Current methods of improving thrombolytic therapy in patients with acute ischemic stroke

8 травня 2023
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Спеціальності :
Резюме

Recanalization therapy is increasingly used in the treatment of acute ischemic stroke. However, in about one third of these patients, recanalization is followed by ischemia/reperfusion injuries, and clinically to worsening of the neurological status. Much research has focused on unraveling the involved mechanisms in order to prevent or efficiently treat these injuries. What we know so far is that oxidative stress and mitochondrial dysfunction are significantly involved in the pathogenesis of ischemia/reperfusion injury. However, despite promising results obtained in experimental research, clinical studies trying to interfere with the oxidative pathways have mostly failed. The current article discusses the main mechanisms leading to ischemia/reperfusion injuries, such as mitochondrial dysfunction, excitotoxicity, and oxidative stress, and reviews the clinical trials with antioxidant molecules highlighting recent developments and future strategies.

References

  • 1. Feigin V.L., Lawes C.M., Bennett D.A. et al. (2009) Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol., 8: 355–369.
  • 2. Danaei G., Finucane M.M., Lu Y. et al. (2011) National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980s: Systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. Lancet, 378: 31–40.
  • 3. NCD Risk Factor Collaboration (NCD-RisC) (2016) Trends in adult body mass index in 200 countries from 1975 to 2014: A pooled analysis of 1698 population-based measurement studies with 19.2 million participants. Lancet, 387: 1377–1396.
  • 4. Li L., Scott C.A., Rothwell P.M.; on behalf of the Oxford Vascular Study (2020) Trends in stroke incidence in high-income countries in the 21st century. Population-based study and systematic review. Stroke, 51: 1372–1380.
  • 5. The National Institute of Neurological Disorders and Stroke rt-PA Study Group (1995) Tissue plasminogen activator for acute ischemic stroke. N. Engl. J. Med., 333: 1581–1588.
  • 6. Hacke W., Kaste M., Bluhmki E. et al. (2008) Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N. Engl. J. Med., 359: 1317–1329.
  • 7. Furlan A., Higashida R., Wechsler L. et al. (1999) Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: A randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA, 282: 2003–2011.
  • 8. Alexandrov A.V., Köhrmann M., Soinne L. et al. (2019) Safety and efficacy of sonothrombolysis for acute ischaemic stroke: A multicentre, double-blind, phase 3, randomised controlled trial. Lancet Neurol., 18: 338–347.
  • 9. Smith W.S., Sung G., Starkman S. et al. (2005) Safety and efficacy of mechanical embolectomy in acute ischemic stroke: Results of the MERCI trial. Stroke, 36: 1432–1438.
  • 10. Powers W.J., Rabinstein A.A., Ackerson T. et al. (2019) Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of patients with acute ischemic stroke: A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke, 50: e344–e418.
  • 11. De Sousa D.A., von Martial R., Abilleira S. et al. (2019) Access to and delivery of acute ischaemic stroke treatments: A survey of national scientific societies and stroke experts in 44 European countries. Eur. Stroke J., 4: 13–28.
  • 12. Rha J.-H., Saver J.L. (2007) The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke, 38: 967–973.
  • 13. Jurcau A., Ardelean I.A. (2021) Molecular pathophysiological mechanisms of ischemia/reperfusion injuries after recanalization therapy for acute ischemic stroke. J. Integr. Neurosci., 20: 727–744.
  • 14. Pizzino G., Irrera N., Cucinotta M. et al. (2017) Oxidative stress: Harms and benefits for human health. Oxidative Med. Cell Longev, 2017: 8416763.
  • 15. Kalogeris T., Baines C.P., Krenz M., Korthuis R.J. (2012) Cell biology of ischemia/reperfusion injury. Int. Rev. Cell. Mol. Biol., 298: 229–317.
  • 16. Simion A., Jurcau A. (2019) The role of antioxidant treatment in acute ischemic stroke: Past, present and future. Neurol. Res. Surg., 2: 1–7.
  • 17. Cobley J.N., Fiorello M.L., Bailey D.M. (2018) 13 reasons why the brain is susceptible to oxidative stress. Redox Biol., 15: 490–503.
  • 18. Jurcau A., Simion A. (2021) Cognition, Statins, and Cholesterol in Elderly Ischemic Stroke Patients: A Neurologist’s Perspective. Medicina, 57: 616.
  • 19. Polidori C.M., Cherubini A., Stahl W. et al. (2002) Plasma carotenoid and malondialdehyde levels in ischemic stroke patients: Relationship to early outcome. Free Radic. Res., 36: 265–268.
