Glial cell line-derived neurotrophic factor (GDNF) was applied topically on the brain surface immediately after permanent middle cerebral artery (MCA) occlusion in rats. In contrast to the cases treated with vehicle, a formation of brain edema was significantly reduced at one day by the treatment with GDNF. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL) staining was markedly reduced in the cases with GDNF treatment at 12 h after MCA occlusion. However, the induction of immunoreactive 70-kd heat shock protein (HSP70) was slightly ameliorated by the GDNF treatment. The present results suggest that the treatment with GDNF has a significant effect on ameliorating brain edema formation after continuous brain ischemia, and the effect is greatly associated with the reduction of apoptotic changes, but slightly with that of stress response of cells.