Neuroprotective and regenerative actions of GDNF and neurturin on nigral dopamine neurons in rat models of Parkinson’s disease – Prospects for clinical use of neurotrophic factors in neurodegenerative disorders

Abstract: Parkinson’s disease is characterized by progressive degeneration of the nigrostriatal dopamine system, which results in tremor, rigidity, akinesia and postural abnormalities. New therapeutic strategies are aimed at halting the neurodegenerative process or restoring the system by transplantation of fetal dopamine neurons. We have investigated the potential of the neurotrophic factors glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) to (1) protect nigral dopamine neurons and induce functional recovery in adult lesioned dopamine neurons and (2) enhance survival, fiber outgrowth and function of transplanted fetal dopamine neurons. Intrastriatal administration of the dopamine neuron specific toxin 6-hydroxydopamine results in a progressive and partial degeneration of the nigrostriatal dopaminergic system (similar to Parkinson’s disease), which render it suitable for studies of neuroprotection, regeneration and functional recovery. GDNF, was able to completely or near-completely protect the nigral dopamine neurons when given over the substantia nigra, into the striatum or intracerebroventricularly (ICV) early after the 6-hydroxydopamine lesion. We also observed that the retraction of nigrostriatal fibers was partially prevented by GDNF administered into the striatum or ICV. The effect of NTN was more moderate with partial protection after intrastriatal injections while ICV administration was uneffective. GDNF was also able to induce regeneration of DA fibers in the striatum and the globus pallidus after intrastriatal injections but the site and magnitude of this response was variable. The lesion produced deficits in both spontaneous and drug-induced behavioral tests. Functional recovery could be obtained by intrastriatal GDNF administration but only when the striatal dopamine innervation was increased. Thus GDNF and NTN are potent neurotrophic factors for the lesioned nigrostriatal dopamine neurons. Sustained administration of GDNF and NTN to fetal dopamine neurons grafted to the striatum of rats with complete unilateral 6-hydroxydopamine lesions, resulted in a marked 1.6-1.9-fold increase in the number of surviving dopamine neurons. GDNF was also found to enhance the fiber outgrowth and function of the transplant. The results indicate that addition of these neurotrophic factors can improve the efficacy of fetal dopamine neurons transplants in patients with Parkinson’s disease.