  • 20. Jurcau A. (2007) The role of antioxidant treatment in acute ischemic stroke: A clinical study. Rom. J. Neurol., 6: 181–188.
  • 21. Menon B., Ramalingam K., Kumar R. (2020) Evaluating the Role of Oxidative Stress in Acute Ischemic Stroke. J., Neurosci. Rural Pract., 11: 156–159.
  • 22. Sun M.-S., Jin H., Sun X. et al. (2018) Free radical damage in ischemia-reperfusion injury: An obstacle in acute ischemic stroke after revascularization therapy. Oxidative Med. Cell Longev., 2018: 3804979.
  • 23. Li W., Yang S. (2016) Targeting oxidative stress for the treatment of ischemic stroke: Upstream and downstream therapeutic strategies. Brain Circ., 2: 153–163.
  • 24. Fucci L., Oliver C.N., Coon M.J., Stadtman E.R. (1983) Inactivation of key metabolic enzymes by mixed-function oxidation reactions: Possible implication in protein turnover and ageing. Proc. Natl. Acad. Sci. USA, 80: 1521–1525.
  • 25. Hall E.D., Braughler J.M. (1989) Central nervous system trauma and stroke. II. Physiological and pharmacological evidence for involvement of oxygen radicals in lipid peroxidation. Free Radic. Biol. Med., 6: 303–313.
  • 26. Cooke M.S., Evans M.D., Dizdaroglu M., Lunec J. (2003) Oxidative DNA damage: Mechanisms, mutation, and disease. FASEB J., 17: 1195–1214.
  • 27. Saito A., Hayashi T., Okuno S. et al. (2005) Modulation of p53 degradation via MDM2-mediated ubiquitylation and the ubiquitin–proteasome system during reperfusion after stroke: Role of oxidative stress. J. Cereb. Blood Flow Metab., 25: 267–280.
  • 28. Vaseva A.V., Marchenko N.D., Ji K. et al. (2012) p53 opens the mitochondrial permeability transition pore to trigger necrosis. Cell, 149: 1536–1548.
  • 29. Davis R.J. (2000) Signal transduction by the JNK group of MAP kinases. Cell, 103: 239–252.
  • 30. Song J., Cho K.J., Cheon S.Y. et al. (2013) Apoptosis signal-regulating kinase 1 (ASK1) is linked to neural stem cell differentiation after ischemic brain injury. Exp. Mol. Med., 45: e69.
  • 31. Russo E., Nguyen H., Lippert T. et al. (2018) Mitochondrial targeting as novel therapy for stroke. Brain Circ., 4: 84–94.
  • 32. Sanderson T.H., Reynolds C.A., Kumar R. et al. (2013) Molecular mechanisms of ischemia-reperfusion injury in brain: Pivotal role of the mitochondrial membrane potential in reactive oxygen species generation. Mol. Neurobiol., 47: 9–23.
  • 33. Ma S., Wang Y., Chen Y., Cao F. (2015) The role of autophagy in myocardial ischemia/reperfusion injury. Biochim. Biophys. Acta BBA Mol. Basis Dis., 1852: 271–276.
  • 34. Fels J.A., Manfredi G. (2019) Sex differences in ischemia/reperfusion injury: The role of mitochondrial permeability transition. Neurochem. Res., 44: 2336–2345.
  • 35. Chen X.-M., Chen H.-S., Xu M.-J., Shen J.-G. (2013) Targeting reactive nitrogen species: A promising therapeutic strategy for cerebral ischemia-reperfusion injury. Acta Pharmacol. Sin., 34: 67–77.
  • 36. Pradeep H., Diya J.B., Shashikumar S., Rajanikat G.K. (2012) Oxidative stress-assassin behind the ischemic stroke. Folia Neuropathol., 50: 219–230.
  • 37. Chang D.I., Hosomi N., Lucero J. et al. (2003) Activation systems for latent matrix metalloproteinase-2 are upregulated immediately after focal cerebral ischemia. J. Cereb. Blood Flow Metab., 23: 1408–1419.
  • 38. Tang X.N., Cairns B., Kim J.Y., Yenari M.A. (2012) NADPH oxidase in stroke and cerebrovascular disease. Neurol. Res., 34: 338–345.
  • 39. Suh S.W., Shin B.S., Ma H. et al. (2008) Glucose and NADPH oxidase drive neuronal superoxide formation in stroke. Ann. Neurol., 64: 654–663.
