Improved graft survival and striatal reinnervation by microtransplantation of fetal nigral cell suspensions in the rat Parkinson model

Nikkhah, Guido; Cunningham, M G; Jödicke, Andreas; Knappe, Ulrich J.; Björklund, Anders

doi:10.1016/0006-8993(94)91532-6

Cited by 167 publications

(84 citation statements)

References 26 publications

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“…When amphetamine-induced turning behavior was analyzed, animals with FVM grafts in the SN or STN, or both, demonstrated no rotational compensation. This lack of compensation has been noted previously with dopaminergic grafts in the SN (Nikkhah et al, 1994;Mendez et al, 1996) and could be related to the inability of grafts in the STN or SN to release dopamine in the ST. The present study confirms the notion that dopaminergic reinnervation of the ST is necessary to restore rotational symmetry in the 6-OHDA rodent model of PD.…”

Section: Discussionmentioning

confidence: 79%

Enhancement of Sensorimotor Behavioral Recovery in Hemiparkinsonian Rats with Intrastriatal, Intranigral, and Intrasubthalamic Nucleus Dopaminergic Transplants

et al. 2001

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One of the critical variables that influences the efficacy of clinical neural transplantation for Parkinson's disease (PD) is optimal graft placement. The current transplantation paradigm that focuses on ectopic placement of fetal grafts in the striatum (ST) fails to reconstruct the basal ganglia circuitry or normalize neuronal activity in important basal ganglia structures, such as the substantia nigra (SN) and the subthalamic nucleus (STN). The aim of this study was to investigate a multitarget neural transplantation strategy for PD by assessing whether simultaneous dopaminergic transplants in the ST, SN, and STN induce functional recovery in hemiparkinsonian rats. Forty-six female Wistar rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway were randomly divided into eight groups and received lesions only or injections of 900,000 embryonic rat ventral mesencephalic cells in the (1) ST, (2) SN, (3) STN, (4) ST and SN, (5) ST, SN, and STN, (6) ST and STN, or (7) SN and STN. The number of cells transplanted was equally divided among grafting sites. Animals with two grafts received 450,000 cells in each structure, and animals with three grafts received 300,000 cells per structure. Recovery was assessed by amphetamine-induced rotations and the stepping tests. Graft survival was assessed using tyrosine hydroxylase immunohistochemistry. At 8 weeks after transplantation, simultaneous dopaminergic transplants in the ST, SN, and STN induced significant improvement in rotational behavior and stepping test scores. Intrastriatal transplants were associated with significant recovery of rotational asymmetry, whereas SN and STN transplants were associated with improved forelimb function scores. These results suggest that restoration of dopaminergic activity to multiple basal ganglia targets, such as the ST and SN, or the ST and STN, promotes a more complete functional recovery of complex sensorimotor behaviors. A multitarget transplant strategy aimed at optimizing dopaminergic reinnervation of the basal ganglia may be crucial in improving clinical outcomes in PD patients.

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Section: Discussionmentioning

confidence: 79%

Enhancement of Sensorimotor Behavioral Recovery in Hemiparkinsonian Rats with Intrastriatal, Intranigral, and Intrasubthalamic Nucleus Dopaminergic Transplants

et al. 2001

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“…Serial coronal sections were cut on a freezing microtome at 30 m thickness. To quantify Colvin et al, 1996. b For additional details, see Dono et al, 1998, Zhou et al, 1998 For additional details, see Coffin et al, 1995. the substantia nigra morphologically, every third section was processed for tyrosine hydroxylase (TH) immunohistochemistry (mouse anti-rat TH monoclonal antibody, 1:2500; catalog #T1299; Sigma, St. Louis, MO) using the avidin-biotin complex kit and 3Ј,3-diaminobenzidine for visualization, as described previously (Nikkhah et al, 1994). Before putting the first antibody, the sections were preincubated using null serum.…”

Section: Tyrosine Hydroxylase Immunohistochemistrymentioning

confidence: 99%

Fibroblast Growth Factor (FGF)-2 and FGF Receptor 3 Are Required for the Development of the Substantia Nigra, and FGF-2 Plays a Crucial Role for the Rescue of Dopaminergic Neurons after 6-Hydroxydopamine Lesion

