Kamal, Ayeesha Kamran

Sonawalla, Ambreen

Wadiwala, Muhammad Faisal

eCommons@AKU

eCommons@AKUSection of Neurology Department of MedicineMay 2012What is the role of free radical scavengers in acutestrokeMuhammad Faisal WadiwalaNational Institute of Neurologic Disorders and StrokeAmbreen SonawallaAga Khan UniversityAyeesha Kamran KamalNational Institute of Neurologic Disorders and StrokeFollow this and additional works at: http://ecommons.aku.edu/pakistan_fhs_mc_med_neurolPart of the Nervous System Commons, and the Neurology CommonsRecommended CitationWadiwala, M., Sonawalla, A., Kamal, A. (2012). What is the role of free radical scavengers in acute stroke. Journal of the PakistanMedical Association, 62(5), 512-3.Available at: http://ecommons.aku.edu/pakistan_fhs_mc_med_neurol/2512 J Pak Med AssocWhat is the role of free radical scavengers in acute stroke?Muhammad Faisal Wadiwala,1 Ambreen Sonawalla,2 Ayeesha Kamran Kamal3Stroke Service and Vascular Fellowship Program, International Cerebrovascular Translational Clinical Research Training Program(Fogarty International Center and National Institute of Neurologic Disorders and Stroke),1,3 Medical College,1 Aga Khan University, Karachi, Pakistan.Corresponding Author: Ayeesha Kamran Kamal. Email: ayeesha.kamal@aku.eduEvidence Based MedicineEffects of Edaravone, a Free Radical Scavenger, onSerum Levels of Inflammatory Biomarkers in Acute BrainInfarction.Why is this study important and noteworthy?Stroke may lead to functional disability. Much of thistissue injury is a result of the release of free radicals, whichdirectly damage cells and also initiate other reactions whichlead to cerebral oedema. Free radicals, throughlipoperoxidation, cause increases in inflammatory cells andmediators, and matrix metalloproteinases (MMP) in thebrain which leads to disruption of the blood-brain-barrier,increase in vascular endothelial permeability and vasogenicbrain oedema.Edaravone, a free radical scavenger, has been shownto reduce the free radicals which are produced duringreperfusion in ischaemic cerebral injury, and inhibitexpression of MMP-9 in ischaemic brain models. However,its effects on serum levels of inflammatory biomarkers havenot been sufficiently studied.This study was a prospective observational study,aimed at investigating the effects of Edaravone treatment onserum levels of inflammatory biomarkers, in patients withacute cerebral infarction. Who were the participants?This study was a prospective observational study,conducted in Japan, enrolling 69 patients (39 men and 30women) who were admitted to the hospital within 12 to 36hours of suffering an acute brain infarction, between April2007 and September 2008. Edaravone was administered toall the patients who had come within 12-24 hours of onsetof symptoms, whereas those admitted after 24-36 hours ofsymptoms served as the control group.This study excluded patients below 18 years, orthose with contraindications to edaravone treatment such asserious kidney dysfunction, liver disorder, orhypersensitivity to ingredients in edaravone. Patients withrecurrent cerebral infarction (<6 months between episodes),or previous history of heart disease such as heart failure orischaemic heart disease, were also excluded, as were thosewith a disability having a modified Rankin scale (mRS)score >2 before onset or those who required surgical orendovascular interventions during hospitalization. Patientswith infections, inflammatory diseases, haematologicdisorders, malignancy requiring treatment, or pregnancywere also excluded.What was the intervention and what were themeasurements?Patients who were admitted 12-24 hours after onsetof symptoms were administered 30 mg of edaravone dilutedin 100 mL of saline, every 12 hours for the next 14 days.The edaravone was administered intravenously via drip-infusion over a 30 minute period. Diagnosis of acute cerebral infarction was made byneurologic examination and computed head tomographyand/or MRI. Serial blood samples were obtained from thepatients at admission, at 48 hours, 7 days and 14 days afteronset of symptoms and tested using ELISA for high-sensitivityC-reactive protein (hs-CRP), Interleukins IL-6, IL-10, IL-18,tumour necrosis factor (TNF)-α, MMP-2 and MMP-9.What was the outcome?Over the 14 days, there was no significant change inMMP-9 levels in the edaravone group (p=0.564) whereas inthe control group MMP-9 levels increased from 3.857 to4.538 ng/mL (p=0.027). Unpaired t tests for other serum biomarkers showedno significant differences between the two groups over theobservation period. There was also no significant differenceseen in the NIHSS score at 14 days, in the mRS score at 3months, after onset of symptoms, or in the duration ofhospitalization.What were the conclusions?In patients with acute cerebral infarction, edaravonesignificantly suppressed circulating serum levels of MMP-9. However, since in humans, the contribution of braintissue to the circulating levels of MMP-9 within 14 daysafter onset of a stroke is unknown, these findings should notbe taken to reflect the effects of edaravone on ischaemicbrain per se. Edaravone did not significantly affect serumlevels of any other inflammatory biomarker. Further,edaravone did not significantly affect functional outcomesin patients.How does this impact our clinical practice?This study does not conclusively demonstrate thatthe suppression of circulating MMP-9 levels by edaravonecorrelates with improved outcomes in relation to strokepathophysiology. However, the use of edaravone may helpcombat the neurotoxicity following tPA-basedrevascularization, since tPA is known to cause neurotoxicityby many pathways, including increasing MMP-9 levels.However, further studies need to be done to confirm thisbeneficial effect. We should stay tuned for the effects ofedaravone which appear exciting in these 'preclinicalstudies". Acknowledgement and Disclosure Statement:The International Cerebrovascular TranslationalClinical Research and Training Program (ICT_CRT) at theAga Khan University is supported by funds from the AwardNumber D43TW008660 from the Fogarty InternationalCenter and the National Institute of Neurologic Disordersand Stroke. The content is solely the responsibility of theauthors and does not necessarily represent the official viewsof the Fogarty International Center or the National Institutesof Health.References1. Isahaya K, Yamada K, Yamatoku M, Sakurai K, Takaishi S, Kato B, et al.Effects of Edaravone, a Free Radical Scavenger, on Serum Levels ofInflammatory Biomarkers in Acute Brain Infarction. J J Stroke CerebrovasDis 2010; 21: 102-7.Vol. 62, No. 5, May 2012 513

What is the role of free radical scavengers in acute stroke?

eCommons@AKUDepartment of Medicine Department of MedicineMay 2012What is the role of free radical scavengers in acutestroke?Muhammad Faisal WadiwalaAga Khan UniversityAmbreen SonawallaAga Khan UniversityAyeesha Kamran KamalAgha Khan University, ayeesha.kamal@aku.eduFollow this and additional works at: http://ecommons.aku.edu/pakistan_fhs_mc_med_medPart of the Neurology CommonsRecommended CitationWadiwala, M. F., Sonawalla, A., Kamal, A. (2012). What is the role of free radical scavengers in acute stroke?. JPMA. The Journal of thePakistan Medical Association, 62(5), 512-513.Available at: http://ecommons.aku.edu/pakistan_fhs_mc_med_med/372512 J Pak Med AssocWhat is the role of free radical scavengers in acute stroke?Muhammad Faisal Wadiwala,1 Ambreen Sonawalla,2 Ayeesha Kamran Kamal3Stroke Service and Vascular Fellowship Program, International Cerebrovascular Translational Clinical Research Training Program(Fogarty International Center and National Institute of Neurologic Disorders and Stroke),1,3 Medical College,1 Aga Khan University, Karachi, Pakistan.Corresponding Author: Ayeesha Kamran Kamal. Email: ayeesha.kamal@aku.eduEvidence Based MedicineEffects of Edaravone, a Free Radical Scavenger, onSerum Levels of Inflammatory Biomarkers in Acute BrainInfarction.Why is this study important and noteworthy?Stroke may lead to functional disability. Much of thistissue injury is a result of the release of free radicals, whichdirectly damage cells and also initiate other reactions whichlead to cerebral oedema. Free radicals, throughlipoperoxidation, cause increases in inflammatory cells andmediators, and matrix metalloproteinases (MMP) in thebrain which leads to disruption of the blood-brain-barrier,increase in vascular endothelial permeability and vasogenicbrain oedema.Edaravone, a free radical scavenger, has been shownto reduce the free radicals which are produced duringreperfusion in ischaemic cerebral injury, and inhibitexpression of MMP-9 in ischaemic brain models. However,its effects on serum levels of inflammatory biomarkers havenot been sufficiently studied.This study was a prospective observational study,aimed at investigating the effects of Edaravone treatment onserum levels of inflammatory biomarkers, in patients withacute cerebral infarction. Who were the participants?This study was a prospective observational study,conducted in Japan, enrolling 69 patients (39 men and 30women) who were admitted to the hospital within 12 to 36hours of suffering an acute brain infarction, between April2007 and September 2008. Edaravone was administered toall the patients who had come within 12-24 hours of onsetof symptoms, whereas those admitted after 24-36 hours ofsymptoms served as the control group.This study excluded patients below 18 years, orthose with contraindications to edaravone treatment such asserious kidney dysfunction, liver disorder, orhypersensitivity to ingredients in edaravone. Patients withrecurrent cerebral infarction (<6 months between episodes),or previous history of heart disease such as heart failure orischaemic heart disease, were also excluded, as were thosewith a disability having a modified Rankin scale (mRS)score >2 before onset or those who required surgical orendovascular interventions during hospitalization. Patientswith infections, inflammatory diseases, haematologicdisorders, malignancy