Chapter 8: Neuroprotection in Parkinson's Disease

Neurotrophic factors (NTFs) are small natural proteins that promote survival of nerve cells as well as the maintenance of their morphological and functional phenotype. NTFs, particularly the glial cell line-derived neurotrophic factor (GDNF), have aroused clinical interest as potential neuroprotective agents that could prevent or retard the progression of Parkinson's disease (PD). Numerous studies have shown that intrastriatal administration of exogenous GDNF has protective effects of mesencephalic dopaminergic neurons in vitro and in vivo. Similarly, intrastriatal grafting of dopamine- and GDNF-producing carotid body glomus cells has clinical benefit in parkinsonian animal models, and possibly in PD patients. However, the clinical effect of continuous intraputaminal recombinant GDNF infusion through a canula in advanced PD patients is practically negligible. These studies have, however, raised numerous concerns regarding the compatibility of recombinant GDNF and the route of administration of the protein. We have recently developed the conditional GDNF knock out mice in which GDNF production can be drastically reduced during adulthood. These animals develop a parkinsonian motor syndrome with selective destruction of dopaminergic substantia nigra neurons as well as noradrenergic neurons in the locus coeruleus. These data suggest that GDNF is absolutely required for the survival of adult catecholaminergic neurons. They also strongly support the view that, if adequately designed, intrastriatal GDNF delivery should have a neuroprotective therapeutic action in PD.