Clinical Investigation of Protective Effects of Melatonin on Patients with Acute Ischemic Stroke
-
Mahsa Rabiee
,
Hesam abdolhoseinpour
,
Amirmahdi Mojtahedzadeh
,
Mojtaba Mojtahedzadeh
,
Maryam Shiemorteza
,
Fatemeh Ghanbarzamani
,
Amirhossein Ghanbarzamani
Abstract
Background: Stroke is one of the leading causes of annual mortality and disability for many individuals worldwide. Ischemic stroke has a high incidence and mortality rate, which significantly affects the quality of life and places an overwhelming mental and financial burden on the patients' families. Melatonin has a neuroprotective effect on patients with acute ischemic stroke. This study aimed to develop the employment of melatonin on clinical features of acute ischemic stroke.
Methods: This double-blind, placebo-controlled clinical trial was conducted on 70 patients with acute ischemic stroke not eligible for reperfusion therapy who were admitted to Bu-Ali Hospital. The consent form was taken, and all of the patients received routine management. Participants were divided into two groups. The 35 patients received 10 mg of melatonin once daily for five days, and others received 10 mg of placebo. National Institute of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) scores were recorded for all patients before treatment and after on days 5, 30, and 90.
Results: The 70 patients included in this study were based on inclusion criteria. The severity of stroke and the functional status of patients were compared in both groups. The melatonin group showed a significant reduction in the NIHSS score from day five up to day thirty compared to the placebo group (P = 0.001). There was no difference in the mRS score between the two groups in this study (P > 0.05). The relative frequency of the adverse event of sleepiness in patients receiving melatonin was significantly higher than in patients receiving placebo (P = 0.022).
Conclusion: Patients who receive melatonin early after stroke have better improvement in post-stroke recovery and disabilities. These findings verify the results of other studies.
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[30] Galano A, Tan DX, Reiter RJ. Melatonin as a natural ally against oxidative stress: a physicochemical examination. J Pineal Res. 2011;51(1):1-6.
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[38] Wu L, Xiong X, Wu X, Ye Y, Jian Z, Zhi Z, et al. Targeting oxidative stress and inflammation to prevent ischemia-reperfusion injury. Front Mol Neurosci. 2020; 13:28.
[39] Genovese T, Mazzon E, Paterniti I, Esposito E, Bramanti P, Cuzzocrea S. Modulation of NADPH oxidase activation in cerebral ischemia/reperfusion injury in rats. Brain Res. 2011; 1372:92-102.
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[46] Adams HP Jr, Davis PH, Leira EC, Chang KC, Bendixen BH, Clarke WR, et al. Baseline NIH Stroke Scale score strongly predicts outcome after stroke: a report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Neurology. 1999;53(1):126-31.
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[2] Hickey A, O'Hanlon A, McGee H, Donnellan C, Shelley E, Horgan F, et al. Stroke awareness in the general population: knowledge of stroke risk factors and warning signs in older adults. BMC Geriatr. 2009; 9:1-8.
[3] Jaracz K, Kozubski W. Quality of life in stroke patients. Acta Neurol Scand. 2003;107(5):324-9.
[4] Zhang C, Ma Y, Zhao Y, Guo N, Han C, Wu Q, et al. Systematic review of melatonin in cerebral ischemia-reperfusion injury: critical role and therapeutic opportunities. Front Pharmacol. 2024; 15:1356112.
[5] Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz MD, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(7):2160-236.
[6] Kuriakose D, Xiao Z. Pathophysiology and treatment of stroke: present status and future perspectives. Int J Mol Sci. 2020;21(20):7609.
[7] Yitshak Sade M, Novack V, Ifergane G, Horev A, Kloog I. Air pollution and ischemic stroke among young adults. Stroke. 2015;46(12):3348-53.
[8] Mackey J, Kleindorfer D, Sucharew H, Moomaw CJ, Kissela BM, Alwell K, et al. Population-based study of wake-up strokes. Neurology. 2011;76(19):1662-7.
[9] Zhou Y, Zhang S, Fan X. Role of polyphenols as antioxidant supplementation in ischemic stroke. Oxid Med Cell Longev. 2021; 2021:5471347.
[10] Zhou Z, Lu J, Liu WW, Manaenko A, Hou X, Mei Q, et al. Advances in stroke pharmacology. Pharmacol Ther. 2018; 191:23-42.
[11] Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2019; 50(12):e344-418.
[12] Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008; 359(13):1317-29.
[13] Yepes M, Roussel BD, Ali C, Vivien D. Tissue-type plasminogen activator in the ischemic brain: more than a thrombolytic. Trends Neurosci. 2009; 32(1):48-55.
[14] Fan X, Yu Z, Liu J, Liu N, Hajjar KA, Furie KL, et al. Annexin A2: a tissue plasminogen activator amplifier for thrombolytic stroke therapy. Stroke. 2010;41(10_suppl_1):S54-8.