requiring treatment, or pregnancywere also excluded.What was the intervention and what were themeasurements?Patients who were admitted 12-24 hours after onsetof symptoms were administered 30 mg of edaravone dilutedin 100 mL of saline, every 12 hours for the next 14 days.The edaravone was administered intravenously via drip-infusion over a 30 minute period. Diagnosis of acute cerebral infarction was made byneurologic examination and computed head tomographyand/or MRI. Serial blood samples were obtained from thepatients at admission, at 48 hours, 7 days and 14 days afteronset of symptoms and tested using ELISA for high-sensitivityC-reactive protein (hs-CRP), Interleukins IL-6, IL-10, IL-18,tumour necrosis factor (TNF)-α, MMP-2 and MMP-9.What was the outcome?Over the 14 days, there was no significant change inMMP-9 levels in the edaravone group (p=0.564) whereas inthe control group MMP-9 levels increased from 3.857 to4.538 ng/mL (p=0.027). Unpaired t tests for other serum biomarkers showedno significant differences between the two groups over theobservation period. There was also no significant differenceseen in the NIHSS score at 14 days, in the mRS score at 3months, after onset of symptoms, or in the duration ofhospitalization.What were the conclusions?In patients with acute cerebral infarction, edaravonesignificantly suppressed circulating serum levels of MMP-9. However, since in humans, the contribution of braintissue to the circulating levels of MMP-9 within 14 daysafter onset of a stroke is unknown, these findings should notbe taken to reflect the effects of edaravone on ischaemicbrain per se. Edaravone did not significantly affect serumlevels of any other inflammatory biomarker. Further,edaravone did not significantly affect functional outcomesin patients.How does this impact our clinical practice?This study does not conclusively demonstrate thatthe suppression of circulating MMP-9 levels by edaravonecorrelates with improved outcomes in relation to strokepathophysiology. However, the use of edaravone may helpcombat the neurotoxicity following tPA-basedrevascularization, since tPA is known to cause neurotoxicityby many pathways, including increasing MMP-9 levels.However, further studies need to be done to confirm thisbeneficial effect. We should stay tuned for the effects ofedaravone which appear exciting in these 'preclinicalstudies". Acknowledgement and Disclosure Statement:The International Cerebrovascular TranslationalClinical Research and Training Program (ICT_CRT) at theAga Khan University is supported by funds from the AwardNumber D43TW008660 from the Fogarty InternationalCenter and the National Institute of Neurologic Disordersand Stroke. The content is solely the responsibility of theauthors and does not necessarily represent the official viewsof the Fogarty International Center or the National Institutesof Health.References1. Isahaya K, Yamada K, Yamatoku M, Sakurai K, Takaishi S, Kato B, et al.Effects of Edaravone, a Free Radical Scavenger, on Serum Levels ofInflammatory Biomarkers in Acute Brain Infarction. J J Stroke CerebrovasDis 2010; 21: 102-7.Vol. 62, No. 5, May 2012 513

English

http://ecommons.aku.edu/cgi/viewcontent.cgi?article=1001&context=pakistan_fhs_mc_med_neurol

What is the role of free radical scavengers in acute stroke?

Abstract

Similar works

Full text

Available Versions

eCommons@AKU

eCommons@AKU