Pharmacological inhibition of phospholipase D protects mice from occlusive thrombus formation and ischemic stroke--brief report.
Arterioscler Thromb Vasc Biol
; 33(9): 2212-7, 2013 Sep.
Article
en En
| MEDLINE
| ID: mdl-23868933
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 ANDRESULTS:
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.Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Fosfolipasa D
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Trombosis
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Plaquetas
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Enfermedades de las Arterias Carótidas
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Infarto de la Arteria Cerebral Media
/
Domperidona
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Inhibidores Enzimáticos
/
Fibrinolíticos
/
Indoles
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Arterioscler Thromb Vasc Biol
Asunto de la revista:
ANGIOLOGIA
Año:
2013
Tipo del documento:
Article
País de afiliación:
Alemania