2658-6533Research Results in Biomedicine2658-6533DOI: 10.18413/2658-6533-2022-8-3-0-72810Pharmacology<strong>Correction of mitochondrial dysfunction with cinnamic acids in experimental hypercytokinemia</strong><strong>Correction of mitochondrial dysfunction with cinnamic acids in experimental hypercytokinemia</strong>PozdnyakovDmitry I.PozdnyakovDmitry I.pozdniackow.dmitry@yandex.ru20228300

Background:&nbsp;Mitochondrial dysfunction is an essential component of the hypercytokine neurotoxicity pathogenesis and is a promising pharmacotherapeutic target. The aim of the study:&nbsp;To evaluate the effect of cinnamic acids on changes in mitochondrial function in brain tissue of rats under experimental hypercytokinemia. Materials and methods:&nbsp;Hypercytokinemia was modeled in rats by intraperitoneal injection of lipopolysaccharide at a dose of 10 mg/kg. The test compounds (cinnamic, ferulic, coumaric, caffeic, synapic acids) and the reference medicine (ethylmethylhydroxypyridine succinate) were administered at a dose of 100 mg/kg, orally for 14 days from the moment of lipopolysaccharide injection. Further, changes of neurological deficits in rats and the activity of succinatedehydrogenase and cytochrome-c-oxidase were assessed, the concentration of mitochondrial hydrogen peroxide and superoxide radical were determined in the mitochondrial fraction of the brain. Results:&nbsp;The use of the reference, caffeic and coumaric acids and, to a lesser extent, cinnamic acid contributed to a decrease in neurological deficit in rats (by 38.5%; 42.3%, 40.4% and 21.2%, respectively, all indicators p&lt;0.05 relative to the negative control group of animals), with an increase in succinate dehydrogenase activity (by 23.0% (p&lt;0.05); 30.0% (p&lt;0.05) and 20.0% (p&lt;0.05), cinnamic acid had no significant effect on enzyme activity) and cytochrome- c-oxidase (by 22.2%; 34.4%; 32.2%; and 22.2%, respectively, all indicators p&lt;0.05 relative to the group of negative control animals), as well as a decrease in the concentration of superoxide radical (by 38.8%; 48.8%; 46.3%; and 33.4%, respectively, all indicators p&lt;0.05 relative to the negative control group of animals) and hydrogen peroxide (by 25.0% (p&lt;0.05); 54.2% (p&lt;0.05); 50.4% and 27.9% (p&lt;0.05), respectively). At the same time, the antiradical activity and the change in the activity of succinatedehydrogenase correlated with the normal gradient of the molecules. Conclusion:&nbsp;The study showed the possibility of using cinnamic acids containing free hydroxyl groups in the aromatic ring to correct posthypercytokine neurotoxicity.

Background:&nbsp;Mitochondrial dysfunction is an essential component of the hypercytokine neurotoxicity pathogenesis and is a promising pharmacotherapeutic target. The aim of the study:&nbsp;To evaluate the effect of cinnamic acids on changes in mitochondrial function in brain tissue of rats under experimental hypercytokinemia. Materials and methods:&nbsp;Hypercytokinemia was modeled in rats by intraperitoneal injection of lipopolysaccharide at a dose of 10 mg/kg. The test compounds (cinnamic, ferulic, coumaric, caffeic, synapic acids) and the reference medicine (ethylmethylhydroxypyridine succinate) were administered at a dose of 100 mg/kg, orally for 14 days from the moment of lipopolysaccharide injection. Further, changes of neurological deficits in rats and the activity of succinatedehydrogenase and cytochrome-c-oxidase were assessed, the concentration of mitochondrial hydrogen peroxide and superoxide radical were determined in the mitochondrial fraction of the brain. Results:&nbsp;The use of the reference, caffeic and coumaric acids and, to a lesser extent, cinnamic acid contributed to a decrease in neurological deficit in rats (by 38.5%; 42.3%, 40.4% and 21.2%, respectively, all indicators p&lt;0.05 relative to the negative control group of animals), with an increase in succinate dehydrogenase activity (by 23.0% (p&lt;0.05); 30.0% (p&lt;0.05) and 20.0% (p&lt;0.05), cinnamic acid had no significant effect on enzyme activity) and cytochrome- c-oxidase (by 22.2%; 34.4%; 32.2%; and 22.2%, respectively, all indicators p&lt;0.05 relative to the group of negative control animals), as well as a decrease in the concentration of superoxide radical (by 38.8%; 48.8%; 46.3%; and 33.4%, respectively, all indicators p&lt;0.05 relative to the negative control group of animals) and hydrogen peroxide (by 25.0% (p&lt;0.05); 54.2% (p&lt;0.05); 50.4% and 27.9% (p&lt;0.05), respectively). At the same time, the antiradical activity and the change in the activity of succinatedehydrogenase correlated with the normal gradient of the molecules. Conclusion:&nbsp;The study showed the possibility of using cinnamic acids containing free hydroxyl groups in the aromatic ring to correct posthypercytokine neurotoxicity.

