Glial cell line-derived neurotrophic factor (GDNF): a drug candidate for the treatment of Parkinson's disease.
Considerable effort has been devoted to the search for molecules that might exert trophic influences on midbrain dopamine neurons, and potentially be of therapeutic value in the treatment of Parkinson's disease. One such candidate is glial cell line-derived neurotrophic factor (GDNF). GNDF is distantly related to the transforming growth factor-beta superfamily and is widely expressed in many neuronal and non-neuronal tissues. GDNF uses a multisubunit receptor system in which GFRalpha-1 and Ret function as the ligand-binding and signalling components, respectively. 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 models of Parkinson's disease. Intraventricular, intrastriatal and intranigral routes of administration are efficacious in both models. In parkinsonian nonhuman primates, GDNF treatment improves bradykinesia, rigidity 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 hours following trophic factor administration in rodents. The powerful neuroprotective and neurorestorative properties of GDNF seen in preclinical studies suggest that trophic factors may play an important role in treating Parkinson's disease.
Grondin
R
R
Department of Anatomy and Neurobiology, University of Kentucky Medical Center, Lexington 40536-0084, USA.
Gash
D M
DM
D000328:Adult; D000818:Animals; D048429:Cell Size; D004298:Dopamine / Q000494:pharmacology*; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006801:Humans; D008253:Macaca mulatta; D051379:Mice; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy*; D051381:Rats; D015398:Signal Transduction; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology; D016896:Treatment Outcome; D014793:Visual Cortex / Q000187:drug effects / Q000473:pathology
C495039:GDNF protein, human; C495040:Gdnf protein, mouse; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D004298:Dopamine