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The effect of fetal mesencephalon implants on primate MPTP-induced parkinsonism. Histochemical and behavioral studies
K S Bankiewicz1, R J Plunkett, D M Jacobowitz
1CNS Implantation Unit, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland.
Abstract:
Parkinsonism or hemiparkinsonism was induced by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in four rhesus monkeys, which then received homologous fetal mesencephalon implants into the caudate nuclei. Cavities were prepared in the medial caudate nucleus 2 to 5 weeks before the fetal grafts were implanted. Control studies were conducted in unoperated MPTP-treated animals. Significant behavioral improvement, which occurred within weeks of implantation of fetal mesencephalon, was sustained for up to 7 months. No recovery was seen in the unoperated control animals. Histological examination revealed numerous surviving tyrosine hydroxylase (TH)-immunoreactive cell bodies. In addition to the graft, abundant TH-immunoreactive fibers were observed in the host caudate nucleus ventral to the region of the implanted and the nonimplanted cavities. Since TH-immunoreactive cell bodies of the substantia nigra compacta (A-9 cells) were destroyed by MPTP treatment and the ventral tegmental area (A-10) remained intact, it is concluded that sprouting of remaining host dopaminergic fibers occurs. These newly formed fibers appeared to emanate from the mesolimbic projection to the striatum. It is likely that the newly sprouted dopaminergic fibers account for the motor improvement elicited by precavitation and fetal mesencephalon implantation. These results suggest that the mechanism of recovery of parkinsonian primates after implantation of fetal dopaminergic tissue into the caudate nucleus is by stimulation of sprouting from host neurons. They also suggest that, with identification of the factors responsible for the formation of the new dopaminergic neuronal processes and with further development, tissue implantation may be an effective therapy for Parkinson's disease in humans.
Insights
Fetal mesencephalon implants improved motor function in MPTP-induced parkinsonian monkeys by stimulating host neuron sprouting. This suggests potential for tissue implantation as a Parkinson's disease therapy.
Area of Science:
- Neuroscience
- Primate Models
- Regenerative Medicine
Background:
- Parkinson's disease is characterized by dopaminergic neuron loss.
- MPTP-induced parkinsonism in primates serves as a relevant model.
- Fetal mesencephalon transplantation is a potential therapeutic strategy.
Purpose of the Study:
- To investigate the efficacy of fetal mesencephalon transplantation in MPTP-induced parkinsonian monkeys.
- To explore the mechanisms underlying motor recovery after transplantation.
- To assess the potential of this approach for Parkinson's disease treatment.
Main Methods:
- Induction of parkinsonism in rhesus monkeys using MPTP.
- Surgical implantation of homologous fetal mesencephalon into the caudate nucleus.
- Behavioral assessment of motor function recovery.
- Histological analysis of tyrosine hydroxylase (TH)-immunoreactive cells and fibers.
Main Results:
- Significant and sustained behavioral improvement observed post-transplantation.
- No recovery in unoperated control animals.
- Histological evidence of surviving graft cells and TH-positive fibers in host tissue.
- Sprouting of host dopaminergic fibers from mesolimbic projections observed.
Conclusions:
- Fetal mesencephalon transplantation promotes motor recovery in parkinsonian primates.
- Recovery is mediated by stimulated sprouting of host dopaminergic neurons.
- This approach holds promise for future Parkinson's disease therapies.