Pharmacological inhibition of phospholipase D protects mice from occlusive thrombus formation and ischemic stroke--brief report.

Abstract

OBJECTIVE:

We recently showed that mice lacking the lipid signaling enzyme phospholipase (PL) D1 or both PLD isoforms (PLD1 and PLD2) were protected from pathological thrombus formation and ischemic stroke, whereas hemostasis was not impaired in these animals. We sought to assess whether pharmacological inhibition of PLD activity affects hemostasis, thrombosis, and thrombo-inflammatory brain infarction in mice.

APPROACH AND RESULTS:

Treatment of platelets with the reversible, small molecule PLD inhibitor, 5-fluoro-2-indolyl des-chlorohalopemide (FIPI), led to a specific blockade of PLD activity that was associated with reduced α-granule release and integrin activation. Mice that received FIPI at a dose of 3 mg/kg displayed reduced occlusive thrombus formation upon chemical injury of carotid arteries or mesenterial arterioles. Similarly, FIPI-treated mice had smaller infarct sizes and significantly better motor and neurological function 24 hours after transient middle cerebral artery occlusion. This protective effect was not associated with major intracerebral hemorrhage or prolonged tail bleeding times.

CONCLUSIONS:

These results provide the first evidence that pharmacological PLD inhibition might provide a safe therapeutic strategy to prevent arterial thrombosis and ischemic stroke.

• Authors: David Stegner, Ina Thielmann, Peter Kraft, Michael A Frohman, Guido Stoll, Bernhard Nieswandt
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 33 Issue 9 Pg. 2212-7 (Sep 2013) ISSN: 1524-4636 [Electronic] United States
• PMID: 23868933 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-fluoro-2-indolyldeschlorohalopemide
• Enzyme Inhibitors
• Fibrinolytic Agents
• Indoles
• Integrins
• Domperidone
• phospholipase D2
• Phospholipase D
• phospholipase D1

Topics

• Animals
• Blood Platelets (drug effects, enzymology)
• Carotid Artery Diseases (blood, enzymology, genetics, physiopathology, prevention & control)
• Disease Models, Animal
• Domperidone (analogs & derivatives, pharmacology)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Fibrinolytic Agents (pharmacology)
• Hemostasis (drug effects)
• Indoles (pharmacology)
• Infarction, Middle Cerebral Artery (blood, enzymology, genetics, physiopathology, prevention & control)
• Integrins (blood)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Phospholipase D (antagonists & inhibitors, deficiency, genetics)
• Recovery of Function
• Thrombosis (blood, enzymology, genetics, physiopathology, prevention & control)
• Time Factors