A novel snake venom-derived GPIb antagonist, anfibatide, protects mice from acute experimental ischaemic stroke and reperfusion injury

Br J Pharmacol. 2015 Aug;172(15):3904-16. doi: 10.1111/bph.13178. Epub 2015 Jun 12.

Abstract

Background and purpose: 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.

Experimental approach: 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.

Key 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 and implications: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bleeding Time
  • Blood Platelets / drug effects
  • Brain Ischemia / metabolism
  • Brain Ischemia / pathology
  • Brain Ischemia / prevention & control*
  • Cell Count
  • Cerebral Hemorrhage / prevention & control
  • Crotalid Venoms / pharmacology*
  • Dose-Response Relationship, Drug
  • Fibrin / metabolism
  • Infarction, Middle Cerebral Artery
  • Lectins, C-Type
  • Male
  • Mice
  • Platelet Glycoprotein GPIb-IX Complex / antagonists & inhibitors*
  • Platelet Glycoprotein GPIb-IX Complex / metabolism
  • Protective Agents / pharmacology*
  • Reperfusion Injury / prevention & control*
  • Stroke / pathology
  • Stroke / prevention & control*
  • Tirofiban
  • Tyrosine / analogs & derivatives
  • Tyrosine / pharmacology
  • von Willebrand Factor / metabolism

Substances

  • Crotalid Venoms
  • Lectins, C-Type
  • Platelet Glycoprotein GPIb-IX Complex
  • Protective Agents
  • agkisacucetin protein, Agkistrodon acutus
  • von Willebrand Factor
  • Tyrosine
  • Fibrin
  • Tirofiban