Questions arising from recent clinical neural transplantation trials in Parkinson's disease have under-scored the necessity for a thorough experimental evaluation of the structural and functional consequences of this procedure. The present study investigated the neuroanatomical host reaction to intrastriatal implants in normal and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP)-treated nonhuman primates. Nine monkeys (Cebus apella) received intrastriatal implants using either a stereotactic approach with a silver tissue carrier or an open microsurgical procedure. Seven of these animals received intrastriatal adrenal medullary autografts, while two received control implants consisting of the tissue carrier alone. One month following transplantation, the hosts' brains were evaluated via immunohistochemical and routine histologic methods. In both MPTP-treated and normal monkeys, enhanced ipsilateral expression of tyrosine hydroxylase-like immunoreactive (TH-IR) fibers in the caudate nucleus was observed, despite minimal survival of adrenal chromaffin cells in the implants. The intensity of this response was greatest adjacent to the implant site, but a clearly increased degree of ipsilateral striatal fiber staining also could be seen several millimeters from the graft. TH-IR fibers also were more dense and of thicker caliber throughout the nigrostriatal and mesolimbic pathways ipsilateral to the implant. Control stereotactic implants, consisting of a silver tissue carrier alone, produced a similar enhancement of immunoreactive fibers, suggesting an induction of TH-IR fibers by the parenchymal injury produced during surgical implantation. There are two major hypotheses proposed to explain why adrenal medullary grafts may promote functional recovery in human parkinsonism: (1) replacement of lost striatal neurotransmitter (dopamine) by the viable grafted tissue, or (2) induction of recovery of remaining host dopaminergic systems by the implantation procedure. Our current data appear to support the latter.
"In addition to the above neurochemical changes as a means of compensating for dopamine depletion , behavioral recovery may also involve " sprouting " by the remaining DA fibers in the striatum ( Fiandaca et al . , 1988 ; Z hang et al . , 1988 ; Sheng et al . , 1993 ; Hansen et al . , 1995 ) . We hypothesize that the three stages of TH fiber changes correspond to how the mesostriatal system responds to DA de - pletion . These three anatomic stages may correspond to the three physiological responses described by Robinson et al . ( 1994 ) , which include"
[Show abstract][Hide abstract] ABSTRACT: Dopaminergic lesions result in the acute loss of striatal dopamine content, the loss of tyrosine hydroxylase-immunoreactive fibers, upregulation of preproenkephalin mRNA expression, and compensatory changes in the synthesis and metabolism of dopamine. Despite the severe loss of fine tyrosine hydroxylase-immunoreactive fibers, larger fibers persist. We found that some tyrosine hydroxylase fiber types increase their branching and become thicker after partial lesion. To determine whether the remaining tyrosine hydroxylase fibers were degenerative or part of a compensatory response, we morphologically characterized striatal tyrosine hydroxylase fibers and compared them to silver-stained degenerative structures. Branched and large tyrosine hydroxylase fiber types were nondegenerative. Furthermore, normal preproenkephalin mRNA expression was maintained despite severe overall loss of tyrosine hydroxylase fibers in striatal regions with abundant branching, whereas preproenkephalin mRNA expression increased in severely depleted regions that lacked branched fibers, indicating that branching or sprouting was involved in the compensation for dopamine depletion and the maintenance of normal preproenkephalin expression. In support of compensatory sprouting by tyrosine hydroxylase fibers, mRNA for growth associated protein-43 was upregulated in dopaminergic midbrain cells. We conclude that an important compensatory response to partial dopaminergic depletion is the formation of new branches or sprouting.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 08/2000; 20(13):5102-14. · 6.34 Impact Factor
"In support of this theory are the recent findings of Farris et al. (1994), demonstrating that treatment with FGF alone has no effect on the lesioned brain when a more refined delivery procedure which creates minimal disturbance to the brain is used. Moreover, it is likely that mechanical damage caused by surgical procedures is similarly responsible for the production of a number of other potentially important factors (Nieto-Sampedro et al. 1982, Fiandaca et al. 1988, Finkelstein et al. 1988, Przedborski et al. 1991). Possibly, the sprouting of TH fibres witnessed in previous studies was a direct result of FGF but rather the migration of other trophic factors into the gel foam implants used to deliver FGF (Otto & Unsicker 1990) or the extravasation of these substances into the brain following ruptures of the blood-brain-barrier during multiple injections of FGF (Date et al. 1991). "
[Show abstract][Hide abstract] ABSTRACT: Two-week infusion of muscle-derived differentiation factor (MDF), or human recombinant acidic fibroblast growth factor (aFGF) and/or its muscle-derived activating substance into the striatum of unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats caused a significant and long lasting (40 days) reduction (48-100%) in amphetamine-induced rotational asymmetry. In parallel with behavioural recovery, striatal tyrosine hydroxylase (TH) activity, dopamine (DA) and dihydroxy-phenyl-acetic acid (DOPAC) levels recovered in a dose-dependent manner in all treated rats when compared to controls. The greatest increments were observed in rats infused with aFGF and its activator. Increases in biochemical indices were not reflected in trophic changes of the dopamine system; thus, the number of TH-immunoreactive neurones and their striatal innervation were unmodified by treatment with MDF. In contrast with the lesioned brain, infusion of these agents into the intact brain produced no change in nigrostriatal dopamine biochemistry. Our results suggest that dopamine differentiation factors may be important in regulating the production of dopamine in the injured brain and, therefore, may be useful in the treatment of DA imbalances associated with certain neurological disorders such as Parkinson's disease.
