Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor with neuroprotective and antiinflammatory properties. By real-time polymerase chain reaction we show that G-CSF transcripts are induced 485-fold at 4 h and 65-fold at 16 h in ischemic lesions after middle cerebral artery occlusion compared to control brains. Further analysis in photochemically induced focal ischemia revealed that G-CSF induction involved both the infarct area and remote nonischemic brain regions. Remote responses could be blocked by the noncompetitive NMDA receptor antagonist MK-801, suggesting periinfarct depolarizations as a trigger. To further confirm this notion, cortical spreading depression (CSD) was induced by focal application of KCl to the brain surface. CSD led to a 90-fold increase in G-CSF mRNA. Contrastingly, the induction of granulocyte-monocyte (GM)-CSF, another member of the hematopoietic growth factor family, was only moderate (sixfold) and restricted to ischemic brain lesions. In conclusion, G-CSF induction in the brain may be part of an intrinsic stress response aimed at limitation of neuronal damage.