Adrenal Medulla Grafts Enhance Recovery of Striatal Dopaminergic Fibers

Abstract

The drug, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), depletes striatal dopamine levels in primates and certain rodents, including mice, and produces parkinsonian-like symptoms in humans and nonhuman primates. To investigate the consequences of grafting adrenal medullary tissue into the brain of a rodent model of Parkinson's disease, a piece of adult mouse adrenal medulla was grafted unilaterally into mouse striatum 1 week after MPTP treatment. This MPTP treatment resulted in the virtual disappearance of tyrosine hydroxylase-immunoreactive fibers and severely depleted striatal dopamine levels. At 2, 4, and 6 weeks after grafting, dense tyrosine hydroxylase-immunoreactive fibers were observed in the grafted striatum, while only sparse fibers were seen in the contralateral striatum. In all cases, tyrosine hydroxylase-immunoreactive fibers appeared to be from the host rather than from the grafts, which survived poorly. These observations suggest that, in mice, adrenal medullary grafts exert a neurotrophic action in the host brain to enhance recovery of dopaminergic neurons. This effect may be relevant to the symptomatic recovery in Parkinson's disease patients who have received adrenal medullary grafts.

Selective Glial Cell Line-Derived Neurotrophic Factor Production in Adult Dopaminergic Carotid Body CellsIn Situand after Intrastriatal Transplantation

“…However, unequivocal evidence for GDNF expression in CB of adult rodents was obtained from heterozygous knock-out GDNF/lacZ mice, in which the cells expressing GDNF contain ␤-galactosidase deposits that can be labeled with the characteristic blue X-gal staining . Using this experimental tool, we compared the level of GDNF expression in the CB and that in the AM, SCG, or retina, which are catecholaminergic donor tissues used in transplantation studies to treat PD in animals and humans (Bohn et al, 1987;Itakura et al, 1988;Yurek and Sladek, 1990;Rosenthal, 1998). The histological illustrations in Figure 1 clearly show the high level of GDNF expression in the CB (blue-green color deposits in A) and its complete absence in the AM (C, D), SCG (E, F ), and retina (G, H ).…”

Functional Regeneration in a Rat Parkinson's Model after Intrastriatal Grafts of Glial Cell Line-Derived Neurotrophic Factor and Transforming Growth Factor β1-Expressing Extra-Adrenal Chromaffin Cells of the Zuckerkandl's Organ

“…Furthermore, the dopaminergic content of grafted striata remained very low, and there were no signs of striatal reinnervation, except for a halo of THϩ fibers immediately around the graft. This perigraft sprouting has already been observed after adrenal medullary grafts implanted in the striatum (Bohn et al, 1987;Bankiewicz et al, 1994;Bresjenac et al, 1997), and it has been demonstrated to be attributable to infiltration of microglia and macrophages that exert a limited trophic action that persists for many months after injury or grafting (Batchelor et al, 1999). In this context, in dead parkinsonian patients with 3-to 40-month-old adrenal medullary grafts, autopsy revealed that there was often a perigraft dopaminergic sprouting response without surviving adrenal cells inside the graft (Hirsch et al, 1990;Kordower et al, 1991).…”

“…The most prevalent therapy is levodopa administration, but it is not efficacious after several years of treatment. In search of an alternative therapy, intrastriatal grafts of dopamine-secreting cells from neural or chromaffin tissues, such as fetal mesencephalon, adrenal medulla, and carotid body, has been reported to ameliorate functional deficits in animal models of Parkinson's disease (Bolam et al, 1987;Bohn et al, 1987;Goetz et al, 1991;Espejo et al, 1998;Luquin et al, 1999). Transplantation is considered a promising treatment for human Parkinson's disease, but its clinical use is still restricted to few cases.…”

“…Among these molecules, glial cell linederived neurotrophic factor (GDNF) has potent in vivo effects (Lin et al, 1993;Tomac et al, 1995;Beck et al, 1995;Gash et al, 1998), and promising results have been obtained with fibroblasts engineered to secrete GDNF (Tseng et al, 1997) or viral vectors expressing GDNF (Mandel et al, 1997;Kirik et al, 2000). In this context, the antiparkinsonian effects of cell grafts of the chromaffin lineage are attributed not only to dopamine release from grafted cells but also to dopaminergic reinnervation of the denervated striatum (Freed et al, 1981;Bohn et al, 1987;Espejo et al, 1998;Dunnett and Björklund, 1999;Luquin et al, 1999), and chromaffin cells are known to express and release GDNF (Unsicker and O'Connor, 1999). However, as explained, adrenal chromaffin cells induce a transient amelioration, a fact that perhaps has precluded the use of extra-adrenal cells, of similar embryological origin.…”

“…It is well known that intrinsic dopaminergic reinnervation of the denervated striatum is a constant feature after grafting chromaffin cells (Freed et al, 1981;Bohn et al, 1987;Espejo et al, 1998;Dunnett and Björklund, 1999;Luquin et al, 1999). The broad THϩ reinnervation measured in striata with extra-adrenal chromaffin cells suggests that grafted cells exerted a trophic action on the denervated striatum leading to sprouting of host dopaminergic fibers.…”