Growth and Functional Efficacy of Intrastriatal Nigral Transplants Depend on the Extent of Nigrostriatal Degeneration

Abstract

Previous studies have shown that the functional efficacy of intrastriatal transplants of fetal dopamine (DA) neurons in the rat Parkinson model depends on their ability to establish a new functional innervation of the denervated striatum. Here we report that the survival, growth, and function of the grafted DA neurons greatly depend on the severity of the lesion of the host nigrostriatal system. Fiber outgrowth, and to a lesser extent also cell survival, were significantly reduced in animals in which part of the intrinsic DA system was left intact. Moreover, graftinduced functional recovery, as assessed in the stepping, pawuse, and apomorphine rotation tests, was obtained only in severely lesioned animals, i.e., in rats with Ͼ70% DA denervation of the host striatum. Functional recovery seen in these animals in which the 6-hydroxydopamine (6-OHDA) lesion was confined to the striatum was more pronounced than that previously obtained in rats with complete lesions of the mesencephalic DA system, indicating that spared portions of the host DA system, particularly those innervating nonstriatal forebrain areas, may be necessary for the grafts to exert their optimal functional effect. These data have implications for the optimal use of fetal nigral transplants in Parkinson patients in different stages of the disease.Key words: Parkinson's disease; transplantation; sensorimotor behavior; stepping; paw use; tyrosine hydroxylase; stereology Impairments in sensorimotor function induced by lesions of the nigrostriatal DA system can be reversed by intrastriatal transplants of nigral DA neurons taken from the fetal ventral mesencephalon (VM). However, functional recovery is incomplete: whereas some aspects of the DA deficiency syndrome are completely reversed (e.g., drug-induced turning behavior and sensorimotor neglect), other deficits, such as forelimb akinesia and skilled paw-use, are only partly or marginally affected by the grafted DA neurons (Björklund et al., 1994;Herman and Abrous, 1994;Winkler et al., 1999). The functional capacity of intrastriatal VM transplants is determined, at least in part, by the extent of striatal reinnervation provided by the grafted DA neurons and the placement of the cells, i.e., the subregion of the striatal complex reached by the graft-derived axons Mandel et al., 1990;Annett et al., 1995). Nevertheless, attempts to improve the functional efficacy of intrastriatal nigral transplants by multiple graft placements have so far been unsuccessful (Nikkhah et al., 1993;Olsson et al., 1995;Winkler et al., 1999). In these experiments the entire caudate putamen was reinnervated to a level of ϳ30 -80% of normal, but recovery of forelimb akinesia and paw use remained incomplete. These studies, however, were performed in rats with a complete unilateral 6-OHDAinduced lesion of the medial forebrain bundle (MFB), resulting in a widespread denervation of both striatal, limbic, and cortical areas. The functional impairments seen in these animals, therefore, reflect a combination of striatal and nonstria...

Noradrenaline neuron degeneration contributes to motor impairments and development of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease

“…Spontaneous forelimb use was measured in the cylinder test (Schallert and Tillerson, 1999), as reported previously Kirik et al (2001). Individual rats were placed in a glass cylinder (diameter 20 cm) and a total of 20 weight-bearing forepaw touches to the glass were recorded.…”

Graft placement and uneven pattern of reinnervation in the striatum is important for development of graft-induced dyskinesia

“…The VM tissue was prepared into a single cell suspension following the procedure described earlier (Nikkhah et al, 1994, Winkler et al, 1999, Kirik et al, 2001, Georgievska et al, 2004.…”

“…The grafts position in the striatum were delineated and a counting frame was randomly placed on the first counting area and moved systematically throughout the inclusion area (Kirik et al, 2001). Guard volumes of 3 µm from the top and the bottom of the section were excluded to avoid problems with lost caps.…”

The Functional Impact of the Intrastriatal Dopamine Neuron Grafts in Parkinsonian Rats Is Reduced with Advancing Disease

“…In contrast, animals with complete lesions of the ascending DA projection system showed poor or no improvement in spontaneous motor behaviors, suggesting that the extent of DA denervation in regions outside the graft-innervated area may be essential for the full beneficial effects of intraputaminal DA cell replacement (Winkler et al, 1999(Winkler et al, , 2005Kirik et al, 2001). This hypothesis is supported by previous observations in grafted PD patients obtained by 18-fluorine-L-3,4-dihydroxyphenylalanine ( 18 F-DOPA) and 11 C-raclopride positron emission tomography (PET) (Piccini et al, 2005).…”