Glial cell line-derived neurotrophic factor (GDNF), a recently described and cloned member of the transforming growth factor (TGF)-β superfamily, has been shown to have marked trophic activity on several populations of central neurons. Survival-promoting and injury protectant activity in vitro and in vivo, using several paradigms, has been demonstrated for ventral mesencephalic dopaminergic neurons and spinal cord motoneurons. In view of a proposed commonality of mechanisms, involving intracellular free radical generation, depolarization-induced Ca²⁺ influx, and mitochondrial respiratory enzyme injury, between such GDNF-responsive paradigms and those of ischemia-induced injury, we tested the effects of GDNF on the extent of neural degeneration induced by transient middle cerebral artery (MCA) occlusion. We now report that intracerebroventricular and intraparenchymal administration of GDNF potently protects the cerebral hemispheres from damage induced by MCA occlusion. In addition, the increase in nitric oxide that accompanies MCA occlusion and subsequent reperfusion is blocked almost completely by GDNF. Thus, this protein may play an important role in the treatment of cerebrovascular occlusive disease.