Thrombolytic efficacy of a modified tissue-type plasminogen activator, SUN9216, in the rat middle cerebral artery thrombosis model.
We have developed a model whereby the middle cerebral artery in an experimental animal can be occluded by a photochemical reaction between rose bengal and green light. This causes endothelial injury followed by platelet adhesion, aggregation and formation of a platelet-rich thrombus at the site of the photochemical reaction. SUN9216, a modified tissue-type plasminogen activator, is a new thrombolytic agent which consists of the fibrin kringle 1 domain of plasminogen and the two kringles, the serine protease domains of the native tissue-type plasminogen activator. The mannose glycosylation site on the kringle 1 of tissue-type plasminogen activator is modified to yield a compound with a longer half-life in the blood than native tissue-type plasminogen activator. We evaluated the thrombolytic effects of recombinant tissue-type plasminogen activator and SUN9216 in the thrombotically occluded rat middle cerebral artery. SUN9216 was administered by continuous infusion or as a single bolus injection 30 min after the middle cerebral artery had been occluded by a thrombus. Both SUN9216 and recombinant tissue-type plasminogen activator caused reopening of the middle cerebral artery by thrombolysis. The efficacy of SUN9216 was higher than that of recombinant tissue-type plasminogen activator. Further, the area of ischaemic cerebral damage caused by the middle cerebral artery occlusion was significantly (P < 0.05) reduced by SUN9216, but in this respect, recombinant tissue-type plasminogen activator was ineffective.
Umemura
K
K
Department of Pharmacology, Hamamatu University School of Medicine, Japan.
Toshima
Y
Y
Nakashima
M
M
D000704:Analysis of Variance; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy; D002536:Cerebral Arteries / Q000187:drug effects* / Q000473:pathology; D002544:Cerebral Infarction / Q000188:drug therapy*; D004195:Disease Models, Animal; D006031:Glycosylation; D007091:Image Processing, Computer-Assisted; D007261:Infusions, Intra-Arterial; D002542:Intracranial Embolism and Thrombosis / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*
D011994:Recombinant Proteins; C081981:lanoteplase; D010959:Tissue Plasminogen Activator