Chromon-3-aldehyde derivatives restore mitochondrial function in rat cerebral ischemia

Document Type: Original Article


1 Department of Pharmacology Pyatigorsk Medical Pharmaceutical Institute, Pyatigorsk, Russia

2 Department of Organic Chemistry, Pyatigorsk Medical Pharmaceutical Institute, Pyatigorsk, Russia



Objective(s): This work aimed to assess the effect of 10 new chromon-3-aldehyde derivatives on changes of mitochondrial function under the conditions of brain ischemia in rats.
Materials and Methods: The work was executed on BALB/c male-mice (acute toxicity was evaluated) and male Wistar rats, which were used to model cerebral ischemia by permanent middle cerebral artery occlusion. The test-substances, 10 derivatives of chromon-3-aldehyde and the reference drug, N-acetylcysteine, were injected after modeling of ischemia for 3 days. After that, neurological symptoms, the area of cerebral infarction, and change in mitochondrial function were evaluated.
Results: It was established that use of all chromon-3-aldehyde derivatives contributed to the recovery of mitochondrial function, which was reflected in enhanced ATP-generating activity, maximum respiration level, respiratory capacity, as well as reduction in the intensity of anaerobic reactions, apoptosis, and normalization of the mitochondrial membrane potential. The most pronounced changes were noted with the use of 6-acetyl substituted chromon-3-aldehyde derivative, the administration of which decreased neurological symptoms and size of brain necrosis area.
Conclusion: The obtained data may indicate the most pronounced neurotropic effect in a number of test-objects has the 6-acetyl substituted derivative of chromon-3 aldehyde, realized by restoration of mitochondrial function, which may be the basis for further study of chromon-3-aldehyde derivatives.


