title: Thrombolytic effects of the snake venom disintegrin saxatilin determined by novel assessment methods: a FeCl3-induced thrombosis model in mice.
abstract: Saxatilin, a novel disintegrin purified and cloned from the venom of the Korean snake Gloydius saxatilis, strongly inhibits activation and aggregation of platelets. Glycoprotein (GP) IIb/IIIa receptor antagonists can resolve thrombus, so saxatilin might also have thrombolytic effects. We investigated the thrombolytic effects of saxatilin in mice using a ferric chloride-induced carotid arterial thrombosis model. Thrombotic occlusion and thrombus resolution were evaluated quantitatively by measuring blood flow in the carotid artery with an ultrasonic flow meter and calculating the degree of flow restoration on a minute-by-minute basis; results were confirmed by histological examination. Saxatilin dissolved thrombi in a dose-dependent manner. Saxatilin at 5 mg/kg restored blood flow to baseline levels. As saxatilin dose increased, time to recanalization decreased. A bolus injection of 10% of a complete dose with continuous infusion of the remaining dose for 60 minutes resulted in effective recanalization without reocclusion. The thrombolytic effect of saxatilin was also demonstrated in vitro using platelet aggregometry by administering saxatilin in preformed thrombi. Bleeding complications were observed in 2 of 71 mice that received saxatilin. Fibrin/fibrinogen zymography and platelet aggregometry studies indicated that saxatilin does not have fibrinolytic activity, but exerted its action on platelets. Integrin-binding assays showed that saxatilin inhibited multiple integrins, specifically α2bβ3 (GP IIb/IIIa), α5β1, αvβ3, αvβ1, and αvβ5, which act on platelet adhesion/aggregation. Saxatilin inhibited multiple integrins by acting on platelets, and was safe and effective in resolving thrombi in mice.
authors.affiliation: Department of Neurology, Yonsei University College of Medicine, Seoul, Korea ; Severance Integrative Research Institute for Cerebral and Cardiovascular Diseases, Yonsei University College of Medicine, Seoul, Korea ; Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Il
authors.initials: I
authors.lastname: Kwon
authors.forename: Sung-Yu
authors.initials: SY
authors.lastname: Hong
authors.forename: Young Dae
authors.initials: YD
authors.lastname: Kim
authors.forename: Hyo Suk
authors.initials: HS
authors.lastname: Nam
authors.forename: Sungsoo
authors.initials: S
authors.lastname: Kang
authors.forename: Seung-Hee
authors.initials: SH
authors.lastname: Yang
authors.forename: Ji Hoe
authors.initials: JH
authors.lastname: Heo
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002339:Carotid Arteries / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002712:Chlorides; D019483:Disintegrins / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005290:Ferric Compounds; D005343:Fibrinolytic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D018056:Hemorheology; D006470:Hemorrhage / Q000139:chemically induced; D016023:Integrins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010974:Platelet Aggregation / Q000187:drug effects; D012910:Snake Venoms / Q000737:chemistry; D015912:Thrombolytic Therapy; D013927:Thrombosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D002712:Chlorides; D019483:Disintegrins; D005290:Ferric Compounds; D005343:Fibrinolytic Agents; D016023:Integrins; D012910:Snake Venoms; C459080:saxatilin; C024555:ferric chloride