GLIAL-CELL LINE-DERIVED NEUROTROPHIC FACTOR PROTECTS AGAINST ISCHEMIA-INDUCED INJURY IN THE CEREBRAL-CORTEX

Glial cell line-derived neurotrophic factor (GDNF), a recently describ ed and cloned member of the transforming growth factor (TGF)-beta supe rfamily, has been shown to have marked trophic activity on several pop ulations of central neurons. Survival-promoting and injury protectant activity in vitro and in vivo, using several paradigms, has been demon strated for ventral mesencephalic dopaminergic neurons and spinal cord motoneurons. In view of a proposed commonality of mechanisms, involvi ng intracellular free radical generation, depolarization-induced Ca2influx, 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 tr ansient middle cerebral artery (MCA) occlusion. We now report that int racerebroventricular and intraparenchymal administration of GDNF poten tly protects the cerebral hemispheres from damage induced by MCA occlu sion. In addition, the increase in nitric oxide that accompanies MCA o cclusion and subsequent reperfusion is blocked almost completely by GD NF. Thus, this protein may play an important role in the treatment of cerebrovascular occlusive disease.