title: Mechanistic insight into neurotoxicity of tissue plasminogen activator-induced thrombolysis products in a rat intraluminal middle cerebral artery occlusion model.
abstract: Thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) after ischemic stroke is effective. However, rtPA potentiates neuronal damage, and interactions between rtPA and thrombolysis products (TLP) have been reported to play a role in this. In the present study we investigated the mechanisms underlying rtPA- and TLP-induced neurotoxicity. Adult male Sprague-Dawley rats were subjected to 60-min intraluminal middle cerebral artery (MCA) occlusion, and then treated with rtPA (10 mg/kg), TLP, or saline. To evaluate the effects of a free radical scavenger, treatment with edaravone and TLP was evaluated. To investigate the role of red blood cells (RBCs), RBC-depleted TLP was used. Neurological deficit scores, infarct volume, and immuno-histochemical localization of oxidative end products for lipid and DNA (4-hydroxy-2-nonenal [4-HNE] and 8-hydroxy-deoxyguanosine [8-OHdG]) were evaluated. TLP increased the infarct volume, worsened the neurological deficits, and increased accumulations of 4-HNE and 8-OHdG. Edaravone treatment significantly reduced the lesion volume and improved the neurological score. Both infarct volume and accumulation of oxidative products were significantly suppressed when RBC-depleted TLP was used. In this mechanical model of MCA occlusion, rtPA-induced TLP, especially in the presence of RBCs, contributed to neuronal damage by accelerating free radical injury.
authors.affiliation: Department of Neurosurgery, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Oka
authors.forename: Hirosuke
authors.initials: H
authors.lastname: Fujisawa
authors.forename: Sadahiro
authors.initials: S
authors.lastname: Nomura
authors.forename: Koji
authors.initials: K
authors.lastname: Kajiwara
authors.forename: Shoichi
authors.initials: S
authors.lastname: Kato
authors.forename: Masami
authors.initials: M
authors.lastname: Fujii
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Izuma
authors.forename: Kanako
authors.initials: K
authors.lastname: Uozumi
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Gondo
authors.forename: Michiyasu
authors.initials: M
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives / Q000494:pharmacology; D015415:Biomarkers; D002545:Brain Ischemia / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000502:physiology; D004249:DNA Damage; D000077553:Edaravone; D004912:Erythrocytes / Q000502:physiology; D016166:Free Radical Scavengers / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D020768:Middle Cerebral Artery / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015912:Thrombolytic Therapy / Q000009:adverse effects*; D010959:Tissue Plasminogen Activator / Q000633:toxicity*
chemical_list: D015415:Biomarkers; D016166:Free Radical Scavengers; D005609:Free Radicals; D010959:Tissue Plasminogen Activator; D000077553:Edaravone; D000983:Antipyrine