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- Mandel, Ronald J., et al.
(författare)
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The Importance of Graft Placement and Task Complexity for Transplant-Induced Recovery of Simple and Complex Sensorimotor Deficits in Dopamine Denervated Rats
- 1990
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Ingår i: European Journal of Neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 2:10, s. 888-894
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Tidskriftsartikel (refereegranskat)abstract
- The present study examined the role of graft placement and behavioural task complexity in determining the functional efficacy of intrastriatal grafts of dopamine-rich fetal ventral mesencephalon (VM) placed in the dopamine (DA) depleted striatum. The functional effects of two different striatal placements of VM grafts were evaluated using tests of drug-induced motor asymmetry, simple sensorimotor orienting response, and a more complex sensorimotor integrative task (disengage behaviour), in which the rat has to perform the orienting response while in the act of eating. Rats with complete unilateral 6-hydroxydopamine (6-OHDA) lesions of the mesostriatal DA pathway, received either implants of dissociated fetal VM in the central or ventrolateral portions of the denervated striatum. Nongrafted lesioned rats served as controls. Nine weeks after grafting, the rats were tested on separate days for disengage behaviour, sensorimotor orientation, and amphetamine-induced rotational behaviour. Consistent with previous findings, the two graft placements had differential effects on drug-induced motor asymmetry and sensorimotor responses: the centrally placed VM grafts reversed amphetamine-induced rotational asymmetry but had little effect on the sensorimotor deficit, whereas the ventrolaterally placed grafts reversed the sensorimotor orientation deficits without any effect on the drug-induced rotation. In contrast, fetal VM grafts, regardless of their placement, did not ameliorate the observed deficits in disengage behaviour; that is the grafted rats that had recovered their sensorimotor response in the absence of food were unable to perform the same orienting response while eating. These results provide evidence that functional intrastriatal VM grafts which are capable of restoring sensorimotor responses or motor asymmetry fail to affect lesion-induced deficits in a task that requires more complex sensorimotor integration. It is suggested that the degree of anatomical integration of the grafted DA neurons into the host circuitry will determine the efficacy of the grafts to influence more complex sensorimotor integrative deficits in the DA lesion model.
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| 2. |
- Widner, H, et al.
(författare)
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Bilateral fetal mesencephalic grafting in two patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
- 1992
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Ingår i: New England Journal of Medicine. - 0028-4793. ; 327:22, s. 63-1556
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Intracerebral transplantation of fetal dopaminergic neurons is a promising new approach for the treatment of Parkinson's disease. Patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) have a relatively stable lesion limited to the nigrostriatal system, rendering them ideal candidates for transplantation. Improvement of motor function after neural grafting has previously been observed in nonhuman primates with MPTP-induced parkinsonism.METHODS: We grafted human fetal tissue from the ventral mesencephalon (obtained six to eight weeks after conception) bilaterally to the caudate and putamen in two immunosuppressed patients with severe MPTP-induced parkinsonism, using a stereotaxic technique. The patients were assessed regularly with clinical rating scales, timed tests of motor performance, and [18F]fluorodopa positron-emission tomography during the 18 months before the operation and the 22 to 24 months after the operation.RESULTS: Both patients had substantial, sustained improvement in motor function and became much more independent. Postoperatively, the second patient's maintenance dose of levodopa was decreased to 150 mg daily, which was 30 percent of the original dose. Striatal uptake of fluorodopa was unchanged 5 to 6 months postoperatively but was markedly and bilaterally increased at 12 to 13 and 22 to 24 months in both patients, closely paralleling the patients' clinical improvement. There were no serious complications.CONCLUSIONS: Bilateral implantation of fetal mesencephalic tissue can induce substantial long-term functional improvement in patients with parkinsonism and severe dopamine depletion and is accompanied by increased uptake of fluorodopa by the striatum. The results in these patients resemble those obtained in MPTP-treated primates and suggest that this will be a useful model for the assessment of transplantation therapies in Parkinson's disease.
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