Control of dopamine-secretion by Tet-Off system in an in vivo model of parkinsonian rat.
We established a PC12 cell line (PC12TH Tet-Off) in which human tyrosine hydroxylase (TH) expression can be negatively controlled by Doxycycline (Dox). First, dopamine (DA)-secretion from PC12TH Tet-Off cells was controlled by Dox-administration in a dose-responsive manner ranging from 0 to 100 ng/ml for 70 days in vitro. Furthermore, Parkinson's disease model of rats receiving encapsulated PC12TH Tet-Off cells displayed a significant decrease of dopamine concentration in the cerebrospinal fluid (CSF) and increase of the number of apomorphine-induced rotations by Dox-administration, as compared to transplanted rats without Dox-administration, although the significant decrease of the reduction ratio of DA concentration in the CSF with Dox-administration was recognized over time. At 2 months post-implantation, concentration of dopamine in the implanted striatum and from the retrieved capsules demonstrated that the control of DA-secretion could be partially achieved for 2 months in vivo. Our results support both the value of cell therapy using Tet-Off system and the technique of encapsulation might be a feasible option for Parkinson's disease especially in resolving the problem of dopamine oversupply in the future, although a more efficient way to control DA-secretion with quicker regulation and much titration of dose should be explored before clinical application.
Kobayashi
Kazuki
K
Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science, Japan.
Yasuhara
Takao
T
Agari
Takashi
T
Muraoka
Kenichiro
K
Kameda
Masahiro
M
Ji Yuan
Wen
W
Hayase
Hitoshi
H
Matsui
Toshihiro
T
Miyoshi
Yasuyuki
Y
Shingo
Tetsuro
T
Date
Isao
I
D000818:Animals; D017920:Antiporters / Q000502:physiology*; D001058:Apomorphine / Q000494:pharmacology; D001426:Bacterial Proteins / Q000502:physiology*; D001522:Behavior, Animal; D017690:Cell Transplantation / Q000379:methods; D004195:Disease Models, Animal; D004298:Dopamine / Q000134:cerebrospinal fluid / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D016627:Oxidopamine / Q000633:toxicity; D016716:PC12 Cells; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism* / Q000628:therapy; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D045442:Rotarod Performance Test / Q000379:methods; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
D017920:Antiporters; D001426:Bacterial Proteins; D018491:Dopamine Agonists; D012333:RNA, Messenger; C079051:tetA protein, Bacteria; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D004318:Doxycycline; D001058:Apomorphine; D004298:Dopamine