Mechanistic insight into neurotoxicity of tissue plasminogen activator-induced thrombolysis products in a rat intraluminal middle cerebral artery occlusion model.
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.
Oka
Fumiaki
F
Department of Neurosurgery, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan.
Fujisawa
Hirosuke
H
Nomura
Sadahiro
S
Kajiwara
Koji
K
Kato
Shoichi
S
Fujii
Masami
M
Izuma
Hiroshi
H
Uozumi
Kanako
K
Gondo
Toshikazu
T
Suzuki
Michiyasu
M
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*
D015415:Biomarkers; D016166:Free Radical Scavengers; D005609:Free Radicals; D010959:Tissue Plasminogen Activator; D000077553:Edaravone; D000983:Antipyrine