Keywords
mitochondrial dysfunction
succinates
Abstract
The aim of the study. To evaluate the effect of succinic acid derivatives on changes of mitochondrial function in rats under cerebral ischemia conditions.
Materials and methods. In this work, the effect of succinic acid, ethylmethylhydroxy-pyridine succinate, and acetylaminosuccinic acid at doses of 50 mg/kg, 100 mg/kg, and 200 mg/kg (per os) on the change of the neuronal mitochondria function was studied. Cerebral ischemia was reproduced by the Tamura method. The following parameters were evaluated: changes in aerobic/anaerobic metabolism, mitochondrial membrane potential, the opening rate of the mitochondrial pore of transitional permeability and the activity of apoptotic systems.
Results. During the study, it was found that the use of the test-compounds at doses of 100 mg/kg and 200 mg/kg contributed to an increase in ATP-generating activity, as well as the maximum respiration level and respiratory capacity, while accompanied by a decrease in the intensity of anaerobic metabolism reactions. Also, upon administration of the test succinic acid derivatives, an increase in the mitochondrial membrane potential and latent opening time of the mitochondrial pore transitional permeability were observed. Moreover, the activity of caspase-3 and apoptosis-inducing factor on groups treated by test objects at doses of 100 mg/kg and 200 mg/kg was significantly lower than that in untreated animals.
Conclusion. The studied succinic acid derivatives contribute to the restoration of mito-chondrial function in cerebral ischemia conditions, while the most effective dose can be considered to be 100 mg/kg.
References
1. Jayaraj RL, Azimullah S, Beiram R, Jalal FY, Rosenberg GA. Neuroinflammation: friend and foe for ischemic stroke. J Neuroinflammation. 2019;16(1):142.
2. Ma Y, Liu Y, Zhang Z, Yang GY. Significance of Complement System in Ischemic Stroke: A Comprehensive Review. Aging Dis. 2019;10(2):429-62.
3. Lallukka T, Ervasti J, Lundström E, Mittendorfer-Rutz E, Friberg E, Virtanen M, et al. Trends in diagnosis-specific work disability before and after stroke: A longitudinal population-based study in Sweden. J Am Heart Assoc. 2018;7(1):e006991.
4. Mondal NK, Behera J, Kelly KE, George AK, Tyagi PK, Tyagi N. Tetrahydrocurcumin epigenetically mitigates mitochondrial dysfunction in brain vasculature during ischemic stroke. Neurochem Int. 2019;122:120-38.
5. Ham PB 3rd, Raju R. Mitochondrial function in hypoxic ischemic injury and influence of aging. Prog Neurobiol. 2017;157:92-116.
6. Yang JL, Mukda S, Chen SD. Diverse roles of mitochondria in ischemic stroke. Redox Biol. 2018;16:263-75.
7. Hatefi Y. The mitochondrial electron transport and oxidative phosphorylation system. Annu. Rev. Biochem. 1985;54:1015-69.
8. Liu F, Lu J, Manaenko A, Tang J, Hu Q. Mitochondria in Ischemic Stroke: New Insight and Implications. Aging Dis. 2018;9(5):924-37.
9. Honda HM, Korge P, Weiss JN. Mitochondria and ischemia/reperfusion injury. Ann NY Acad Sci. 2005;1047:248-58.
10. Nguyen H, Zarriello S, Rajani M, Tuazon J, Napoli E, Borlongan CV. Understanding the Role of Dysfunctional and Healthy Mitochondria in Stroke Pathology and Its Treatment. Int J Mol Sci. 2018;19(7):2127.
11. Bernardi P, Rasola A, Forte M, Lippe G. The Mitochondrial Permeability Transition Pore: Channel Formation by F-ATP Synthase, Integration in Signal Transduction, and Role in Pathophysiology. Physiol Rev. 2015;95(4):1111-55.
12. Hawkins BJ, Levin MD, Doonan PJ, Petrnko NB, Davis CW, Patel VV, et al. Mitochondrial complex II prevents hypoxic but not calcium- and proapoptotic Bcl-2 protein-induced mitochondrial membrane potential loss. J Biol Chem. 2010;285(34):26494-505.
13. Xiao Y, Zhang Z, Wang Y, Gao B, Chang J, Zhu D. Two-Stage Crystallization Combining Direct Succinimide Synthesis for the Recovery of Succinic Acid From Fermentation Broth. Front Bioeng Biotechnol. 2020;7:471.
14. Volchegorskii IA, Miroshnichenko IY, Rassokhina LM, Faizullin RM, Malkin MР, Pryakhina KE, et.al. Comparative analysis of the anxiolytic effects of 3-hydroxypyridine and succinic acid derivatives. Bull Exp Biol Med. 2015;158(6): 756-61.
15. Ferro A, Carbone E, Zhang J, Marzouk E, Villegas M, Siegel A, et al. Short-term succinic acid treatment mitigates cerebellar mitochondrial OXPHOS dysfunction, neurodegeneration and ataxia in a Purkinje-specific spinocerebellar ataxia type 1 (SCA1) mouse model. PLoS One. 2017;12(12):e0188425.
