Protection and regeneration of nigral dopaminergic neurons by neurturin orGDNF in a partial lesion model of Parkinson's disease after administrationinto the striatum or the lateral ventricle

Both glial cell line-derived neurotrophic factor (GDNF) and its recently di scovered congener, neurturin (NTN), have been shown to excert neuroprotecti ve effects on lesioned nigral dopamine (DA) neurons when administered at th e level of the substantia nigra. In the present study, we have explored the relative in vivo potency of these two neurotrophic factors using two alter native routes of administration, into the striatum or the lateral ventricle , which may be more relevant in a clinical setting. In rats subjected to an intrastriatal (IS) 6-hydroxydopamine (6-OHDA) lesion, GDNF and NTN were in jected every third day for 3 weeks starting on the day after the 6-OHDA inj ection. GDNF provided almost complete (90-92%) protection of the lesioned n igral DA neurons after both IS and intracerebroventricular (ICV) administra tion. NTN, by contrast, was only partially effective after IS injection (72 % sparing) and totally ineffective after ICV injection. Although the trophi c factor injections protected the nigral neurons from lesion-induced cell d eath, the level of expression of the phenotypic marker, tyrosine hydroxylas e (TH), was markedly reduced in the rescued cell bodies. The extent of 6-OH DA-induced DA denervation in the striatum was unaffected by both types of t reatment; consistent with this observation, the high rate of amphetamine-in duced turning seen in the lesioned control animals was unaltered by either GDNF or NTN treatment. In the GDNF-treated animals, and to a lesser extent also after IS NTN treatment, prominent axonal sprouting was observed within the globus pallidus, at the level where the lesioned nigrostriatal axons a re known to end at the time of onset of the neurotrophic factor treatment. The results show that GDNF is highly effective as a neuroprotective and axo n growth-stimulating agent in the IS 6-OHDA lesion model after both IS and ICV administration. The lower efficacy of NTN after IS, and particularly IC V, administration may be explained by the poor solubility and diffusion pro perties at neutral pH.