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

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

Arteriosclerosis, thrombosis, and vascular biology (2013-07-23)
David Stegner, Ina Thielmann, Peter Kraft, Michael A Frohman, Guido Stoll, Bernhard Nieswandt
ZUSAMMENFASSUNG

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

MATERIALIEN
Produktnummer
Marke
Produktbeschreibung

Sigma-Aldrich
Phospholipase D aus Streptomyces chromofuscus, ≥50,000 units/mL, buffered aqueous glycerol solution
Sigma-Aldrich
Phospholipase D aus Kohl, Type IV, lyophilized powder, ≥100 units/mg solid
Sigma-Aldrich
Domperidon, powder, ≥98% (HPLC)
Sigma-Aldrich
Phospholipase D from Streptomyces sp., Type VII, lyophilized powder, ≥150 units/mg solid
Sigma-Aldrich
Phospholipase D from Arachis hypogaea (peanut), Type II, lyophilized powder, ≥60 units/mg protein
Domperidon, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
FIPI hydrochloride hydrate, ≥98% (HPLC), powder