[15] Lo EH, Dalkara T, Moskowitz MA. Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci. 2003;4(5):399-414.
[16] Bramlett HM, Dietrich WD. Pathophysiology of cerebral ischemia and brain trauma: similarities and differences. J Cereb Blood Flow Metab. 2004;24(2):133-50.
[17] Pawluk H, Woźniak A, Grześk G, Kołodziejska R, Kozakiewicz M, Kopkowska E, et al. The role of selected pro-inflammatory cytokines in pathogenesis of ischemic stroke. Clin Interv Aging. 2020; 15:469-84.
[18] Vidale S, Consoli A, Arnaboldi M, Consoli D. Postischemic inflammation in acute stroke. J Clin Neurol. 2017;13(1):1-9.
[19] Qin C, Yang S, Chu YH, Zhang H, Pang XW, Chen L, et al. Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther. 2022;7(1):215.
[20] Pawluk H, Kołodziejska R, Grześk G, Woźniak A, Kozakiewicz M, Kosinska A, et al. Increased oxidative stress markers in acute ischemic stroke patients treated with thrombolytics. Int J Mol Sci. 2022;23(24):15625.
[21] Chen H, Yoshioka H, Kim GS, Jung JE, Okami N, Sakata H, et al. Oxidative stress in ischemic brain damage: mechanisms of cell death and potential molecular targets for neuroprotection. Antioxid Redox Signal. 2011;14(8):1505-17.
[22] Qin Y, Zhang Q, Liu Y. Analysis of knowledge bases and research focuses of cerebral ischemia-reperfusion from the perspective of mapping knowledge domain. Brain Res Bull. 2020; 156:15-24.
[23] Allen CL, Bayraktutan U. Oxidative stress and its role in the pathogenesis of ischaemic stroke. Int J Stroke. 2009;4(6):461-70.
[24] Sun MS, Jin H, Sun X, Huang S, Zhang FL, Guo ZN, 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.
[25] Kleinschnitz C, Grund H, Wingler K, Armitage ME, Jones E, Mittal M, et al. Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration. PLoS Biol. 2010;8(9):e1000479.
[26] Casas AI, Geuss E, Kleikers PW, Mencl S, Herrmann AM, Buendia I, et al. NOX4-dependent neuronal autotoxicity and BBB breakdown explain the superior sensitivity of the brain to ischemic damage. Proc Natl Acad Sci U S A. 2017;114(46):12315-20.
[27] Arendt J, Aulinas A. Physiology of the pineal gland and melatonin. 2022.
[28] Sadanandan N, Cozene B, Cho J, Park YJ, Saft M, Gonzales-Portillo B, et al. Melatonin-A potent therapeutic for stroke and stroke-related dementia. Antioxidants. 2020;9(8):672.
[29] Zawilska JB, Skene DJ, Arendt J. Physiology and pharmacology of melatonin in relation to biological rhythms. Pharmacol Rep. 2009;61(3):383-410.
[30] Galano A, Tan DX, Reiter RJ. Melatonin as a natural ally against oxidative stress: a physicochemical examination. J Pineal Res. 2011;51(1):1-6.
[31] Reiter RJ. Oxidative damage in the central nervous system: protection by melatonin. Prog Neurobiol. 1998;56(3):359-84.
[32] Cutler RG. Oxidative stress: its potential relevance to human disease and longevity determinants. Age. 1995;18(3):91-6.
[33] Li D, He T, Zhang Y, Liu J, Zhao H, Wang D, et al. Melatonin regulates microglial polarization and protects against ischemic stroke-induced brain injury in mice. Exp Neurol. 2023; 367:114464.
[34] Mengel A, Zurloh J, Boßelmann C, Brendel B, Stadler V, Sartor-Pfeiffer J, et al. Delirium REduction after administration of melatonin in acute ischemic stroke (DREAMS): A propensity score-matched analysis. Eur J Neurol. 2021;28(6):1958-66.
[35] Chen HY, Hung YC, Chen TY, Huang SY, Wang YH, Lee WT, et al. Melatonin improves presynaptic protein, SNAP-25, expression and dendritic spine density and enhances functional and electrophysiological recovery following transient focal cerebral ischemia in rats. J Pineal Res. 2009;47(3):260-70.
[36] Lee EJ, Lee MY, Chen HY, Hsu YS, Wu TS, Chen ST, et al. Melatonin attenuates gray and white matter damage in a mouse model of transient focal cerebral ischemia. J Pineal Res. 2005;38(1):42-52.
[37] Faraji F, Zanjani AT, Ashtiani AR, Motamedi G, Nourigheimasi S. Melatonin for Clinical Improvement in Patients with Ischemic Stroke: A Randomized Clinical Trial. Iran Red Crescent Med J. 2023;25(2).