  • 40. Suzuki G., Okamoto K., Kusano T. et al. (2015) Evaluation of neuronal protective effects of xanthine oxidoreductase inhibitors on severe whole-brain ischemia in mouse model and analysis of xanthine oxidoreductase activity in the mouse brain. Neurol. Med.-Chir., 55: 77–85.
  • 41. Nishino T., Okamoto K., Eger B.T. et al. (2008) Mammalian xanthine oxidoreductase—Mechanism of transition from xanthine dehydrogenase to xanthine oxidase. FEBS J., 275: 3278–3289.
  • 42. Xu X., Zhang L., Ye X. et al. (2018) Nrf2/ARE pathway inhibits ROS-induced NLRP3 inflammasome activation in BV2 cells after cerebral ischemia reperfusion. Inflamm. Res., 67: 57–65.
  • 43. Liu L., Locascio L.M., Doré S. (2019) Critical role of Nrf2 in experimental ischemic stroke. Front. Pharmacol., 10: 153.
  • 44. Nemoto S., Fergusson M.M., Finkel T. (2005) SIRT 1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1α. J. Biol. Chem., 280: 16456–16460.
  • 45. Kalaivani P., Ganesh M., Sathiya S. et al. (2014) Alteration in bioenergetic regulators, SirT1 and Parp1 expression precedes oxidative stress in rats subjected to transient cerebral focal ischemia: Molecular and histopathologic evidences. J. Stroke Cerebrovasc. Dis., 23: 2753–2766.
  • 46. Khoury N., Koronowski K.B., Young J.I. et al. (2018) The NAD+-Dependent Family of Sirtuins in Cerebral Ischemia and Preconditioning. Antioxid. Redox Signal., 28: 691–710.
  • 47. Sundaresan N.R., Gupta M., Kim G. et al. (2009) SIRT 3 blocks the cardiac hypertrophic response by augmenting FOXO3a-dependent antioxidant defense mechanisms in mice. J. Clin. Investig., 119: 2758–2771.
  • 48. Tymianski M. (2017) Combining neuroprotection with endovascular treatment of acute stroke: Is there hope? Stroke, 48: 1700–1705.
  • 49. Campbell B.C.V., Christensen S., Tress B.M. et al. (2013) Failure of collateral blood flow is associated with infarct growth in ischemic stroke. J. Cereb. Blood Flow Metab., 33: 1168–1172.
  • 50. Dávalos A., Blanco M., Pedraza S. et al. (2004) The clinical-DWI mismatch: A new diagnostic approach to the brain tissue at risk of infarction. Neurology, 62: 2187–2192.
  • 51. Schwartz R.H., Bayley M., Lanctôt K.L. et al. (2016) Post-stroke depression, obstructive sleep apnea, and cognitive impairment: Rationale for, and barriers to, routine screening. Int. J. Stroke, 11: 509–518.
  • 52. Myint P.K., Luben R.N., Welch A.A. et al. (2008) Plasma vitamin C concentrations predict risk of incident stroke over 10 y in 20,649 participants of the European Prospective Investigation into Cancer-Norfolk prospective population study. Am. J. Clin. Nutr., 87: 64–69.
  • 53. Zhang X.H., Lei H., Liu A.J. et al. (2011) Increased oxidative stress is responsible for severer cerebral infarction in stroke-prone spontaneously hypertensive rats. CNS Neurosci. Ther., 17: 590–598.
  • 54. Ducruet A.F., Mack W.J., Mocco J. et al. (2011) Preclinical evaluation of postischemic dehydroascorbic acid administration in a large-animal stroke model. Transl. Stroke Res., 2: 399–403.
  • 55. Rabadi M.H., Kristal B.S. (2007) Effect of vitamin C supplementation on stroke recovery: A case-control study. Clin. Interv. Aging, 2: 147–151.
  • 56. Schürks M., Glynn R.J., Rist P.M. et al. (2010) Effects of vitamin E on stroke subtypes: Meta-analysis of randomised controlled trials. Br. J. Med., 341: c5702.
  • 57. Serrander L., Cartier L., Bedard K. et al. (2007) Nox4 activity is determined by MRNA levels and reveals a unique pattern of ROS generation. Biochem. J., 406: 105–114.
  • 58. Shirley R., Ord E.N.J., Work L.M. (2014) Oxidative stress and the use of antioxidants in stroke. Antioxidants, 3: 472–501.
