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Background  Granulocyte colony-stimulating factor (G-CSF) is a pharmacologic agent inducing neutrophil mobilization and a new candidate for neuroprotection and neuroregeneration in stroke. Its effects when used in combination with tissue plasminogen activator (tPA) were explored during the acute phase of ischemic stroke.    Methods  We used a middle cerebral artery occlusion (MCAO) model of cerebral ischemia, associated with treatment with tPA, in male spontaneously hypertensive rats (SHR). Granulocyte colony-stimulating factor (G-CSF; 60 μg/kg) was injected just before tPA. Neutrophil response in peripheral blood and in the infarct area was quantified in parallel to the infarct volume. Protease matrix metallopeptidase 9 (MMP-9) release from circulating neutrophils was analyzed by immunochemistry and zymography. Vascular reactivity and hemorrhagic volume in the infarct area was also assessed.    Results  Twenty four hours after ischemia and tPA, G-CSF administration induced a significant increase of neutrophils in peripheral blood ( P  <0.05). At 72 hours post-ischemia, G-CSF was significantly associated with an increased risk of hemorrhage in the infarct area (2.5 times more likely;  P  <0.05) and significant cerebral endothelium-dependent dysfunction.  Ex vivo,  an increased MMP-9 release from neutrophils after tPA administration correlated to the increased hemorrhagic risk ( P  <0.05). In parallel, G-CSF administration was associated with a decreased neutrophil infiltration in the infarct area (-50%;  P  <0.05), with a concomitant significant neuroprotective effect (infarct volume: -40%;  P  <0.05).    Conclusions  We demonstrate that G-CSF potentiates the risk of hemorrhage in experimental stroke when used in combination with tPA by inducing neutrophilia. This effect is concomitant to an increased MMP-9 release from peripheral neutrophils induced by the tPA treatment. These results highlight the potential hemorrhagic risk of associating G-CSF to thrombolysis during the acute phase of stroke.

journal of neuroinflammation

Impact of the neutrophil response to granulocyte colony-stimulating factor on the risk of hemorrhage when used in combination with tissue plasminogen activator during the acute phase of experimental stroke