Long-term survival of grafted cells, dopamine synthesis/release, synaptic connections, and functional recovery after transplantation of fetal nigral cells in rats with unilateral 6-OHDA lesions in the nigrostriatal dopamine pathway.
In animal models of hemi-Parkinson's disease, survival of grafted nigral cells, their synaptic connections, dopamine (DA) synthesis/release, and recovery from motor disturbances were investigated, and these were compared among 3 groups of animals raised for 3 months, 1 year and 2 years after the transplantation. Fetal nigral DAergic cell suspensions were transplanted in the ipsilateral caudate nucleus of rats with unilateral 6-OHDA lesions in the nigrostriatal DA pathway. Motor disturbances, assessed by methamphetamine-induced rotation, recovered partly in the 2nd week, significantly in the 4th week after the grafting, and remained stable thereafter. Many tyrosine hydroxylase (TH)-positive cells were detected along the grafting tracks. The number of TH-positive cells was similar in the 3 groups of animals. These TH-positive cells made synaptic connections in the host caudate. By in vivo microdialysis measurement, extracellular DA, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) around the grafted sites recovered to 30-100% of those of controls. No significant differences were observed in the concentration of DA, DOPAC and HVA among 3 groups of animals. They also responded to methamphetamine loading though the magnitudes were smaller. Using a TH cDNA probe, TH-positive cells were found to express TH mRNA in in situ hybridization-autoradiographic analysis. Data indicate that grafted fetal DAergic cells survive, synthesize and release DA, make synaptic connections in the host brain and ameliorate motor disturbances for over 2 years. There were no differences in these parameters among the 3 groups of animals, and no untoward side effects were observed even at 2 years after the grafting. Thus it was confirmed that the grafting of neuronal cells into the brain is a promising approach to restore disturbed function.
Nishino
H
H
Department of Physiology, Nagoya City University Medical School, Japan.
Hashitani
T
T
Kumazaki
M
M
Sato
H
H
Furuyama
F
F
Isobe
Y
Y
Watari
N
N
Kanai
M
M
Shiosaka
S
S
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D016380:Brain Tissue Transplantation / Q000502:physiology*; D002395:Catecholamines / Q000378:metabolism; D002421:Caudate Nucleus / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology; D003712:Dendrites / Q000648:ultrastructure; D004298:Dopamine / Q000502:physiology*; D005260:Female; D016332:Fetal Tissue Transplantation; D006892:Hydroxydopamines / Q000633:toxicity; D008694:Methamphetamine / Q000494:pharmacology; D008854:Microscopy, Electron; D009043:Motor Activity / Q000187:drug effects*; D009498:Neurotoxins / Q000633:toxicity*; D016627:Oxidopamine; D051381:Rats; D011919:Rats, Inbred Strains; D013378:Substantia Nigra / Q000166:cytology / Q000502:physiology / Q000637:transplantation*; D013569:Synapses / Q000502:physiology / Q000648:ultrastructure; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D002395:Catecholamines; D006892:Hydroxydopamines; D009498:Neurotoxins; D008694:Methamphetamine; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine