Free radical scavenger edaravone administration protects against tissue plasminogen activator induced oxidative stress and blood brain barrier damage.
One of the therapeutics for acute cerebral ischemia is tissue plasminogen activator (t-PA). Using t-PA after 3 hour time window increases the chances of hemorrhage, involving multiple mechanisms. In order to show possible mechanisms of t-PA toxicity and the effect of the free radical scavenger edaravone, we administered vehicle, plasmin, and t-PA into intact rat cortex, and edaravone intravenously. Plasmin and t-PA damaged rat brain with the most prominent injury in t-PA group on 4-HNE, HEL, and 8-OHdG immunostainings. Such brain damage was strongly decreased in t-PA plus edaravone group. For the neurovascular unit immunostainings, occludin and collagen IV expression was decreased in single plasmin or t-PA group, which was recovered in t-PA plus edaravone group. In contrast, matrix metalloproteinase-9 intensity was the strongest in t-PA group, less in plasmin, and was the least prominent in t-PA plus edaravone group. In vitro data showed a strong damage to tight junctions for occludin and claudin 5 in both administration groups, while there were no changes for endothelial (NAGO) and perivascular (GFAP) stainings. Such damage to tight junctions was recovered in t-PA plus edaravone group with similar recovery in Sodium-Fluorescein permeability assay. Administration of t-PA caused oxidative stress damage to lipids, proteins and DNA, and led to disruption of outer parts of neurovascular unit, greater than the effect in plasmin administration. Additive edaravone ameliorated such an oxidative damage by t-PA with protecting outer layers of blood-brain barrier (in vivo) and tight junctions (in vitro).
Lukic-Panin
Violeta
V
Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan. violetal@cc.okayama-u.ac.jp
Deguchi
Kentaro
K
Yamashita
Toru
T
Shang
Jingwei
J
Zhang
Xuemei
X
Tian
FengFeng
F
Liu
Ning
N
Kawai
Hiromi
H
Matsuura
Tohru
T
Abe
Koji
K
D000117:Acetylglucosamine / Q000378:metabolism; D000818:Animals; D000983:Antipyrine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000473:pathology; D001930:Brain Injuries / Q000473:pathology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D024141:Collagen Type IV / Q000378:metabolism; D004195:Disease Models, Animal; D004347:Drug Interactions; D000077553:Edaravone; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D005343:Fibrinolytic Agents / Q000009:adverse effects*; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D062793:Occludin; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D010959:Tissue Plasminogen Activator / Q000009:adverse effects*
D024141:Collagen Type IV; D005343:Fibrinolytic Agents; D016166:Free Radical Scavengers; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D062793:Occludin; C568987:Ocln protein, rat; D010959:Tissue Plasminogen Activator; D000077553:Edaravone; D000983:Antipyrine; D000117:Acetylglucosamine