cinnamic acidsneurotoxicitymitochondrial dysfunctionhypercytokinemiacinnamic acidsneurotoxicitymitochondrial dysfunctionhypercytokinemiaСписок литературыFajgenbaum DC, June CH. Cytokine Storm. New England Journal of Medicine. 2020;383(23):2255-2273. DOI: https://doi.org/10.1056/NEJMra2026131Kempuraj D, Selvakumar GP, Ahmed ME, et al. COVID-19, Mast Cells, Cytokine Storm, Psychological Stress, and Neuroinflammation. Neuroscientist. 2020;26(5-6):402-414. DOI: https://doi.org/10.1177/1073858420941476Yang QQ, Zhou JW. Neuroinflammation in the central nervous system: Symphony of glial cells. GLIA. 2019;67(6):1017-1035. DOI: https://doi.org/10.1002/glia.23571Garabadu D, Agrawal N, Sharma A, et al. Mitochondrial metabolism: a common link between neuroinflammation and neurodegeneration. Behavioural Pharmacology. 2019;30(8):642-652. DOI: https://doi.org/10.1097/FBP.0000000000000505Swerdlow RH. Mitochondria and Mitochondrial Cascades in Alzheimer&#39;s Disease. Journal of Alzheimer&#39;s Disease. 2018;62(3):1403-1416. DOI: https://doi.org/10.3233/JAD-170585Wilkins HM, Swerdlow RH. Relationships Between Mitochondria and Neuroinflammation: Implications for Alzheimer&#39;s Disease. Current Topics in Medicinal Chemistry. 2016;16(8):849-57. DOI: https://doi.org/10.2174/1568026615666150827095102DiSabato DJ, Quan N, Godbout JP. Neuroinflammation: the devil is in the details. Journal of Neurochemistry. 2016;139(S2):136-153. DOI: https://doi.org/10.1111/jnc.13607Stacchiotti A, Corsetti G. Natural Compounds and Autophagy: Allies Against Neurodegeneration. Frontiers in Cell and Developmental Biology. 2020;8:555409. DOI: https://doi.org/10.3389/fcell.2020.555409Teixeira J, Soares P, Benfeito S, et al. Rational discovery and development of a mitochondria-targeted antioxidant based on cinnamic acid scaffold. Free Radical Research. 2012;46(5):600-11. DOI: https://doi.org/10.3109/10715762.2012.662593Voronkov AV, Pozdnyakov DI, Adjiakhmetova SL, et al. The effect of some cinnamic acid derivatives on the change in the activity of enzymes of the tricarboxylic acid cycle in rats under conditions of cerebral ischemia. Medical Academic Journal. 2020;20(2):27-32. Russian. DOI: https://doi.org/10.17816/MAJ33994Percie du Sert N, Hurst V, Ahluwalia A, et al. The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. PLoS Biology. 2020;18(7):e3000410. DOI: https://doi.org/10.1371/journal.pbio.3000410Zhang H, Sha J, Feng X, et al. Dexmedetomidine ameliorates LPS induced acute lung injury via GSK-3&beta;/STAT3-NF-&kappa;B signaling pathway in rats. International Immunopharmacology. 2019;74:105717. DOI: https://doi.org/10.1016/j.intimp.2019.105717Kirova YU, Shakova FM, Germanova EL, et al. The effect of Mexidol on cerebral mitochondriogenesis at a young age and during aging. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova. 2020;120(1):62-69. 2020;120(1):62-69. Russian. DOI: https://doi.org/10.17116/jnevro202012001162Vasilevskaya E, Makarenko A, Tolmacheva G, et al.&nbsp; Local Experimental Intracerebral Hemorrhage in Rats. Biomedicines. 