Oxidative stress in the pathogenesis of stroke and its correction

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We reviewed the role of oxidative stress (OS) in the pathogenesis of ischemic (IS) and hemorrhagic stroke (HS). OS plays a major role in programmed cell death, increased permeability of the blood-brain barrier, astroglial and microglial activation, and local inflammatory response. We also reviewed the current state of neuro- and cytoprotection studies and their translation in clinical practice. With respect to experimental and clinical data the efficacy of long term administration of multimodal cytoprotective drug with antioxidant effect — ethylmethylhydroxypyridine succinate (Mexidol) is discussed during the acute and early recovery period after stroke.

Keywords:

stroke

reperfusion

oxidative stress

programmed cell death

ethylmethylhydroxypyridine succinate

Mexidol

Authors:

M.V. Zhuravleva

I.M. Sechenov First Moscow State Medical University (Sechenov University);
Scientific Centre of Medical Application Expertise of the Ministry of the Healthcare of the Russian Federation

ORCID: 0000-0002-9198-8661

N.S. Vasyukova

Federal Scientific Center-all-Russian Research Skriabin and Kovalenko Institute of Experimental Veterinary Medicine the Russian Academy of Sciences

E.V. Kuznetsova

Research Institute for Healthcare and Medical Management

T.R. Kameneva

Konchalovsky City Clinical Hospital

Received:

16.01.2023

Accepted:

17.01.2023

List of references:

GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990—2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol. 2021;20(10):795-820. https://doi.org/10.1016/S1474-4422(21)00252-0
Bai J, Tan R, An Z, Xu Y. Quantitative estimation of intracellular oxidative stress in human tissues. Brief Bioinform. 2022;23(4):bbac206. https://doi.org/10.1093/bib/bbac206
Tauffenberger A, Magistretti PJ. Reactive oxygen species: beyond their reactive behavior. Neurochem Res. 2021;46(1):77-87. https://doi.org/10.1007/s11064-020-03208-7
Herculano-Houzel S. Scaling of brain metabolism with a fixed energy budget per neuron: implications for neuronal activity, plasticity and evolution. PLoS One. 2011;6(3):e17514. https://doi.org/10.1371/journal.pone.0017514
Dienel GA, Rothman DL. Reevaluation of astrocyte-neuron energy metabolism with astrocyte volume fraction correction: impact on cellular glucose oxidation rates, glutamate-glutamine cycle energetics, glycogen levels and utilization rates vs. exercising muscle, and Na+/K+ pumping rates. Neurochem Res. 2020;45(11):2607-2630. https://doi.org/10.1007/s11064-020-03125-9
Allen CL, Bayraktutan U. Oxidative stress and its role in the pathogenesis of ischaemic stroke. Int J Stroke. 2009;4(6):461-70. https://doi.org/10.1111/j.1747-4949.2009.00387.x
Wang Z, Wei X, Liu K, et al. NOX2 deficiency ameliorates cerebral injury through reduction of complexin II-mediated glutamate excitotoxicity in experimental stroke. Free Radic Biol Med. 2013;65:942-951. https://doi.org/10.1016/j.freeradbiomed.2013.08.166
Mancuso C, Barone E, Guido P, et al. Inhibition of lipid peroxidation and protein oxidation by endogenous and exogenous antioxidants in rat brain microsomes in vitro. Neurosci Lett. 2012;518(2):101-105. https://doi.org/10.1016/j.neulet.2012.04.062
Walther J, Kirsch EM, Hellwig L, et al. Reinventing the penumbra — the emerging clockwork of a multi-modal mechanistic paradigm. Transl Stroke Res. 2022. Epub ahead of print. https://doi.org/10.1007/s12975-022-01090-9
Takagi K, Ginsberg MD, Globus MY, et al. Changes in amino acid neurotransmitters and cerebral blood flow in the ischemic penumbral region following middle cerebral artery occlusion in the rat: correlation with histopathology. J Cereb Blood Flow Metab. 1993;13(4):575-585. https://doi.org/10.1038/jcbfm.1993.75
Abramov AY, Scorziello A, Duchen MR. Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation. J Neurosci. 2007;27(5):1129-1138. https://doi.org/10.1523/JNEUROSCI.4468-06.2007
Rao AM, Hatcher JF, Kindy MS, Dempsey RJ. Arachidonic acid and leukotriene C4: role in transient cerebral ischemia of gerbils. Neurochem Res. 1999;24(10):1225-1232. https://doi.org/10.1023/a:1020916905312
Li Z, Bi R, Sun S, et al. The role of oxidative stress in acute ischemic stroke-related thrombosis. Oxid Med Cell Longev. 2022;2022:8418820. https://doi.org/10.1155/2022/8418820
Sun MS, Jin H, Sun X, et al. Free radical damage in ischemia-reperfusion injury: an obstacle in acute ischemic stroke after revascularization therapy. Oxid Med Cell Longev. 2018;2018:3804979. https://doi.org/10.1155/2018/3804979
Lu H, Hu H, He Z, et al. Therapeutic imaging window of cerebral infarction revealed by multisequence magnetic resonance imaging: An animal and clinical study. Neural Regen Res. 2012;7(31):2446-2455. https://doi.org/10.3969/j.issn.1673-5374.2012.31.006
Karki P, Birukov KG. Rho and reactive oxygen species at crossroads of endothelial permeability and inflammation. Antioxid Redox Signal. 2019;31(13):1009-1022. https://doi.org/10.1089/ars.2019.7798
Morotti A, Busto G, Bernardoni A, et al. Comparison of perihematomal perfusion in deep and lobar intracerebral hemorrhage. Neuroradiol. 2020;62(2):257-261. https://doi.org/10.1007/s00234-019-02331-9
Murthy SB, Cho SM, Gupta A, et al. A pooled analysis of diffusion-weighted imaging lesions in patients with acute intracerebral hemorrhage. JAMA Neurol. 2020;77(11):1390-1397. https://doi.org/10.1001/jamaneurol.2020.2349
Wang Z, Zhou F, Dou Y, et al. Melatonin alleviates intracerebral hemorrhage-induced secondary brain injury in rats via suppressing apoptosis, inflammation, oxidative stress, DNA damage, and mitochondria injury. Transl Stroke Res. 2018;9(1):74-91. https://doi.org/10.1007/s12975-017-0559-x
