Glial-cell-line-derived neurotrophic factor (
GDNF) promotes mesencephalic dopaminergic neuronal survival in several in vitro and in vivo models. As the demise of dopaminergic neurons is the cause for
Parkinson's disease (PD) symptoms,
GDNF is a promising agent for its treatment. However, this
neurotrophin is unable to cross the blood-brain barrier, which has complicated its clinical use. Therefore, ways to deliver
GDNF into the central nervous system in an effective manner are needed. The HIV-1-Tat-derived
cell-penetrating peptide (
CPP) provides a means to deliver fusion
proteins into the brain. We generated a fusion
protein between the 11
amino acid CPP of Tat and the rat
GDNF mature
protein to deliver
GDNF across the blood-brain barrier. We showed previously that Tat-
GDNF enhances the
neuroprotective effect of
GDNF in in vivo models for nerve
trauma and
ischemia. Here, we tested its effect in a subchronic scheme of
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (
MPTP) application into the mouse as a model for PD to evaluate the effect of Tat-
GDNF fusion
protein in dopaminergic neuron survival. We showed that the fusion
protein did indeed reach the dopaminergic neurons. However, the in vivo application of Tat-
GDNF did not provide neuroprotection of dopaminergic neurons, as revealed by immunohistochemistry and counting of the number of
tyrosine-hydroxylase-immunoreactive neurons in the substantia nigra pars compacta. Possibly,
GDNF does protect nigro-striatal projections of those neurons that survive
MPTP treatment but does not increase the number of surviving dopaminergic neurons. A concomitant treatment of Tat-
GDNF with an anti-apoptotic Tat-fusion
protein might be beneficial.