title: 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.
  
  
  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.affiliation: University Hospital Würzburg, Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Stegner
authors.forename: Ina
authors.initials: I
authors.lastname: Thielmann
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.forename: Michael A
authors.initials: MA
authors.lastname: Frohman
authors.forename: Guido
authors.initials: G
authors.lastname: Stoll
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology; D002340:Carotid Artery Diseases / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004294:Domperidone / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006487:Hemostasis / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology*; D020244:Infarction, Middle Cerebral Artery / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D016023:Integrins / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010739:Phospholipase D / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D020127:Recovery of Function; D013927:Thrombosis / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D013997:Time Factors
chemical_list: C546435:5-fluoro-2-indolyldeschlorohalopemide; D004791:Enzyme Inhibitors; D005343:Fibrinolytic Agents; D007211:Indoles; D016023:Integrins; D004294:Domperidone; C105606:phospholipase D2; D010739:Phospholipase D; C106801:phospholipase D1
keywords: 5-fluoro-2-indolyl des-chlorohalopemide; cerebral stroke; phospholipase D; thrombosis