Gu Y, Yang S. Effects of hemoglobin on the expression and distribution of inducible nitric oxide synthase after intracerebral hemorrhage. Zhonghua Yi Xue Za Zhi. 2014;94(36):2857-2860.
Regan RF, Chen J, Benvenisti-Zarom L. Heme oxygenase-2 gene deletion attenuates oxidative stress in neurons exposed to extracellular hemin. BMC Neurosci. 2004;5:34. https://doi.org/10.1186/1471-2202-5-34
Zille M, Karuppagounder SS, Chen Y, et al. Neuronal death after hemorrhagic stroke in vitro and in vivo shares features of ferroptosis and necroptosis. Stroke. 2017;48(4):1033-1043. https://doi.org/10.1161/STROKEAHA.116.015609
Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060-1072. https://doi.org/10.1016/j.cell.2012.03.042
Zhou SY, Cui GZ, Yan XL, et al. Mechanism of ferroptosis and its relationships with other types of programmed cell death: insights for potential interventions after intracerebral hemorrhage. Front Neurosci. 2020;14:589042. https://doi.org/10.3389/fnins.2020.589042
Choi SH, Lee DY, Kim SU, et al. Thrombin-induced oxidative stress contributes to the death of hippocampal neurons in vivo: role of microglial NADPH oxidase. J Neurosci. 2005;25(16):4082-4090. https://doi.org/10.1523/JNEUROSCI.4306-04.2005
Krenzlin H, Frenz C, Schmitt J, et al. High CSF thrombin concentration and activity is associated with an unfavorable outcome in patients with intracerebral hemorrhage. PLoS One. 2020;15(11):e0241565. https://doi.org/10.1371/journal.pone.0241565
Lee HS, Namkoong K, Kim DH, et al. Hydrogen peroxide-induced alterations of tight junction proteins in bovine brain microvascular endothelial cells. Microvasc Res. 2004;68(3):231-238. https://doi.org/10.1016/j.mvr.2004.07.005
McCaffrey G, Willis CL, Staatz A, et al. Occludin oligomeric assemblies at tight junctions of the blood-brain barrier are altered by hypoxia and reoxygenation stress. J Neurochem. 2009;110(1):58-71. https://doi.org/10.1111/j.1471-4159.2009.06113.x
Fang Y, Gao S, Wang X, et al. Programmed cell deaths and potential crosstalk with blood-brain barrier dysfunction after hemorrhagic stroke. Front Cell Neurosci. 2020;14:68. https://doi.org/10.3389/fncel.2020.00068
Wang R, Zhu Y, Liu Z, et al. Neutrophil extracellular traps promote tPA-induced brain hemorrhage via cGAS in mice with stroke. Blood. 2021;138(1):91-103. https://doi.org/10.1182/blood.2020008913
Guo Y, Dong L, Gong A, et al. Damage to the blood-brain barrier and activation of neuroinflammation by focal cerebral ischemia under hyperglycemic condition. Int J Mol Med. 2021;48(1):142. https://doi.org/10.3892/ijmm.2021.4975
Zhang M, Mao Y, Ramirez SH, et al. Angiotensin II induced cerebral microvascular inflammation and increased blood-brain barrier permeability via oxidative stress. Neuroscience. 2010;171(3):852-858. https://doi.org/10.1016/j.neuroscience.2010.09.029
Berge E, Whiteley W, Audebert H, et al. European Stroke Organisation (ESO) guidelines on intravenous thrombolysis for acute ischaemic stroke. Eur Stroke J. 2021;6(1):I-LXII. https://doi.org/10.1177/2396987321989865
Xia Z, Wu X, Li J, et al. Minimally invasive surgery is superior to conventional craniotomy in patients with spontaneous supratentorial intracerebral hemorrhage: a systematic review and meta-analysis. World Neurosurg. 2018;115:266-273. https://doi.org/10.1016/j.wneu.2018.04.181
Piradov MA, Gulevskaya TS, Gnedovskaya EV, et al. Multiple organ dysfunction syndrome in severe stroke: clinic-morphological study. Neurological journal. 2006;11(5):9-13. (In Russ.).
Qin W, Zhang X, Yang S, et al. Risk factors for multiple organ dysfunction syndrome in severe stroke patients. PLoS One. 2016;11(11):e0167189. https://doi.org/10.1371/journal.pone.0167189
Chamorro Á, Dirnagl U, Urra X, Planas AM. Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation. Lancet Neurol. 2016;15(8):869-881. https://doi.org/10.1016/S1474-4422(16)00114-9
Ikeda S, Harada K, Ohwatashi A, et al. Effects of edaravone, a free radical scavenger, on photochemically induced cerebral infarction in a rat hemiplegic model. Sci World J. 2013;2013:175280. https://doi.org/10.1155/2013/175280
