GLIAL-CELL LINE-DERIVED NEUROTROPHIC FACTOR (GDNF) - A DRUG CANDIDATEFOR THE TREATMENT OF PARKINSONS-DISEASE

Considerable effort has been devoted to the search for molecules that might exert trophic influences on midbrain dopamine neurons, and poten tially be of therapeutic value in the treatment of Parkinson's disease . One such candidate is glial cell line-derived neurotrophic factor (G DNF). GNDF is distantly related to the transforming growth factor-P su perfamily and is widely expressed in many neuronal and nonneuronal tis sues. GDNF uses a multisubunit receptor system in which GFR alpha-1 an d Ret function as the ligand-binding and signalling components, respec tively. In addition to its effects on cultured fetal midbrain dopamine neurons, GDNF promotes recovery of the injured nigrostriatal dopamine system and improves motor functions in rodent and nonhuman primate mo dels of Parkinson's disease. Intraventricular, intrastriatal and intra nigral routes of administration are efficacious in both models. In par kinsonian nonhuman primates, GDNF treatment improves bradykinesia, rig idity and postural instability. In this model, adult midbrain dopamine neurons stimulated by GDNF show increased cell size, neuritic extent, and expression of phenotypic markers. The neurorestorative effects of a single administration of GDNF last for at least a month and can be maintained in rhesus monkeys by monthly injections. GDNF also induces neuroprotective changes in dopamine neurons, which are active within h ours following trophic factor administration in rodents. The powerful neuroprotective and neurorestorative properties of GDNF seen in precli nical studies suggest that trophic factors may play an important role in treating Parkinson's disease.