  • 59. Chen H., Song Y.S., Chan P.H. (2009) Inhibition of NADPH oxidase is neuroprotective after ischemia-reperfusion. J. Cerebr. Blood Flow Metab., 29: 1262–1272.
  • 60. Itoh T., Kawakami M., Yamauchi Y. et al. (1986) Effect of allopurinol on ischemia and reperfusion-induced cerebral injury in spontaneously hypertensive rats. Stroke, 17: 1284–1287.
  • 61. Dawson J., Quinn T.J., Harrow C. et al. (2009) The effect of allopurinol on the cerebral vasculature of patients with subcortical stroke; a randomized trial. Br. J. Clin. Pharmacol., 68: 662–668.
  • 62. Zhang J.-F., Zhang Y.-L., Wu Y.-C. (2018) The role of SIRT1 in ischemic stroke: Pathogenesis and therapeutic strategies. Front. Neurosci., 12: 833.
  • 63. Panigrahi M., Sadguna Y., Shivakumar B.R. et al. (1996) Alpha-lipoic acid protects against reperfusion injury following cerebral ischemia in rats. Brain Res., 717: 184–188.
  • 64. Choi K.-H., Park M.-S., Kim H.-S. et al. (2015) Alpha-lipoic acid treatment is neurorestorative and promotes functional recovery after stroke in rats. Mol. Brain, 8: 9.
  • 65. Choi K.-H., Park M.-S., Kim J.-T. et al. (2016) Lipoic acid use and functional outcomes after thrombolysis in patients with acute ischemic stroke and diabetes. PLoS ONE, 11: e0163484.
  • 66. Zhao Z., Cheng M., Maples K.R. et al. (2001) NXY-059, a novel free radical trapping compound, reduces cortical infarction after permanent focal cerebral ischemia in the rat. Brain Res., 909: 46–50.
  • 67. Marshall J.W., Duffin K.J., Green A.R., Ridley R.M. (2001) NXY-059, a free radical-trapping agent, substantially lessens the functional disability resulting from cerebral ischemia in a primate species. Stroke, 32: 190–198.
  • 68. Lees K.R., Zivin J.A., Ashwood T. et al. (2006) NXY-059 for acute ischemic stroke. N. Engl. J. Med., 354: 588–600.
  • 69. Shuaib A., Lees K.R., Lyden P. et al. (2007) NXY-059 for the treatment of acute ischemic stroke. N. Engl. J. Med., 357: 562–571.
  • 70. Sena E., Wheble P., Sandercock P., Macleod M. (2007) Systematic review and meta-analysis of the efficacy of tirilazad in experimental stroke. Stroke, 38: 388–394.
  • 71. Tirilazad International Steering Committee (2000) Tirilazad mesylate in acute ischemic stroke: A systematic review. Stroke, 31: 2257–2262.
  • 72. Khan M., Sekhon B., Jatana M. et al. (2004) Administration of N-acetylcysteine after focal cerebral ischemia protects brain and reduces inflammation in a rat model of experimental stroke. J. Neurosci. Res., 76: 519–527.
  • 73. Reiter R.J., Mayo J.C., Tan D.-X. et al. (2016) Melatonin as an antioxidant: Under promises but over delivers. J. Pineal Res., 61: 253–268.
  • 74. Trovarelli G., de Medio G.E., Dorman R.V. et al. (1981) Effect of cytidine diphosphate choline (CDP-choline) on ischemia-induced alterations of brain lipid in the gerbil. Neurochem. Res., 6: 821–833.
  • 75. Bustamante A., Giralt D., Garcia-Bonilla L. et al. (2012) Citicoline in pre-clinical animal models of stroke: A meat-analysis shows the optimal neuroprotective profile and the missing steps for jumping into a stroke clinical trial. J. Neurochem., 123: 217–225.
  • 76. Dávalos A., Alvarez-Sabín J., Castillo J. et al. (2012) International Citicoline Trial on acUte Stroke (ICTUS) trial investigators. Citicoline in the treatment of acute ischaemic stroke: An international, randomised, multicentre, placebo-controlled study (ICTUS trial). Lancet, 380: 349–357.
  • 77. Higashi Y. (2009) Edaravone for the treatment of acute cerebral infarction: Role of endothelium-derived nitric oxide and oxidative stress. Exp. Opin. Pharmacother., 10: 323–331.
  • 78. Miyamoto S., Ogasawara K., Kuroda S. et al. (2022) Japan Stroke Society Guideline 2021 for the Treatment of Stroke. Int. J. Stroke, 17(9): 1039–1041.