Weisbrot-Lefkowitz M, Reuhl K, Perry B, et al. Overexpression of human glutathione peroxidase protects transgenic mice against focal cerebral ischemia/reperfusion damage. Brain Res Mol Brain Res. 1998;53(1-2):333-338. https://doi.org/10.1016/s0169-328x(97)00313-6
Sheng H, Bart RD, Oury TD, et al. Mice overexpressing extracellular superoxide dismutase have increased resistance to focal cerebral ischemia. Neuroscience. 1999;88(1):185-191. https://doi.org/10.1016/s0306-4522(98)00208-5
Paul S, Candelario-Jalil E. Emerging neuroprotective strategies for the treatment of ischemic stroke: An overview of clinical and preclinical studies. Exp Neurol. 2021;335:113518. https://doi.org/10.1016/j.expneurol.2020.113518
Duan R, Sun K, Fang F, et al. An ischemia-homing bioengineered nano-scavenger for specifically alleviating multiple pathogeneses in ischemic stroke. J Nanobiotech. 2022;20(1):397. https://doi.org/10.1186/s12951-022-01602-7
Rumiantseva SA, Fedin AI, Bolevich SB, et al. Effect of early correction of energy and free-radical homeostasis on the clinical-morphological presentation of cerebral infarction. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2010;110(8):16-21. (In Russ.).
Kulai NS, Kovalchuk EYu. Assessment of the efficacy of Mexidol in the combination with hyperbaric oxygen in acute ischemic stroke. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2018;118(3-2):69-72. (In Russ.). https://doi.org/10.17116/jnevro20181183269-72
O’Collins VE, Macleod MR, Donnan GA, Howells DW. Evaluation of combination therapy in animal models of cerebral ischemia. J Cereb Blood Flow Metab. 2012;32(4):585-597. https://doi.org/10.1038/jcbfm.2011.203
Chefranova ZhYu, Makotrova TA, Udachin VA, Koledintseva EV. Efficacy of Mexidol in the combination with thrombolytic therapy in patients with ischemic stroke. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2012;112(4):49-52. (In Russ.).
Voronina TA. Mexidol: the spectrum of pharmacological effects. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2012;112(12):86-90. (In Russ.).
Bolezni mozga: translyatsionnye, klinicheskie i sotsial’nye aspekty. Gusev EI, Guekht AB, eds. M.: OOO «Sam Poligrafist»; 2020;496 s.
Shchulkin AV. A modern concept of antihypoxic and antioxidant effects of Mexidol. Zhurnal Nevrologii i Psikhiatrii im. S.S. Korsakova. 2018;118(12-2):87-93. (In Russ.). https://doi.org/10.17116/jnevro201811812287
Shchulkin AV, Yakusheva EN, Chernykh IV. The distribution of Mexidol in the rat’s brain and its subcellular fractions. Zhurnal Nevrologii i Psikhiatrii im. S.S. Korsakova. 2014;114(8):70-73. (In Russ.).
Kirova YuI, Shakova FM, Germanova EL, et al. The effect of Mexidol on cerebral mitochondriogenesis at a young age and during aging. Zhurnal Nevrologii i Psikhiatrii im. S.S. Korsakova. 2020;120(1):62-69. (In Russ.). https://doi.org/10.17116/jnevro202012001162
Yakusheva EN, Mylnikov PYu, Chernykh IV, Shchulkin AV. Mexidol effect on the factor induced by hypoxia HIF-1α expression in the rat cerebral cortex in ischemia. Zhurnal Nevrologii i Psikhiatrii im. S.S. Korsakova. 2017;117(10):87-91. (In Russ.). https://doi.org/10.17116/jnevro201711710187-91
Yakusheva EN, Mylnikov PYu, Chernykh IV, Shchulkin AV. An effect of Mexidol on the expression of the transcription factor Nrf2 in the rat cerebral cortex in ischemia. Zhurnal Nevrologii i Psikhiatrii im. S.S. Korsakova. 2018;118(5):64-68. (In Russ.). https://doi.org/10.17116/jnevro20181185164
Pan Z, Ma G, Kong L, Du G. Hypoxia-inducible factor-1: Regulatory mechanisms and drug development in stroke. Pharmacol Res. 2021;170:105742. https://doi.org/10.1016/j.phrs.2021.105742
Farina M, Vieira LE, Buttari B, et al. The Nrf2 pathway in ischemic stroke: a review. Molecules. 2021;26(16):5001. https://doi.org/10.3390/molecules26165001.
Shchulkin AV. Effect of Mexidol on the development of the phenomenon of the neuronal excitotoxicity in vitro. Zhurnal Nevrologii i Psikhiatrii im. S.S. Korsakova. 2012;112(2):35-39. (In Russ.).
Gromova OA, Torshin IIu, Stel’mashuk EV, et al. A study of the neuroprotective effect of Mexidol on the cell model of glutamate stress. Zhurnal Nevrologii i Psikhiatrii im. S.S. Korsakova. 2017;117(12):71-77. (In Russ.). https://doi.org/10.17116/jnevro201711712171-77
