Trophic factors therapy in Parkinson's disease

Abstract

Parkinson's disease (PD) is a progressive, neurodegenerative disorder for which there is currently no effective neuroprotective therapy. Patients are typically treated with a combination of drug therapies and/or receive deep brain stimulation to combat behavioral symptoms. The ideal candidate therapy would be the one which prevents neurodegeneration in the brain, thereby halting the progression of debilitating disease symptoms. Neurotrophic factors have been in the forefront of PD research, and clinical trials have been initiated using members of the GDNF family of ligands (GFLs). GFLs have been shown to be trophic to ventral mesencephalic cells, thereby making them good candidates for PD research. This paper examines the use of GDNF and neurturin, two members of the GFL, in both animal models of PD and clinical trials.

Fig. 1

GDNF immunohistochemistry in aged monkeys receiving LV-GDNF or LV-βGal (control) in the striatum and substantia nigra. (A) Robust GDNF immunoreactivity is seen within the caudate and putamen in a LV-GDNF-treated aged monkey. (B) In contrast, no GDNF immunoreactivity is observed in a control LV-βGal-treated animal (IC, internal capsule). (C) Robust GDNF immunoreactivity is also observed within the midbrain of a LV-GDNF-treated monkey. (D) GDNF immunoreactivity within the forebrain of a LV-GDNF-treated monkey. Staining is seen within the injection site in the putamen (Pt) and within both segments of the globus pallidus (GPe and GPi) from anterograde transport. (E) GDNF immunohistochemistry is also seen in the substantia nigra pars reticulata from anterograde transport. Holes in the tissue are from postmortem for HPLC analysis. Asterisk in (E) represents a LV-GDNF injection site (CP, cerebral peduncle). Scale bar in (D) represents 1600 μm for panels A, B, and D; 1150 μm for panel C; and 800 μm for panel E.

Fig. 2

Tyrosine hydroxylase staining in aged monkeys receiving LV-GDNF to the right striatum. (A) LV-GDNF administration to the right striatum increases TH immunoreactivity within the right caudate and putamen in aged monkeys. (B) In monkeys receiving control LV-βGal injections to the right striatum, there is symmetrical and less intense staining for TH. (C) There are greater numbers and larger TH-immunoreactive neurons within the substantia nigra (SN) of LV-GDNF-treated animals relative to (D) a LV-βGal-treated monkeys. (E) LV-GDNF-treated aged monkeys display increased TH mRNA relative to (F) LV-βGal-treated monkeys in the SN. Scale bar in (F) represents 4500 μm for panels A and B; 250 μm for panels C and D; and 100 μm for panels E and F.

Fig. 3

TH immunoreactivity in unilaterally MPTP-lesioned young monkeys. (A and B) Low-power dark-field photomicrographs through the right striatum of TH-immunostained sections of MPTP-treated monkeys treated with (A) LV-βGal or (B) LV-GDNF. (A) There is a comprehensive loss of TH immunoreactivity in the caudate and putamen of LV-βGal-treated animal. In contrast, near normal level of TH immunoreactivity is seen in LV-GDNF-treated animals. Low-power (C and D) and intermediate-power (E and F) photomicrographs of TH-immunostained section through the substantia nigra of animals treated with LV-βGal (C and E) and LV-GDNF (D and F). There is a loss of TH-immunoreactive neurons in the LV-βGal-treated animals on the side of the MPTP injection. TH-immunoreactive sprouting fibers as well as a supranormal number of TH-immunoreactive nigral perikarya are seen in LV-GDNF-treated animals on the side of the MPTP injection. (G and H) Bright-field low-power photomicrographs of a TH-immunostained section from a LV-GDNF-treated monkey. (G) Note the normal TH-immunoreactive fiber density through the globus pallidus on the intact side, which was not treated with LV-GDNF. (H) In contrast, an enhanced network of TH-immunoreactive fibers is seen on the side treated with both MPTP and LV-GDNF. Scale bar in (G) represents the following magnifications: panels A–D at 3500 μm and panels E–H at 1150 μm.