[38] Wu L, Xiong X, Wu X, Ye Y, Jian Z, Zhi Z, et al. Targeting oxidative stress and inflammation to prevent ischemia-reperfusion injury. Front Mol Neurosci. 2020; 13:28.
[39] Genovese T, Mazzon E, Paterniti I, Esposito E, Bramanti P, Cuzzocrea S. Modulation of NADPH oxidase activation in cerebral ischemia/reperfusion injury in rats. Brain Res. 2011; 1372:92-102.
[40] Zhao Z, Cheng M, Maples KR, Ma JY, Buchan AM. NXY-059, a novel free radical trapping compound, reduces cortical infarction after permanent focal cerebral ischemia in the rat. Brain Res. 2001; 909(1-2):46-50.
[41] Drieu A, Levard D, Vivien D, Rubio M. Anti-inflammatory treatments for stroke: from bench to bedside. Ther Adv Neurol Disord. 2018; 11:1756286418789854.
[42] Margaill I, Plotkine M, Lerouet D. Antioxidant strategies in the treatment of stroke. Free Radic Biol Med. 2005;39(4):429-43.
[43] Mehrpooya M, Mazdeh M, Rahmani E, Khazaie M, Ahmadimoghaddam D. Melatonin supplementation may benefit patients with acute ischemic stroke not eligible for reperfusion therapies: Results of a pilot study. J Clin Neurosci. 2022; 106:66-75.
[44] Ekundayo OJ, Saver JL, Fonarow GC, Schwamm LH, Xian Y, Zhao X, et al. Patterns of emergency medical services use and its association with timely stroke treatment: findings from Get with the Guidelines-Stroke. Circ Cardiovasc Qual Outcomes. 2013;6(3):262-9.
[45] Shahid J, Kashif A, Shahid MK. A comprehensive review of physical therapy interventions for stroke rehabilitation: impairment-based approaches and functional goals. Brain Sci. 2023;13(5):717.
[46] Adams HP Jr, Davis PH, Leira EC, Chang KC, Bendixen BH, Clarke WR, et al. Baseline NIH Stroke Scale score strongly predicts outcome after stroke: a report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Neurology. 1999;53(1):126-31.
[47] Saver JL, Chaisinanunkul N, Campbell BC, Grotta JC, Hill MD, Khatri P, et al. Standardized nomenclature for modified rankin scale global disability outcomes: consensus recommendations from stroke therapy academic industry roundtable XI. Stroke. 2021;52(9):3054-62.
[48] Feigin VL, Abajobir AA, Abate KH, Abd-Allah F, Abdulle AM, Abera SF, et al. Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Neurol. 2017;16(11):877-97.
[49] Paciaroni M, Bogousslavsky J. Primary and secondary prevention of ischemic stroke. Eur Neurol. 2010;63(5):267-78.
[50] Kisialiou A, Grella R, Carrizzo A, Pelone G, Bartolo M, Zucchella C, et al. Risk factors and acute ischemic stroke subtypes. J Neurol Sci. 2014;339(1-2):41-6.
[51] Katan M, Luft A. Global burden of stroke. Semin Neurol. 2018;38(2):208-11.
[52] Kang X, Zuo Z, Hong W, Tang H, Geng W. Progress of research on exosomes in the protection against ischemic brain injury. Front Neurosci. 2019; 13:1149.
[53] Fischer U, Arnold M, Nedeltchev K, Brekenfeld C, Ballinari P, Remonda L, et al. NIHSS score and arteriographic findings in acute ischemic stroke. Stroke. 2005;36(10):2121-5.
[54] Kwah LK, Diong J. National institutes of health stroke scale (NIHSS). J Physiother. 2014;60(1):61.
[55] Mittal M, Siddiqui MR, Tran K, Reddy SP, Malik AB. Reactive Oxygen Species in Inflammation and Tissue Injury. Antioxid Redox Signal. 2014;20(7):1126-67.
[56] Rodrigo R, Fernandez-Gajardo R, Gutiérrez R, Manuel Matamala J, Carrasco R, Miranda-Merchak A, et al. Oxidative stress and pathophysiology of ischemic stroke: novel therapeutic opportunities. CNS Neurol Disord Drug Targets. 2013;12(5):698-714.
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| Melatonin Acute ischemic stroke Neuroprotective agents Brain ischemia | ||
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How to Cite
1.
Rabiee M, abdolhoseinpour H, Mojtahedzadeh A, Mojtahedzadeh M, Shiemorteza M, Ghanbarzamani F, Ghanbarzamani A. Clinical Investigation of Protective Effects of Melatonin on Patients with Acute Ischemic Stroke. Arch Anesth & Crit Care. 2025;.