  • 79. Lukic-Panin V., Deguchi K., Yamashita T. et al. (2010) Free radical scavenger edaravone administration protects against tissue plasminogen activator induced oxidative stress and blood brain barrier damage. Curr. Neurovasc. Res., 7: 319–329.
  • 80. Kimura K., Aoki J., Sakamoto Y. et al. (2012) Administration of edaravone, a free radical scavenger, during t-PA infusion can enhance early recanalization in acute stroke patients — a preliminary study. J. Neurol. Sci., 313: 132–136.
  • 81. Enomoto M., Yatsushige H., Fushimi K., Otomo Y. (2019) Clinical effects of early edaravone use in acute ischemic stroke patients treated by endovascular reperfusion therapy. Stroke, 50: 652–658.
  • 82. Shirley R., Ord E.N.J., Work L.M. (2014) Oxidative stress and the use of antioxidants in stroke. Antioxidants, 3: 472–501.
  • 83. Namura S., Nagata I., Takami S. et al. (2001) Ebselen reduces cytochrome c release from mitochondria and subsequent DNA fragmentation after transient focal cerebral ischemia in mice. Stroke, 32: 1906–1911.
  • 84. Takasago T., Peters E.E., Graham D.I. et al. (1997) Neuroprotective efficacy of ebselen, an anti-oxidant with anti-inflammatory actions, in a rodent model of permanent middle cerebral artery occlusion. Br. J. Pharmacol., 122: 1251–1256.
  • 85. Yamaguchi T., Sano K., Takakura K. et al. (1998) Ebselen in acute ischemic stroke: A placebo-controlled, double-blind clinical trial. Ebselen Study Group. Stroke, 29: 12–17.
  • 86. Lesage A.S., Peeters L., Leysen J.E. (1996) Lubeluzole, a novel long-term neuroprotectant, inhibits the glutamate-activated nitric oxide synthase pathway. J. Pharmacol. Exp. Ther., 279: 759–766.
  • 87. Diener H.C., Cortens M., Ford G. et al. (2000) Lubeluzole in acute ischemic stroke treatment: A double-blind study with an 8-h inclusion window comparing a 10-mg daily dose of lubeluzole with placebo. Stroke, 31: 2543–2551.
  • 88. Gandolfo C., Sandercock P., Conti M. (2002) Lubeluzole for acute ischaemic stroke. Cochrane Database Syst. Rev., CD001924.
  • 89. Murphy M.P. (2014) Antioxidants as therapies: Can we improve on nature? Free Radic. Biol. Med., 66: 20–23.
  • 90. Parkinson Study Group QE Investigators; Beal M.F., Oakes D., Shoulson I. et al. (2014) A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: No evidence of benefit. JAMA Neurol., 71: 543–552.
  • 91. Plotnikov E.Y., Silachev D.N., Jankauskas S.S. et al. (2012) Mild uncoupling of respiration and phosphorylation as a mechanism providing nephronand neuroprotective effects of penetrating cations of the SkQ family. Biochemistry, 77: 1029–1037.
  • 92. Ohsawa I., Ishikawa M., Takahashi K. et al. (2007) Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat. Med., 13: 688–694.
  • 93. Herskovits A.Z., Guarente L. (2014) SIRT1 in neurodevelopment and brain senescence. Neuron, 81: 471–483.
  • 94. Shin J.A., Lee K.E., Kim H.S., Park E.M. (2012) Acute resveratrol treatment modulates multiple signaling pathways in the ischemic brain. Neurochem. Res., 37: 2686–2696.
  • 95. Ray A., Cleary M.P. (2017) The potential role of leptin in tumor invasion and metastasis. Cytokine Growth Factor Rev., 38: 80–97.
  • 96. Dabrowska S., Andrzejewska A., Lukomska B., Janowski M. (2019) Neuroinflammation as a target for treatment of stroke using mesenchymal stem cells and extracellular vesicles. J. Neuroinflamm., 16: 178.
  • 97. Jurcau A., Simion A. (2022) Neuroinflammation in Cerebral Ischemia and Ischemia/Reperfusion Injuries: From Pathophysiology to Therapeutic Strategies. Int. J. Mol. Sci., 23: 14.
  • 98. Hess D.C., Wechsler L.R., Clark W.M. et al. (2017) Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): A randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol., 16: 360–368.
  • 99. Sandhir R., Yadav A., Sunkaria A., Singhal N. (2015) Nano-antioxidants: An emerging strategy for intervention against neurodegenerative conditions. Neurochem. Int., 98: 209–226.