Glial cell line-derived neurotrophic factor (GDNF) gene delivery protects dopaminergic terminals from degeneration

Previously, we observed that injection of an adenoviral (Ad) vector express ing glial cell line derived neurotrophic factor (GDNF) into the striatum, b ut not the substantia nigra (SN), prior to a partial B-OHDA lesion protects dopaminergic (DA) neuronal function and prevents the development of behavi oral impairment in the aged rat. This suggests that striatal injection of A dGDNF maintains nigrostriatal function either by protecting DA terminals or by stimulating axonal sprouting to the denervated striatum, To distinguish between these possible mechanisms, the present study examines the effect o f GDNF gene delivery on molecular markers of DA terminals and neuronal spro uting in the aged (20 month) rat brain. AdGDNF or a control vector coding f or P-galactosidase (AdLac Z) was injected unilaterally into either the stri atum or the SN. One week later, rats received a unilateral intrastriatal in jection of 6-OHDA on the side of vector injection. Two weeks postlesion, ra ts injected with AdGDNF into either the striatum or the SN exhibited a redu ction in the area of striatal denervation and increased binding of the DA t ransporter ligand [I-125]PCIT in the lesioned striatum compared to control animals. Furthermore, injections of AdGDMF into the striatum, but not the S N, increased levels of tyrosine hydroxylase mRNA in lesioned DA neurons in the SN and prevented the development of amphetamine-induced rotational asym metry. In contrast, the level of T1. a-tubulin mRNA, a marker of neuronal s prouting, was not increased in lesioned DA neurons in the SN following inje ction of AdGDNF either into the striatum or into the SN,These results sugge st that GDNF gene delivery prior to a partial lesion ameliorates damage cau sed by 6-OHDA in aged rats by inhibiting the degeneration of DA terminals r ather than by inducing sprouting of nigrostriatal axons. (C) 2001 Academic Press.