Pigment epithelium derived factor (PEDF) is neuroprotective in two in vitro models of Parkinson's disease.
Transplantation of retinal pigment epithelial (RPE) cells in the basal ganglia has been proposed as a novel cell-based therapy for Parkinson's disease (PD), by providing a constant source of dopamine replacement via the melanin synthetic pathway enzyme tyrosinase. We have demonstrated previously that human RPE cells also produce a neurotrophic effect on primary cultures of rat striata mesencephalic (dopaminergic) neurons and showed that pigment epithelium derived factor (PEDF) accounted for a major portion of the neurotrophic effect. We now have also begun studies that demonstrate that the neurotrophic effect of PEDF corresponds to neuroprotection against toxins used to produce experimental PD. This was shown in (1) rotenone and (2) 6-hydroxydopamine (6-OHDA) in vitro models. The toxins were added at day 10 in culture, PEDF was added 1h prior. The cultures were fixed and analyzed after tyrosine hydroxylase (TH) immunocytochemical staining. Cell count of TH+ neurons clearly shows the neuroprotective potential of PEDF in both neurotoxin models. The neurotoxic effect of rotenone (25nM) on dopaminergic neurons is reversed by addition of PEDF. At a concentration of 1ng/ml PEDF the neurotoxic effect of rotenone is completely counteracted. PEDF (1ng/ml) has also a neuroprotective effect in the 6-OHDA midbrain in vitro model. The effect is most pronounced at concentrations of 25microM and 50microM 6-OHDA. We conclude that the neurotrophic factor PEDF, produced from RPE cells, can improve neuronal survival in models of PD, and plan to test if this effect can be observed using in vivo models of PD following RPE transplantation.
Falk
Torsten
T
College of Medicine, University of Arizona, Department of Neurology, Tucson, AZ 85724, USA. tfalk@u.arizona.edu <tfalk@u.arizona.edu>
Zhang
Shiling
S
Sherman
Scott J
SJ
D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005136:Eye Proteins / Q000627:therapeutic use*; D005260:Female; D007306:Insecticides / Q000633:toxicity; D009414:Nerve Growth Factors / Q000627:therapeutic use*; D016501:Neurites / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone / Q000633:toxicity; D015843:Serpins / Q000627:therapeutic use*; D046509:Tissue Culture Techniques; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D000099174:Pigment Epithelium-Derived Factor
D018663:Adrenergic Agents; D005136:Eye Proteins; D007306:Insecticides; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D016627:Oxidopamine; D012402:Rotenone; D015843:Serpins; D014446:Tyrosine 3-Monooxygenase; D000099174:Pigment Epithelium-Derived Factor