp.5, Pr. Akademika Hlushkova, Kyiv, Ukraine, 03022
  2. Taras Shevchenko National University of Kyiv
    64, Volodymyrska Str., Kyiv, Ukraine, 01601

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder, characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. The causes of PD are not fully understood; however, increasing evidence implicates disturbed respiratory function of the mitochondria and a lack of energy in cells. Aim. To study the effects of 2.3-diazepine (2.3-DP), a new derivative of benzodiazepine, on liver tissue respiration (LTR) and energy dependent processes of bile and bile acids (BAs) production in a rat model of PD. Methods. PD was induced by intraperitoneal injections of rotenone (ROT). LTR (the intensity of the oxygen uptake) was assessed using the polarograph LP-9 (Czech Republic). Secreted bile was collected during 1 hour of the experiment through the polyethylene catheter inserted into the common bile duct. BAs were separated by the method of thin layer chromatography. Results. ROT diminished the index of liver oxygen consumption by 34 % (p<0.001), reduced bile flow by 33.8 % (p<0.001) and disturbed the conjugation of cholic acid with amino acids taurine and glycine reducing the index of conjugation by 29.2 % (p<0.001). ROT also increased by 25.6 % (p<0.001) the part of acidic pathway in the biosynthesis of BAs. The application of 2.3-DP results in full or partial recovery of LTR, bile flow, concentrations of BAs and their ratio in the bile of rats with PD. Conclusion. 2.3-DP markedly affected function of the liver parenchyma in a rat model of PD. This drug changed the intensity of LTR, bile flow and notably modified bile chemical compositions.
Keywords: Parkinson’s disease, 2.3-diazepine, tissue respiration, bile, bile acids

References

[1] Kalia LV, Lang AE. Parkinson's disease. Lancet. 2015;386(9996):896-912.
[2] Coppedè F. Genetics and epigenetics of Parkinson's disease. ScientificWorldJournal. 2012;2012:489830.
[3] Park JS, Davis RL, Sue CM. Mitochondrial Dysfunction in Parkinson's Disease: New Mechanistic Insights and Therapeutic Perspectives. Curr Neurol Neurosci Rep. 2018;18(5):21.
[4] Baig F, Lawton M, Rolinski M, Ruffmann C, Nithi K, Evetts SG, Fernandes HR, Ben-Shlomo Y, Hu MT. Delineating nonmotor symptoms in early Parkinson's disease and first-degree relatives. Mov Disord. 2015;30(13):1759-66.
[5] Zhao H, Wang C, Zhao N, Li W, Yang Z, Liu X, Le W, Zhang X. Potential biomarkers of Parkinson's disease revealed by plasma metabolic profiling. J Chromatogr B Analyt Technol Biomed Life Sci. 2018;1081-1082:101-108.
[6] Cannon JR, Greenamyre JT. Gene-environment interactions in Parkinson's disease: specific evidence in humans and mammalian models. Neurobiol Dis. 2013;57:38-46.
[7] Sherer TB, Betarbet R, Testa CM, Seo BB, Richardson JR, Kim JH, Miller GW, Yagi T, Matsuno-Yagi A, Greenamyre JT. Mechanism of toxicity in rotenone models of Parkinson's disease. J Neurosci. 2003;23(34):10756-64.
[8] Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci. 2000;3(12):1301-6.
[9] Jenner P. A2A antagonists as novel non-dopaminergic therapy for motor dysfunction in PD. Neurology. 2003;61(11 Suppl 6):S32-8.
[10] Fonseca-Fonseca LA, Wong-Guerra M, Ramírez-Sánchez J, Montano-Peguero Y, Padrón Yaquis AS, Rodríguez AM, da Silva VDA, Costa SL, Pardo-Andreu GL, Núñez-Figueredo 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.
[11] Khabarov KM, Kharaneko OI, Bogza SL. 2,3 Benzodiazepine-1-thione in the synthesis of substituted and hetero-annelated 2,3-benzodiazepines. Chem Heterocycl Compd. 2009; 45(4): 468–74.
[12] Gallagher D, Belmonte D, Deurenberg P, Wang Z, Krasnow N, Pi-Sunyer FX, Heymsfield SB. Organ-tissue mass measurement allows modeling of REE and metabolically active tissue mass. Am J Physiol. 1998;275(2):E249-58.
[13] Chang YT, Luo XG, Ren Y. Behavior alteration and damage of dopaminergic neurons of substantia nigra caused by rotenone in rats. Jiepouxue Yanjiu Jingzhan. 2011; 7: 60–2.
[14] Bures J, Burešová O, Huston JP. Techniques and Basic Experiments for the Study of Brain and Behavior. Elsevier. 1976; 37–89.
[15] Berezovsky VA. Oxygen tension in animal and human tissues. Kyiv, Naukova dumka, 1975; 230p.
[16] Tsybenko VA, Egorova LS, Mikhaĭlova NV, Zhakhalova LA, Dubileĭ TA. [Neurogenic control of oxidative metabolism in the liver]. Fiziol Zh SSSR Im I M Sechenova. 1988;74(5):737-45.
[17] Ghazaee SP, Gorenko ZA, Karbovska LS, Veselsky SP, Yanchuk PI, Makarchuk MY. Desmopressin stimulates bile secretion in anesthetized rats. Gen Physiol Biophys. 2010;29(2):151-9.
[18] Matsumura T, Sato N, Kawano S, Hijioka T, Eguchi H, Kamada T. Effect of hepatic blood oxygenation on bile secretion in rats. Adv Exp Med Biol. 1988;222:585-9.
[19] Claudel T, Staels B, Kuipers F. The Farnesoid X receptor: a molecular link between bile acid and lipid and glucose metabolism. Arterioscler Thromb Vasc Biol. 2005;25(10):2020-30.
[20] Hovorukha TM, Nazarenko AI, Zhalilo LI, Fil' HB, Baban VM, Seredenko MM. [Disturbances in biliary secretion during tissue hypoxia and attempts at their corrections]. Fiziol Zh. 2002;48(1):35-40.
[21] Hofmann AF, Mysels KJ. Bile acid solubility and precipitation in vitro and in vivo: the role of conjugation, pH, and Ca2+ ions. J Lipid Res. 1992;33(5):617-26.
[22] Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem. 2003;72:137-74.
[23] Rosa AI, Duarte-Silva S, Silva-Fernandes A, Nunes MJ, Carvalho AN, Rodrigues E, Gama MJ, Rodrigues CMP, Maciel P, Castro-Caldas M. Tauroursodeoxycholic Acid Improves Motor Symptoms in a Mouse Model of Parkinson's Disease. Mol Neurobiol. 2018;55(12):9139-9155.
[24] Pfeiffer RF. Gastrointestinal Dysfunction in Parkinson's Disease. Curr Treat Options Neurol. 2018;20(12):54.
[25] Morais LH, Lima MM, Martynhak BJ, Santiago R, Takahashi TT, Ariza D, Barbiero JK, Andreatini R, Vital MA. Characterization of motor, depressive-like and neurochemical alterations induced by a short-term rotenone administration. Pharmacol Rep. 2012;64(5):1081-90.
[26] Uversky VN. Neurotoxicant-induced animal models of Parkinson's disease: understanding the role of rotenone, maneb and paraquat in neurodegeneration. Cell Tissue Res. 2004;318(1):225-41.