1. Feigin VL, Krishnamurthi RV, Parmar P, Norrving B, Mensah GA, Bennett DA, et al. Update on the global burden of ischemic and hemorrhagic stroke in 1990-2013: the GBD 2013 study. Neuroepidemiology 2015;45:161–176.
2.    Wang W, Jiang B, Sun H, Ru X, Sun D, Wang L, et al. Prevalence, incidence, and mortality of stroke in China: results from a nationwide population-based survey of 480 687 adults. Circ 2017; 135:759-771.
3.    Hankey GJ. Stroke. Lancet 2017; 389:641-654.
4.    Alawieh A, Elvington A, Zhu H, Yu J, Kindy MS, Atkinson C, et al. Modulation of post-stroke degenerative and regenerative processes and subacute protection by site-targeted inhibition of the alternative pathway of complement. J Neuroinflammation 2015;12:247-263.
5.    Ham PB, Raju R. Mitochondrial function in hypoxic ischemic injury and influence of aging. Prog Neurobiol 2017;157:92–116.
6.    Moskowitz MA, Lo EH, Iadecola C. The science of stroke: mechanisms in search of treatments. Neuron 2010;67:181–198.
7.    Yang JL, Mukda S, Chen SD. Diverse roles of mitochondria in ischemic stroke. Redox Biol 2018;16:263–275.
8.    Niizuma K, Yoshioka H, Chen H, Kim GS, Jung JE, Katsu M,, et al. Mitochondrial and apoptotic neuronal death signaling pathways in cerebral ischemia. Biochim Biophys Acta 2010;1802:92–99.
9.    Gu Z, Nakamura T, Lipton SA. Redox reactions induced by nitrosative stress mediate protein misfolding and mitochondrial dysfunction in neurodegenerative diseases. Mol Neurobiol 2010;41:55–72.
10.    Leist M, Single B, Castoldi AF, Kühnle S, Nicotera P. Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J Exp Med 1997;185:1481–1486.
11.    Crompton M. Mitochondrial intermembrane junctional complexes and their role in cell death. J Physiol 2000;529 Pt 1(Pt 1):11–21.
12.    Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, et al. Cytochrome c and datp-dependent formation of apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997;91:479–489.
13.    Culmsee C, Zhu C, Landshamer S, Becattini B, Wagner E, Pellecchia M, et al. Apoptosis-inducing factor triggered by poly(ADP-ribose) polymerase and Bid mediates neuronal cell death after oxygen-glucose deprivation and focal cerebral ischemia. J Neurosci 2005;25:10262–10272.
14.    Plesnila N, Zhu C, Culmsee C, Groger M, Moskowitz MA, Blomgren K. Nuclear translocation of apoptosis-inducing factor after focal cerebral ischemia. J Cereb Blood Flow Metab 2004;24:458–466.
15.    Demetgül C, Beyazit N. Synthesis, characterization and antioxidant activity of chitosan-chromone derivatives. Carb polymers 2018;181: 812-817.
16.    Li W, Li J, Shen H, Cheng J, Li Z, Xu X. Synthesis, nematicidal activity and docking study of novel chromone derivatives containing substituted pyrazole Chin Chem Lett 2018;29: 911-914.
17.    Wang G, Chen M, Wang J, Pen Y, Li L, Xie ZZ, et al. Synthesis, biological evaluation and molecular docking studies of chromone hydrazone derivatives as α-glucosidase inhibitors. Bioorg Med Chem Lett 2017;27: 2957-2961.
18.    Ungwitayatorn J, Wiwat C, Samee W, Nunthanavanit P, Phosrithong N. Synthesis, in vitro evaluation, and docking studies of novel chromone derivatives as HIV-1 protease inhibitor. J Mol Str 2011; 1001: 152-161.
19.    Li F, Wu JJ, Wang J, Yang X-L, Cai P, Liu Q-H, et al. Synthesis and pharmacological evaluation of novel chromone derivatives as balanced multifunctional agents against Alzheimer’s disease. Bioorg Med Chem 2017;25:3815-3826.
20.    Voronkov AV, Pozdnyakov DI, Rukovitsyna VM, Veselova OF, Olokhova EA. –°hromone-3-aldehyde derivatives improve muscle function by suppressing the formation of apoptosis-inducing factor Pharmacologyonline 2019;1;429-437.
21.    Voronkov AV, Pozdnyakov DI, RukovitsynaVM, Veselova OF, Olokhova EA, Oganesyan ET. Antiradical and chelating properties of chromon-3- aldehyde derivatives. Eksp & Klin Farm. 2019; 82: 32-35.
22.    Rukovitsina VM, Pozdnyakov DI. Chromon-3-aldehyde derivatives possessing anti-ischemic activity. Belikov Meetings. Book of abstracts. RIA-CMW inc; 2018. p 53-56. (in Russian).