Shchul’kin AV, Abalenikhina YuV, Erokhina PD, Yakusheva EN. Antioxidant activity and toxicity of Ethyl-Methyl-Hydroxypyridine Succinate and Edaravone: comparative in vitro experiment. Experimental and clinical pharmacology. 2021;84(11):9-12. (In Russ.). https://doi.org/10.30906/0869-2092-2021-84-11-9-12
Shavarova EK, Cazakhmedov ER, Alekseeva MV, et al. Role of antioxidant therapy in patients with moderate and severe COVID-19. Infekc. bolezni (Infectious diseases). 2021;19(1):159-164. (In Russ.). https://doi.org/10.20953/1729-9225-2021-1-159-164
Izhbul’dina GI. Changes in the hemostasis system and free-radical lipid oxidation in the acute stage of ischemic stroke in patients on neuroprotection treatment. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2012;112(3-2):31-37. (In Russ.).
Novikova LB, Sharafutdinova LR, Sharapova KM. The use of Mexidol in acute period of ischemic stroke. Zhurnal nevrologii i psikhiatrii im- S.S. Korsakova. 2013;113(9):83-85. (In Russ.).
Shchepankevich LA, Nikolaev YuA, Dolgova NA, Chipova DT. Optimization of hypolipidemic therapy in patients with ischemic stroke and diabetes mellitus. Zhurnal Nevrologii i Psikhiatrii im. S.S. Korsakova. 2016;116(2):42-45. (In Russ.). https://doi.org/10.17116/jnevro20161162142-45
Godunova AR, Rakhimova AA, Leontyeva OI, et al. An influence of submaximal doses of Mexidol on oxidant stress and inflammation in the acute period of ischemic stroke. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2018;118(2):27-30. (In Russ.). https://doi.org/10.17116/jnevro20181182127-30
Skvortsova VI, Stakhovskaya LV, Nartsyssov YaR, et al. The randomized double-blind placebo-controlled study of efficacy and safety of Mexidol in the complex therapy of ischemic stroke in the acute period. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2006;106(18):47-53. (In Russ.).
Lutskiĭ MA. An analysis of Mexidol efficacy in the complex treatment of patients with ischemic stroke. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2010;110(4-2):57-59. (In Russ.).
Fedin AI, Evseev VN, Kuznetsov OR, Rumiantseva SA. Antioxidant treatment in ischemic stroke: clinic-electophysiological correlations. Russian Medical Journal. 2009;17(5):332-334. (In Russ.).
Odinak MM, Yanishevskiĭ SN, Tsygan NV, et al. The use of succinates for the correction of metabolic disorders in the penumbra in patients with stroke. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2013;113(2):12-17. (In Russ).
Stakhovskaya LV, Shamalov NA, Khasanova DR, et al. Results of a randomized double blind multicenter placebo-controlled, in parallel groups trial of the efficacy and safety of prolonged sequential therapy with Mexidol in the acute and early recovery stages of hemispheric ischemic stroke (EPICA). Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2017;117(3-2):55-65. (In Russ.). https://doi.org/10.17116/jnevro20171173255-65
Loskutnikov MA, Domashenko MA, Vakin TM, et al. The trial of the efficacy and safety of sequential therapy with Mexidol forte 250 in acute and early recovery stages of hemispheric ischemic stroke. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2020;120(10):22-26. (In Russ.). https://doi.org/10.17116/jnevro202012010122
Strelnikova IA, Svetkina AA, Androfagina OV. The efficacy and safety of Mexidol Forte 250 as part of long-term sequential therapy in patients with carotid stroke. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2020;120(3-2):54-58. (In Russ.). https://doi.org/10.17116/jnevro202012003254
Golovkin VI, Mametveliev MA, Kuzyeva FYa, Gulak DA. The efficacy and safety of Ethyl-Methyl-Hydroxypyridine Succinate in sequential therapy of ischemic stroke in elderly patients. Proceedings of the International Congress «XXII Davidenkov’s readings». 2020;12-20. (In Russ.).
Seregin VI, Dronova TV. The use of Mexidol in the intensive treatment of acute severe ischemic stroke. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2015;115(3-2):85-87. (In Russ.). https://doi.org/10.17116/jnevro20151153285-87
Musin SgG. Experience of Mexidol using in thrombolytic therapy of ischemic stroke. Bulletin of Experimental Biology and Medicine. 2012;1:37-41. (In Russ.).