Cesnulevicius²,

et al. 2007

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Basic fibroblast growth factor (FGF-2) is involved in the development and maintenance of the nervous system. Exogenous administration of FGF-2 increased dopaminergic (DA) graft survival in different animal models of Parkinson's disease. To study the physiological function of the endogenous FGF-2 system, we analyzed the nigrostriatal system of mice lacking FGF-2, mice overexpressing FGF-2, and FGF-receptor-3 (FGFR3)-deficient mice both after development and after 6-hydroxydopamine lesion. FGFR3-deficient mice (ϩ/Ϫ) displayed a reduced number of DA neurons compared with the respective wild type. Whereas absence of FGF-2 led to significantly increased numbers of DA neurons, enhanced amount of the growth factor in mice overexpressing FGF-2 resulted in less tyrosine hydroxylase expression and a reduced DA cell density. The volumes of the substantia nigra were enlarged in both FGF-2 Ϫ/Ϫ and in FGF-2 transgenic mice, suggesting an important role of FGF-2 for the establishment of the proper number of DA neurons and a normal sized substantia nigra during development. In a second set of experiments, the putative relevance of endogenous FGF-2 after neurotoxin application was investigated regarding the number of rescued DA neurons after partial 6-OHDA lesion. Interestingly, the results after lesion were directly opposed to the results after development: significantly less DA neurons survived in FGF-2 Ϫ/Ϫ mice compared with wild-type mice. Together, the results indicate that FGFR3 is crucially involved in regulating the number of DA neurons. The lack of FGF-2 seems to be (over)compensated during development, but, after lesion, compensation mechanisms fail. The transgenic mice showed that endogenous FGF-2 protects DA neurons from 6-OHDA neurotoxicity.

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“…The functional constraints seen with intrastriatal graft placement, most apparent in the failure to restore more complex sensorimotor behaviors, have largely been attributed to the lack of sufficient restoration of dopamine levels and/or the ectopic implantation site (Bjiirklund, 1992;Bjiirklund et al, 1987Bjiirklund et al, , 1994Herman et al, 1989). The microtransplantation approach has made it possible to achieve increased dopamine-tissue levels and more extensive TH-positive fiber outgrowth from multiple VM deposits spread throughout the head of the caudate putamen (Nikkhah et al, 1994a). However, graft-derived TH-positive reinnervation was confined to the telencephalon, leaving the SN completely devoid of a dopaminergic innervation.…”

Section: Intranigral Vm Graft Neonatalmentioning

confidence: 99%

Dopaminergic microtransplants into the substantia nigra of neonatal rats with bilateral 6-OHDA lesions. II. Transplant-induced behavioral recovery

et al. 1995

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Transplants of fetal ventral mesencephalic (VM) dopamine neurons implanted into the substantia nigra in 6-hydroxy-dopamine (6-OHDA)- lesioned neonatal pups establish axonal connections with the denervated caudate putamen (Nikkhah et al., 1995). In the present study, we have explored the functional capabilities of these animals after they reached adulthood on a battery of spontaneous and drug-induced behavioral tasks. The results demonstrate that unilateral intranigral VM grafts in bilaterally lesioned neonates induce a marked bias in spontaneous- and stress-induced rotation contralateral to the implant not present in the lesion-only controls. Amphetamine and apomorphine induced vigorous contra- and ipsilateral rotation, respectively. Moreover, grafted animals achieved 75% of the performance level in contralateral skilled forelimb use when compared to normal controls, which was significantly above lesion-only animals (50% of normal). Spontaneous nocturnal locomotor activity was elevated 2.2-fold in the grafted animals. Sensorimotor orientation and disengage behavior was spared by the neonatal dopamine lesion and unaffected by the grafts. The level of functional restoration seen in the present study was more extensive than reported previously in neonatally 6-OHDA-lesioned rats where the VM grafts were implanted ectopically into the striatum. However, functional recovery remained incomplete also after intranigral graft placement compared to normal intact animals. The present approach should provide a new promising avenue for the continued exploration of the mechanisms involved in functional recovery and structural repair in the damaged nigrostriatal system.

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Improved graft survival and striatal reinnervation by microtransplantation of fetal nigral cell suspensions in the rat Parkinson model

Cited by 167 publications

References 26 publications

Enhancement of Sensorimotor Behavioral Recovery in Hemiparkinsonian Rats with Intrastriatal, Intranigral, and Intrasubthalamic Nucleus Dopaminergic Transplants

Enhancement of Sensorimotor Behavioral Recovery in Hemiparkinsonian Rats with Intrastriatal, Intranigral, and Intrasubthalamic Nucleus Dopaminergic Transplants

Fibroblast Growth Factor (FGF)-2 and FGF Receptor 3 Are Required for the Development of the Substantia Nigra, and FGF-2 Plays a Crucial Role for the Rescue of Dopaminergic Neurons after 6-Hydroxydopamine Lesion

Dopaminergic microtransplants into the substantia nigra of neonatal rats with bilateral 6-OHDA lesions. II. Transplant-induced behavioral recovery

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