A novel snake venom-derived GPIb antagonist, anfibatide, protects mice from acute experimental ischaemic stroke and reperfusion injury.
OBJECTIVE
Ischaemic stroke is a serious disease with limited therapy options. Glycoprotein (GP)Ib binding to von Willebrand factor (vWF) exposed at vascular injury initiates platelet adhesion and contributes to platelet aggregation. GPIb has been suggested as an effective target for antithrombotic therapy in stroke. Anfibatide is a GPIb antagonist derived from snake venom and we investigated its protective effect on experimental brain ischaemia in mice.


METHODS
Focal cerebral ischaemia was induced by 90 min of transient middle cerebral artery occlusion (MCAO). These mice were then treated with anfibatide (4, 2, 1 μg·kg(-1) ), injected i.v., after 90 min of MCAO, followed by 1 h of reperfusion. Tirofiban, a GPIIb/IIIα antagonist, was used as a positive control.


RESULTS
Twenty-four hours after MCAO, anfibatide-treated mice showed significantly improved ischaemic lesions in a dose-dependent manner. The mice had smaller infarct volumes, less severe neurological deficits and histopathology of cerebrum tissues compared with the untreated MCAO mice. Moreover, anfibatide decreased the amount of GPIbα, vWF and accumulation of fibrin(ogen) in the vasculature of the ischaemic hemisphere. Tirofiban had similar effects on infarct size and fibrin(ogen) deposition compared with the MCAO group. Importantly, the anfibatide-treated mice showed a lower incidence of intracerebral haemorrhage and shorter tail bleeding time compared with the tirofiban-treated mice.


CONCLUSIONS
Our data indicate anfibatide is a safe GPIb antagonist that exerts a protective effect on cerebral ischaemia and reperfusion injury. Anfibatide is a promising candidate that could be beneficial for the treatment of ischaemic stroke.
Department of Pharmacology, School of Basic Medical Science, Anhui Medical University, Hefei, Anhui, China.
Ting-Ting
TT
Li
Department of Pharmacology, School of Basic Medical Science, Anhui Medical University, Hefei, Anhui, China.
Man-Li
ML
Fan
Department of Pharmacology, School of Basic Medical Science, Anhui Medical University, Hefei, Anhui, China.|Department of Pharmacy, Xuancheng People's Hospital, Xuancheng, China.
Shi-Xiang
SX
Hou
Zhaoke Pharmaceutical Co. Ltd, Hefei, Anhui, China.
Xiao-Yi
XY
Li
Department of Anesthesiology, School of Medicine, Washington University, St. Louis, MO, USA.
Devin M
DM
Barry
Department of Pharmaceutical Chemistry, Jiangsu Changjiang Pharmaceutical Co. Ltd, Shanghai, China.
Hui
H
Jin
Department of Pharmacology, Anhui Academy of Medical Sciences, Hefei, Anhui, China.
Sheng-Yong
SY
Luo
Department of Pharmacology, School of Basic Medical Science, Anhui Medical University, Hefei, Anhui, China.
Feng
F
Kong
Zhaoke Pharmaceutical Co. Ltd, Hefei, Anhui, China.
Lit-Fui
LF
Lau
Zhaoke Pharmaceutical Co. Ltd, Hefei, Anhui, China.
Xiang-Rong
XR
Dai
Department of Pharmacy, Xuancheng People's Hospital, Xuancheng, China.|Zhaoke Pharmaceutical Co. Ltd, Hefei, Anhui, China.
Guo-Hui
GH
Zhang
Department of Pharmacology, School of Basic Medical Science, Anhui Medical University, Hefei, Anhui, China.
Lan-Lan
LL
Zhou
D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000187:drug effects; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002452:Cell Count; D002543:Cerebral Hemorrhage / Q000517:prevention & control; D003435:Crotalid Venoms / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005337:Fibrin / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery; D037181:Lectins, C-Type; D008297:Male; D051379:Mice; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000517:prevention & control*; D020521:Stroke / Q000473:pathology / Q000517:prevention & control*; D000077466:Tirofiban; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology; D014841:von Willebrand Factor / Q000378:metabolism
D003435:Crotalid Venoms; D037181:Lectins, C-Type; D019038:Platelet Glycoprotein GPIb-IX Complex; D020011:Protective Agents; D014841:von Willebrand Factor; D014443:Tyrosine; D005337:Fibrin; C000592236:agkisacucetin protein, Agkistrodon acutus; D000077466:Tirofiban