Multitracer assessment of dopamine function after transplantation of embryonic stem cell-derived neural stem cells in a primate model of Parkinson's disease.
The ability of primate embryonic stem (ES) cells to differentiate into dopamine (DA)-synthesizing neurons has raised hopes of creating novel cell therapies for Parkinson's disease (PD). As the primary purpose of cell transplantation in PD is restoration of dopaminergic neurotransmission in the striatum, in vivo assessment of DA function after grafting is necessary to achieve better therapeutic effects. A chronic model of PD was produced in two cynomolgus monkeys (M-1 and M-2) by systemic administration of neurotoxin. Neural stem cells (NSCs) derived from cynomolgus ES cells were implanted unilaterally in the putamen. To evaluate DA-specific functions, we used multiple [(11)C]-labeled positron emission tomography (PET) tracers, including [beta-(11)C]L-3,4-dihydroxyphenylalanine (L-[beta-(11)C]DOPA, DA precursor ligand), [(11)C]-2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane ([(11)C]beta-CFT, DA transporter ligand) and [(11)C]raclopride (D(2) receptor ligand). At 12 weeks after grafting NSCs, PET demonstrated significantly increased uptake of L-[beta-(11)C]DOPA (M-1:41%, M-2:61%) and [(11)C]beta-CFT (M-1:31%, M-2:36%) uptake in the grafted putamen. In addition, methamphetamine challenge in M-2 induced reduced [(11)C]raclopride binding (16%) in the transplanted putamen, suggesting release of DA. These results show that transplantation of NSCs derived from cynomolgus monkey ES cells can restore DA function in the putamen of a primate model of PD. PET with multitracers is useful for functional studies in developing cell-based therapies against PD.
Muramatsu
Shin-Ichi
S
Divison of Neurology, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan. muramats@ms.jichi.ac.jp
Okuno
Tsuyoshi
T
Suzuki
Yutaka
Y
Nakayama
Takashi
T
Kakiuchi
Takeharu
T
Takino
Naomi
N
Iida
Asako
A
Ono
Fumiko
F
Terao
Keiji
K
Inoue
Nobuo
N
Nakano
Imaharu
I
Kondo
Yasushi
Y
Tsukada
Hideo
H
D000818:Animals; D002250:Carbon Radioisotopes; D002478:Cells, Cultured; D003042:Cocaine / Q000031:analogs & derivatives; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D053595:Embryonic Stem Cells / Q000637:transplantation*; D007980:Levodopa; D008252:Macaca fascicularis; D008694:Methamphetamine / Q000494:pharmacology; D009069:Movement Disorders / Q000150:complications / Q000628:therapy; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D010300:Parkinson Disease / Q000150:complications / Q000628:therapy*; D049268:Positron-Emission Tomography; D011699:Putamen / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D020891:Raclopride; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D002250:Carbon Radioisotopes; D015259:Dopamine Agents; D020891:Raclopride; D008694:Methamphetamine; D007980:Levodopa; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D014446:Tyrosine 3-Monooxygenase; D003042:Cocaine; D004298:Dopamine