Neurobiology of Disease 03/1995; 2(1):1-12. DOI:10.1006/nbdi.1995.0001 · 5.08 Impact Factor
"Rats in group 3 displayed robust sprouting yet the poorest chromaffin cell survival. This is consistent with previous observations that TH-immunoreactive sprouting is seen within the striatum of parkinsonian monkeys (Bankiewicz et al., 1988; Fiandaca et al., 1988; Plunkett et al., 1990) and Parkinson's disease patients (Hurtig et al., 1989; Kordower et al., 199 1) following adrenal autografts that degenerate soon after implantation or even following sham transplantation (Bankiewicz et al., 1988; Fiandaca et al., 1988; Plunkett et al., 1990). Figure 9. Implants of isolated adrenal chromaffin cells recombined with autologous fibroblasts and endothelial cells induced a host-derived THimmunoreactive sprouting response. "
[Show abstract][Hide abstract] ABSTRACT: Previous investigations have demonstrated that adrenal chromaffin cells survive poorly when grafted into the striatum of rodents, nonhuman primates, and patients with Parkinson's disease. This poor survival has been attributed to the low levels of endogenous NGF within the striatum. However, chromaffin cells isolated from the nonchromaffin constituents of the adrenal medulla (fibroblasts and endothelial cells) have recently been demonstrated to survive grafting into a number of CNS sites. The present study determined whether nonchromaffin constituents of the adrenal medulla may be responsible for poor graft survival. We compared the survival of intrastriatally grafted isolated bovine chromaffin cells with that observed following implantation of either perfused adrenal medullary suspensions containing all adrenal medullary cell types or isolated chromaffin cells that were then reseeded with autologous fibroblasts and endothelial cells. Implants of perfused adrenal medullary cells survived poorly and most graft sites were infiltrated with macrophages. The chromaffin cells in this group that did survive appeared to be in the process of degeneration. In contrast, large numbers of isolated chromaffin cells survived for up to 2 months following transplantation. These cells maintained their endocrine phenotype and stained for all enzymatic markers of catecholamine synthesis as well as chromogranin A. Morphologically, these cells resembled chromaffin cells seen in situ and the perigraft region was essentially devoid of macrophages. When isolated chromaffin cells were reseeded with autologous fibroblasts and endothelial cells, the implants degenerated and few, if any, surviving chromaffin cells were observed. Interestingly, these latter grafts induced a host-derived sprouting response of tyrosine hydroxylase-immunoreactive fibers. These data demonstrate that large numbers of adrenal chromaffin cells can survive intrastriatal implantation in the absence of exposure to exogenous NGF. Rather, the nonchromaffin cells of the adrenal medulla (fibroblasts and endothelial cells) appear to compromise the viability of grafted chromaffin cells. Once they are eliminated from the graft, robust survival of chromaffin cells occurs. If clinical trials employing adrenal medullary grafts are still to be considered for the treatment of Parkinson's disease, isolation of the chromaffin cells should be considered to enhance graft viability.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 11/1993; 13(10):4496-510. · 6.34 Impact Factor
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