Granulocyte-Colony Stimulating Factor Delays PWI/DWI Mismatch Evolution and Reduces Final Infarct Volume in Permanent-Suture and Embolic Focal Cerebral Ischemia Models in the Rat

Abstract

Background and Purpose-Granulocyte-colony stimulating factor (G-CSF) is used clinically to attenuate neutropenia after chemotherapy. G-CSF acts as a growth factor in the central nervous system, counteracts apoptosis, and is neuroprotective in rodent transient ischemia models. Methods-We assessed the effect of G-CSF on ischemic lesion evolution in a rat permanent-suture occlusion model with diffusion-and perfusion-weighted magnetic resonance imaging and the neuroprotective effect of G-CSF in a rat embolic stroke model. Results-With a constant perfusion deficit, vehicle-treated animals showed an expanding apparent diffusion coefficient lesion volume that matched the perfusion deficit volume at Ϸ3 hours, with the 24-hour infarct volume equivalent to the perfusion deficit. In G-CSF-treated rats, the apparent diffusion coefficient lesion volume did not increase after treatment initiation, and the infarct volume at 24 hours reflected the initial apparent diffusion coefficient lesion volume. In the embolic model, we observed a significant decrease in infarct volume in G-CSF-treated animals compared with the vehicle-treated group. Conclusions-These results confirm the potent neuroprotective activity of G-CSF in different focal ischemia models. The magnetic resonance imaging data demonstrate that G-CSF preserved the perfusion/diffusion mismatch.

Novel Approaches to Neuroprotection Trials in Acute Ischemic Stroke

“…7,17,19 The use of early treatment is also corroborated in a primate study in which cynomolgus macaques were subjected to small embolic strokes induced by intracarotid injections of polystyrene microemboli, effectively producing a permanent vessel occlusion. Administration of the neuroprotectant NA-1 at 1 hour after stroke onset reduced the number and volume of the resulting infarcts.…”

“…Imaging experiments of rats subjected to pMCAO suggest that, in the absence of intervention, stroke damage measured by 3 hours is similar to that observed at 24 hours. [17][18][19] Cats are even more sensitive to ischemia such that, irrespective of the level of reperfusion, markers of tissue death 2 to 3 hours after pMCAO already predict the size of the final infarcts. 20 In cynomolgus macaques, stroke damage in animals subjected to pMCAO also reaches a plateau by 3 to 4 hours ( Figure).…”

Identifying and utilizing the ischemic penumbra

“…Treatment experiments demonstrated that granulocyte colony stimulating factor initiated 1 hour after stroke onset in the permanent occlusion suture model halted the enlargement of the DWI, maintaining the DWI-PWI mismatch for many hours, and reduced the extent of histologically confirmed infarction at 24 hours. 24 In the embolic rat stroke model, high-flow normobaric hyperoxia also stopped the enlargement of the DWI lesion, and when combined with IV tissue plasminogen activator (tPA) at 3 hours after stroke onset, it allowed this therapy to significantly reduce infarct volume at 24 hours in comparison with a control group (room air and tPA at 3 hours). 25 Characterizing penumbral tissue by using absolute ADC values and quantitative CBF measurements with arterial spin-labeling PWI appears to be more precise than the relatively simplistic approach with bolus contrast PWI.…”

Bone Marrow Cell Transplantation Time-Dependently Abolishes Efficacy of Granulocyte Colony-Stimulating Factor After Stroke in Hypertensive Rats

“…Many studies reproduced this finding and 2 meta-analyses consistently confirmed a significant impact of G-CSF on the infarct volume, the most frequently used surrogate for neuroprotection. 2,3 Interestingly, the same meta-analysis revealed, in contrast to one recent study, 14 that the infarct volume was not influenced by G-CSF treatment in permanent stroke, 2 likely owing to the fact that the neuroprotective time window is shorter in permanent stroke (3 hours) compared with the classical ischemia/ reperfusion models (up to 12 hours). 15 In SHR, neuroprotection is even limited to the first 60 minutes after MCAO.…”