Trophic effects of
neurturin, a member of the
glial cell line-derived neurotrophic factor-family, have been demonstrated on mesencephalic dopaminergic neurons, suggesting its therapeutic potential for
Parkinson's disease. This study was designed to test the neuroprotective and regenerative effects of an intrastriatal injection of
neurturin based on behavioral, neurochemical and histochemical changes in a rat model of progressive
Parkinson's disease. An extensive and progressive dopaminergic lesion was unilaterally made by intrastriatal convection-enhanced delivery of
6-hydroxydopamine (6-OHDA), in which 20 microg of
6-OHDA dissolved in 20 microl of vehicle was infused at a rate of 0.2 microl/min. For neuroprotection study, recombinant human
neurturin (5 microg in 5 microl of vehicle) was stereotaxically injected into the unilateral striatum. The
6-OHDA lesion was made on the ipsilateral side 3 days after the
neurturin treatment.
Tyrosine hydroxylase (TH)-immunoreactive neurons of the substantia nigra were protected from progressive degeneration in the
neurturin-treated animals compared with the vehicle-treated animals 2 and 8 weeks after the
6-OHDA lesion. Eight weeks after the
6-OHDA lesion,
dopamine concentration significantly increased in the striatum of
neurturin-treated animals with improvement of
methamphetamine-induced rotation behavior. For neuroregeneration study, 5 microg of
neurturin was injected into the striatum 12 weeks after the
6-OHDA lesion. Four weeks after
neurturin or vehicle injection, there were no significant differences in the survival of nigral TH-immunoreactive neurons between the groups. However, TH-immunoreactive fibers were thicker and more abundant in the striatum of the
neurturin-treated rats compared to those of the control group, suggesting
neurturin-induced growth of the dopaminergic axons. Striatal
dopamine levels also significantly increased in the
neurturin-treated rats compared with those in the control group of rats, accompanied by the recovery of
methamphetamine-induced rotation in the
neurturin-treated rats. In conclusion, an intrastriatal injection of
neurturin is a useful method to protect nigral dopaminergic neurons from extensive cell death in a model of progressive
Parkinson's disease, as well as to promote the axonal regeneration and dopaminergic function.