16. Weinberg JM, Venkatachalam MA, Roeser NF, Nissim I. Mitochondrial dysfunction during hypoxia/reoxygenation and its correction by anaerobic metabolism of citric acid cycle intermediates. Proc Natl Acad Sci USA. 2000;97(6):2826-31.
17. Nowak G, Clifton GL, Bakajsova D. Succinate ameliorates energy deficits and prevents dysfunction of complex I in injured renal proximal tubular cells. J Pharmacol Exp Ther. 2008;324(3):1155-62.
18. Pozdnyakov DI, Nygaryan SA, Voronkov AV. Ethylmethyl-hydroxypyridine succinate, acetylcysteine and choline alphoscerate improve mitochondrial function under condition of cerebral ischemia in rat. Bangladesh Pharmacol. 2019;14(3):152-8.
19. Tamura A, Graham DI, McCulloch J, Teasdale GM. Focal cerebral ischaemia in the rat: 1. Description of technique and early neuropathological consequences following middle cerebral artery occlusion. J Cereb Blood Flow Metab. 1981;1(1):53-60.
20. Patel SP, Sullivan PG, Pandya JD, et al. N-acetylcysteine amide preserves mitochondrial bioenergetics and improves functional recovery following spinal trauma. Exp Neurol. 2014;257:95-105.
21. Pozdnyakov DI, Voronkov AV, Miroshnichenko KA, Adzhiahmetova SL, Chervonnaya NM, Rukovitcina VM. Pyrimidine-4H-1OH derivatives restore mitochondrial function in experimental chronic traumatic encephalopathy. Pharmacologyonline.2019;3:36-45
22. He F. Bradford Protein Assay. Bio-101:2015.e45.
23. Zhyliuk V, Mamchur V, Pavlov S. Role of functional state of neuronal mitochondria of cerebral cortex in mechanisms of nootropic activity of neuroprotectors in rats with alloxan hyperglycemia. Eksperimental’naia i klinicheskaia farmakologiia. 2015;78: 10-4.
24. Klacanova K, Kovalska M, Chomova M, et al. Global brain ischemia in rats is associated with mitochondrial release and downregulation of Mfn2 in the cerebral cortex, but not the hippocampus. Int J Mol Med. 2019;43(6):2420-8.
25. Kumar R, Bukowski MJ, Wider JM, Reynalds CA, Calo L, Bradley L, et al. Mitochondrial dynamics following global cerebral ischemia. Mol Cell Neurosci. 2016;76:68-75.
26. Rouslin W, Long I, Richard B, Broge CW. Why are ATP depletion rates in situ in ischemic myocardium so much lower than one might predict from the activity of the mitochondrial ATPase in sonicated heart mitochondria? J Mol Cell Cardiol. 1997;29:1505-10.
27. Kuznetsov AV, Javadov S, Margreiter R, Grimm M, Hagenbuchner J, Ausserlechner MJ. The Role of Mitochondria in the Mechanisms of Cardiac Ischemia-Reperfusion Injury. Antiox. 2019;8(10):454.
28. Deroche-Gamonet V, Revest JM, Fiancette JF, Balado E, Koehl M, Grosjean N, et.al. Depleting adult dentate gyrus neurogenesis increases cocaine-seeking behavior. Mol Psych. 2019;24(2): 312-20.
29. Оyedotun KS, Lemire BD. The quaternary structure of the Saccharomyces cerevisiae succinate dehydrogenase. Homology modeling, cofactor docking, and molecular dynamics simulation studies. J Biol Chem. 2004;279(10):9424-1.
30. Sotler R, Poljšak B, Dahmane R, Jukić T, Pavan Jukić D, Rotim C, Trebše P, Starc A. Prooxidant activities of antioxidants and their impact on health. Acta Clin Croat. 2019; 58(4):726-36.
31. Palagina IA. Pro-/antioxidant reactions and nitrogen oxide metabolism under sub-chronic effect of succinic acid derivatives. The Ukrainian Biochemical Journal. 2017;89(4):22-33.
32. Hurst S, Hoek J, Sheu SS. Mitochondrial Ca2+ and regulation of the permeability transition pore. J Bioenerg Biomembr. 2017;49(1):27-47.
33. Panneer Selvam S, Roth BM, Nganga R, Kim J, Cooley MA, Helke K, et al. Balance between senescence and apoptosis is regulated by telomere damage-induced association between p16 and caspase-3. J Biol Chem. 2018;293(25):9784-800.
34. Milasta S, Dillon CP, Sturm OE, Verbist KC, Brewer TL, Quarato G, et al. Apoptosis-Inducing-Factor-Dependent Mitochondrial Function Is Required for T Cell but Not B Cell Function. Immun. 2016;44(1):88-102.
35. Radak D, Katsiki N, Resanovic I, Jovanovic A, Sudar-Milovanovic E, Zafirovic S, et al. Apoptosis and Acute Brain Ischemia in Ischemic Stroke. Curr Vasc Pharmacol. 2017;15(2):115-22.
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 Unported License.
Copyright (c) 2021 Authors