Single administration of GDNF into the striatum induced protection and repair of the nigrostriatal dopaminergic system in the intrastriatal 6-hydroxydopamine injection model of hemiparkinsonism

Purpose: Neurotrophic factor delivery into the brain is a promising approach in the treatment of Parkinson's disease. Glial cell line-derived neurotrophic factor (GDNF) is one of the most potent neurotrophic factors for dopaminergic neurons. Although multiple injections of GDNF into the brain are commonly performed in experimental studies, the present study investigates the efficacy of using a single injection of GDNF, which may be useful in clinically applying this treatment. Methods: Unilateral 6-hydroxydopamine (6-OHDA) administration into the striatum was performed in Sprague-Dawley rats to create a partial lesion of the nigrostriatal DA system. These parkinsonian model rats received a single injection of human recombinant GDNF into the same portion of the striatum either 24 h before or 4 weeks after 6-OHDA treatment. Results: GDNF injected into the striatum before 6-OHDA administration potently protected the dopaminergic system, as shown by the numbers of mesencephalic dopaminergic neuron cell bodies and dopaminergic nerve terminal densities in the striatum. Dopaminergic neuron cell bodies and fiber densities were also significantly restored when GDNF was given after 6-OHDA administration, although the degree of restoration was lower than in the protective experiment. GDNF administration ameliorated apomorphine-induced rotational behavior in animals receiving it either before or after 6-OHDA treatment. However, the degree of improvement was less prominent when GDNF was injected after 6-OHDA. Conclusion: Intracerebral GDNF administration exerts both protective and regenerative effects on the nigrostriatal dopaminergic system, a finding which may have implications for the development of new treatment strategies for Parkinson's disease.