23.    Pozdnyakov DI, Nygaryan SA, Voronkov AV, Sosnovskaya AV, Sherechkova EI. Ethylmethylhydroxypyridine succinate, acetylcysteine and choline alphoscerate improve mitochondrial function under condition of cerebral ischemia in rat. Bangladesh J Pharmacol 2019; 14: 152-158.
24.    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;1:53–60.
25.    McGraw KP, Pashayan AG, Wendel OT. Brain Infarction in Mongolian gerbil worsened in the treatment of phenoxybenzamine. Stroke 1976; 7: 485- 488
26.    Pozdnyakov DI., Voronkov AV., Miroshnichenko KA., Adzhiahmetova SL., Chervonnaya NM., Rukovitcina VM. Pyrimidine-4H-1OH derivatives restore mitochondrial function in experimental chronic traumatic encephalopathy. Pharmacologyonline2019;3:36-45
27.    Patel SP, Sullivan PG, Pandya JD, Goldstein GA, VanRooyen JL, Yonutas HM, et al. N-acetylcysteine amide preserves mitochondrial bioenergetics and improves functional recovery following spinal trauma. Exp Neurol. 2014;257:95-105.
28.    He F. Bradford Protein Assay Bio-101: e45.
29.    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 Eksp & Klin Farm. 2015;78. 10-4.
30.    Dixon WJ. Staircase Bioassay: The Up-and-Down Method. Neurosci. Biobehav Rev1991; 15, 47-50.
31.    Globally Harmonized System of Classification and Labelling of Chemicals (GHS) Part 3 Health Hazards, United Nations, 2017.
32.    Liu F, Lu J, Manaenko A, Tang J, Hu Q. Mitochondria in ischemic stroke: new insight and implications. Aging Dis 2018;9:924–937.
33.    Chandel NS. Evolution of mitochondria as signaling organelles. Cell Metab 2015;22:204–206.
34.    Viscomi C, Bottani E, Zeviani M. Emerging concepts in the therapy of mitochondrial disease. Biochim Biophys Acta 2015;1847:544–557.
35.    Heller A, Brockhoff G, Goepferich A. Targeting drugs to mitochondria. Eur J Pharm Biopharm 2012;82:1–18.
36.    Zhao K, Zhao GM, Wu D, Soong Y, Birk AV, Schiller PW, et al. Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. J Biol Chem2004;279: 34682-34690.
37.    Borchert A, Wilichowski E, Hanefeld F. Supplementation with creatine monohydrate in children with mitochondrial encephalomyopathies. Muscle Nerve 1999;22:1299–1300.
38.    Widmeier E. Treatment with 2, 4-Dihydroxybenzoic Acid Prevents FSGS Progression and Renal Fibrosis in Podocyte-Specific Coq6 Knockout Mice. J Am Soc Nephrol 2019;30:393-405.
39.    Kanabus M, Heales SJ, Rahman S. Development of pharmacological strategies for mitochondrial disorders. Br J Pharmacol 2014;171:1798–1817.
40.    Lu N, Wang B, Deng X, Zhao H, Wang Y, Li D. Autophagy occurs within an hour of adenosine triphosphate treatment after nerve cell damage: the neuroprotective effects of adenosine triphosphate against apoptosis. Neural Regen Res 2014;9:1599–1605.
41.    Yadav N, Kumar S, Marlowe T, Chaudhary AK, Kumar R, Wang J, et al. Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents. Cell Death Dis 2015;6:e1969.
42.    Rottenberg H, Hoek JB. The path from mitochondrial ROS to aging runs through the mitochondrial permeability transition pore. Aging Cell 2017;16:943–955.
43.    Hurst S, Hoek J, Sheu SS. Mitochondrial Ca2+ and regulation of the permeability transition pore. J Bioenerg Biomembr 2017;49:27–47.
44.    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;293:9784–9800.
45.    Milasta S, Dillon CP, Sturm OE, Verbist KC, Brewer TL, Qarato G. et al. Apoptosis-Inducing-Factor-Dependent Mitochondrial Function Is Required for T Cell but Not B Cell Function. Immunity 2016;44:88–102.
46.    Voronkov AV, Pozdnyakov DI, Rukovitsina VM, Oganesyan ET. Antioxidant activity of new chromon-3-aldehyde derivatives under conditions of muscular dysfunction. Issues of Bio Med and Pharm Chem 2018;21: 38-42.
47.    Kawase M, Tanaka T, Kan H, Tani S, Nakashima H, Sakagami H. Biological activity of 3-formylchromones and related compounds. In Vivo2007 ;21:829-834.
48.    Sakagami H, Shimada C, Kanda Y, Amano O, Sugimoto M, Ota S, et al. Effects of 3-styrylchromones on metabolic profiles and cell death in oral squamous cell carcinoma cells. Toxicol Rep 2015;2:1281–1290.
49.    Zhang Y, Zheng K, Yan H, Jin G, Shao C, Zhou X, et al. Growth inhibition and apoptosis induced by 6-fluoro-3-formylchromone in hepatocellular. BMC Gastroenterol 2014;14:62-66.