2021;9(6):585. DOI: https://doi.org/10.3390/biomedicines9060585Voronkov AV, Pozdnyakov DI, Adjiakhmetova SL, et al. Mitochondrial dysfunction in neurodegenerative and ischemic brain lesions. Experimental and pharmacological aspects. K: Buk; 2020. Russian.Hill MD, Goyal M, Menon BK, et al. Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial. The Lancet. 2020;395(10227):878-887. DOI: https://doi.org/10.1016/S0140-6736(20)30258-0Fargualy AM, Habib NS, Ismail KA, et al. Synthesis, biological evaluation and molecular docking studies of some pyrimidine derivatives. European Journal of Medicinal Chemistry. 2013;66:276-95. DOI: https://doi.org/10.1016/j.ejmech.2013.05.028Zhu Z, Guo R, Li Y, et al. Comparison of three analytical methods for superoxide produced by activated immune cells. Journal of Pharmacological and Toxicological Methods. 2020;101:106637. DOI: https://doi.org/10.1016/j.vascn.2019.106637Norelli M, Camisa B, Barbiera G, et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nature Medicine. 2018;24(6):739-748. DOI: https://doi.org/10.1038/s41591-018-0036-4Mukhara D, Oh U, Neigh GN. Neuroinflammation. Handbook of Clinical Neurology. 2020;175:235-259. DOI: https://doi.org/10.1016/B978-0-444-64123-6.00017-5Yang L, Zhou R, Tong Y, et al. Neuroprotection by dihydrotestosterone in LPS-induced neuroinflammation. Neurobiology of Disease. 2020;140:104814. DOI: https://doi.org/10.1016/j.nbd.2020.104814Alhadidi Q, Shah ZA. Cofilin Mediates LPS-Induced Microglial Cell Activation and Associated Neurotoxicity Through Activation of NF-&kappa;B and JAK-STAT Pathway. Molecular Neurobiology. 2018;55(2):1676-1691. DOI: https://doi.org/10.1007/s12035-017-0432-7Park J, Min JS, Kim B, et al. Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-&kappa;B pathways. Neuroscience Letters. 2015;584:191-6. DOI: https://doi.org/10.1016/j.neulet.2014.10.016Cadenas S. Mitochondrial uncoupling, ROS generation and cardioprotection. Biochimica et Biophysica Acta (BBA) - Bioenergetics. 2018;1859(9):940-950. DOI: https://doi.org/10.1016/j.bbabio.2018.05.019Zhao RZ, Jiang S, Zhang L, et al. Mitochondrial electron transport chain, ROS generation and uncoupling (Review). International Journal of Molecular Medicine. 2019;44(1):3-15. DOI: https://doi.org/10.3892/ijmm.2019.4188Jornayvaz FR, Shulman GI. Regulation of mitochondrial biogenesis. Essays in Biochemistry. 2010;47:69-84. DOI: https://doi.org/10.1042/bse0470069Stetler RA, Leak RK, Yin W, et al. Mitochondrial biogenesis contributes to ischemic neuroprotection afforded by LPS pre-conditioning. Journal of Neurochemistry. 2012;123(S2):125-37. DOI: https://doi.org/10.1111/j.1471-4159.2012.07951.xOganesyan ET, Shatokhin S. The use of quantum-chemical parameters for predicting the antiradical (but&middot;) activity of related structures containing a cinnamoyl fragment. III. chalcones, flavonones and flavones with the phloroglucin type of the &quot;A&quot; ring. Pharmacy &amp; Pharmacology. 2020;8(6):446-455. DOI: https://doi.org/10.19163/2307-9266-2020-8-6-446-455