Co-Grafts in Dopamine-Depleted Primates: Preliminary Results and Theoretical Issues Related to Human Applications for Parkinson’s Disease
Transplantation of embryonic mesencephalon has been attempted in several hundred Parkinson’s disease patients worldwide. Initial reports support the role of these dopamine-producing grafts in ameliorating some of the signs and symptoms of the disease (Lindvall et al., 1989; Lindvall et al., 1990; Freed et al., 1992; Spencer et al., 1992; Widner et al., 1992). In particular, many patients 1) require less daily levodopa after grafting, 2) have a greater percentage of “on” time, and 3) show reduced dyskinesias. Nevertheless, considerable variation exists in the methodological approach followed by each group of clinical investigators, in part because it is difficult to perform experiments with human neural tissue that would provide unequivocal answers to technical questions about optimal survival parameters for the grafted tissue. For example, a study of the survival rate of grafted human dopamine neurons utilized the rat as a host (Brundin et al, 1988). This investigation found poor (i.e. 2-5%) survival of dopamine neurons, which may be influenced by several factors including the relatively small size of the rat brain. Perhaps, there is insufficient room to permit survival of great numbers of these proportionally larger human neurons in the confines of the rat striatum. Moreover, the role, if any, played by immunosuppression is unclear. As a consequence of this low survival, some clinical experiments have utilized mesencephalic tissue from several embryos in attempts to increase the total number of viable dopamine neurons, but this results in a considerably larger number of grafted non-dopaminergic neurons and the role of these presumably “silent” neurons is unknown. Since these grafts contain substantial numbers of neuroblasts and progenitor cells of the ventral mesencephalon, they presumably could be replete with neuronal and glial representatives of the mesencephalic reticular formation, the red nucleus, the ventral tegmentum, the oculomotor and trochlear nuclei, the proprioceptive nucleus of the trigeminal complex, serotonergic neurons of the dorsal raphe and many others for example. Since we are unaware of the influence that these neurons may exert on the host brain, it might be prudent to limit the potential contribution of this non-dopaminergic constituent of ventral mesencephalic grafts. This suggests that attention should be paid to mechanisms for enhancing the yield of grafted dopamine neurons.
KeywordsDopamine Tyrosine Norepinephrine Neurol Catecholamine
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- Bakay RAE, Fiandaca MS, Barrow DL, Schiff A and Collins DC (1985): Preliminary report on the use of fetal tissue transplantation to correct MPTP-induced parkinsonian-like syndrome in primates. Appl Neurophys 48: 358–361.Google Scholar
- Brundin P, Strecker RE, Widner H, Clarke DJ, Nilsson OG, Astedt B, Lindvall O and Björklund A (1988): Human fetal dopamine neurons grafted in a rat model of Parkinson’s disease: immunological aspects, spontaneous and drug-induced behaviour, and dopamine release. Exp Brain Res 70: 192–208.PubMedGoogle Scholar
- Dunnett SB, Rogers DC and Richards SJ (1989): Nigrostriatal reconstruction after 6OHDA lesions in rats: Combination of dopamine-rich nigral grafts and nigrostriatal “bridge” grafts. Exper Brain Res 75: 523–535.Google Scholar
- Elsworth JD, Sladek Jr, JR, Redmond Jr, DE, Taylor JR, Collier TJ and Roth RH (1994): Early gestational mesencephalon grafts, but not later gestational mesencephalon, cerebellum, or sham grafts, increase dopamine in caudate nucleus of MPTP-treated monkeys. Neurosci (submitted).Google Scholar
- Freed CR, Breeze RE, Rosenberg NL, Schneck SA, Kriek E, Qi JX, Lone T, Zhang YB, Snyder JA, Wells TH, Ramig LO, Thompson L, Mazziotta JC, Huang SC, Grafton ST, Brooks D, Sawle G, Schroter G and Ansari AA (1992): Survival of implanted fetal dopamine cells and neurologic improvement 12 to 46 months after transplantation for Parkinson’s disease. New Eng J Med 327: 1549–55.PubMedCrossRefGoogle Scholar
- Lindvall O, Rehncrona S, Brundin P, Gustavii B, Astedt B, Widner H, Lindholm T, Björklund A, Leender K, Rothwell JC, Frackowiak R, Marsden CD, Johnels B, Steg G, Freedman R, Hoffer BJ, Seiger A, Bygdeman M, Strömberg I and Olson L (1989): Human fetal dopamine neurons grafted into the striatum in two patients with severe parkinson’s disease. Arch Neurol 46: 615–631.PubMedCrossRefGoogle Scholar
- Sladek JR Jr, Blanchard BC, Collier TC, Elsworth JD, Taylor JR, Roth RH and Redmond DE Jr (1994): Optimal survival of grafted mesencephalic dopamine (DA) neurons is attained from tissue taken during neurogenesis of the substantia nigra in nonhuman primate. Soc Neurosci Abstr 20: 1328.Google Scholar
- Spencer DD, Robbins RJ, Naftolin F, Marek KL, Vollmer T, Leranth C, Roth RH, Price LH, Gjedde A, Bunney BS, Sass KJ, Elsworth JD, Kier LE, Makuch R, Hoffer PB and Redmond DE Jr (1992): Unilateral transplantation of human fetal mesencephalic tissue into the caudate nucleus of Parkinsonian patients: functional effects for 18 months. New Eng J Med 327: 1541–1548.PubMedCrossRefGoogle Scholar
- Taylor JR, Elsworth JD, Sladek JR Jr, Collier TJ, Roth RH and Redmond DE Jr (1994): Sham surgery does not ameliorate MPTP-induced behavioral deficits in monkeys. Cell Transplant, in press.Google Scholar
- Wechsler RT, Sladek JR Jr, Blanchard BC, Collier TJ, Elsworth JD, Taylor JR, Roth RH and Redmond DE Jr (1993): Sprouting of host dopamine fibers in response to grafts of embryonic striatum in adult African green monkeys. Soc Neurosci Abstr 19: 1509.Google Scholar
- Wechsler RT, Blanchard BC, Collier TJ, Elsworth JD, Taylor JR, Roth RH, Redmond DE Jr and Sladek JR Jr (1994): Host striatum projects fibers into transplanted fetal mesencephalon in a parkinsonian primate model. Soc Neurosci Abstr 20: 1328.Google Scholar
- Widner H, Tetrud J, Rehncrona S, Snow B, Brundin P, Gustavii B, Björklund A, Lindvall O and Langston JW (1992): Bilateral fetal mesencephalic grafting in two patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). New Eng J Med 327: 1557–1563.CrossRefGoogle Scholar