title: Neurotoxic effects of exogenous recombinant tissue-type plasminogen activator on the normal rat brain.
abstract: Thrombolytic therapy with intravenous and intra-arterial recombinant tissue-type plasminogen activator (rtPA) has been established for the treatment of acute ischemic stroke. However, tPA has also been suggested to have neurotoxic effects. The purpose of this study was to examine direct neurotoxicity of rtPA in vivo. The animals (Wistar rats) were divided to the following three groups: low-dose (15 micromol/L) rtPA group (n = 6); high-dose (30 micromol/L) rtPA group (n = 6); and control (physiological saline) group (n = 6). The rtPA solution was perfused into the cortex via a microdialysis probe. The volume of the lesion was quantified histologically by image analysis of the lesions. Blood-brain barrier (BBB) disruption was evaluated by intravenous injection of Evans blue, and injury to the basal lamina was evaluated by immunohistochemistry using an anti-laminin antibody. In the rtPA-perfused animals, a pale lesion was produced around the probe, and microscopically, neurons showed necrotic changes. The volume of the lesions increased significantly as the concentration of perfused rtPA was increased. Marked extravasation of Evans blue was observed, and laminin immunoreactivity of blood vessels in the rtPA-induced lesions was lost. These results suggest that rtPA promotes acute direct neurotoxicity and participates in disruption of the microvascular basal lamina to cause BBB disruption, thereby increasing edema formation.
authors: Department of Neurosurgery, Yamaguchi University School of Medicine, Minamikogushi, Ube, Japan.
authors: Hisaharu
authors: H
authors: Goto
authors: Hirosuke
authors: H
authors: Fujisawa
authors: Fumiaki
authors: F
authors: Oka
authors: Sadahiro
authors: S
authors: Nomura
authors: Koji
authors: K
authors: Kajiwara
authors: Shoichi
authors: S
authors: Kato
authors: Masami
authors: M
authors: Fujii
authors: Tsuyoshi
authors: T
authors: Maekawa
authors: Michiyasu
authors: M
authors: Suzuki
mesh_terms: D000818:Animals; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects; D001831:Body Temperature / Q000502:physiology; D001921:Brain / Q000473:pathology*; D001929:Brain Edema / Q000473:pathology; D016923:Cell Death / Q000502:physiology; D004396:Coloring Agents; D005070:Evans Blue; D005110:Extracellular Space / Q000502:physiology; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D007797:Laminin / Q000378:metabolism; D008297:Male; D020258:Neurotoxicity Syndromes / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000633:toxicity; D010959:Tissue Plasminogen Activator / Q000633:toxicity*
chemical_list: D004396:Coloring Agents; D007797:Laminin; D011994:Recombinant Proteins; D005070:Evans Blue; D010959:Tissue Plasminogen Activator