Early transplantation of an encapsulated glial cell line-derived neurotrophic factor-producing cell demonstrating strong neuroprotective effects in a rat model of Parkinson disease.
OBJECTIVE
Glial cell line-derived neurotrophic factor (GDNF) has been shown to confer neuroprotective effects on dopaminergic neurons. The authors investigated the effects of GDNF on 6-hydroxydopamine (6-OHDA)-treated dopaminergic neurons in vitro and in vivo.


METHODS
First, the authors examined how 1, 10, or 100 ng/ml of GDNF, administered to cells 24 hours before, simultaneously with, or 2 or 4 hours after 6-OHDA was added, affected dopaminergic neurons. In a primary culture of E14 murine ventral mesencephalic neurons, earlier treatment with the higher dosage of GDNF suppressed 6-OHDA-induced loss of dopaminergic neurons better than later treatment. Next, the authors examined whether continuous infusion of GDNF at earlier time points would demonstrate a greater neuroprotective effect in a rat model of Parkinson disease (PD). They established a human GDNF-secreting cell line, called BHK-GDNF, and encapsulated the cells into hollow fibers. The encapsulated cells were unilaterally implanted into the striatum of adult rats 1 week before; simultaneously with; or 1, 2, or 4 weeks after 6-OHDA was given to induce lesions of the same striatum. With the earlier transplantation of a BHK-GDNF capsule, there was a significant reduction in the number of amphetamine-induced rotations displayed by the animals. Rats that had received earlier implantation of BHK-GDNF capsules displayed more tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta and a tendency for glial proliferation in the striatum.


CONCLUSIONS
These neuroprotective effects may be related to glial proliferation and signaling via the GDNF receptor alpha1. The results of this study support a role for this grafting technique in the treatment of PD.
Yasuhara
Takao
T
Department of Neurological Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan. tyasu37@cc.okayama-u.ac.jp
Shingo
Tetsuro
T
Muraoka
Kenichiro
K
Kobayashi
Kazuki
K
Takeuchi
Akira
A
Yano
Akimasa
A
Wenji
Yuan
Y
Kameda
Masahiro
M
Matsui
Toshihiro
T
Miyoshi
Yasuyuki
Y
Date
Isao
I
D018663:Adrenergic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000661:Amphetamine / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002460:Cell Line; D017690:Cell Transplantation / Q000379:methods*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D018014:Gene Transfer Techniques; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D009414:Nerve Growth Factors / Q000008:administration & dosage / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D016627:Oxidopamine / Q000008:administration & dosage / Q000494:pharmacology; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology* / Q000601:surgery*; D011108:Polymers / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D012399:Rotation; D013997:Time Factors
D018663:Adrenergic Agents; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D011108:Polymers; D016627:Oxidopamine; D000661:Amphetamine