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

Abstract

Clinical trials involving intrastriatal transplants of human embryonic mesencephalic tissue have provided proof-of-principle that nigral dopamine (DA) neurons can survive and functionally integrate into the host neural circuitry. However, the degree of graft-induced symptomatic relief differs significantly between the patients. This variability has led to investigations aimed at identifying factors that could affect the clinical outcome. The extent and pattern of dopaminergic denervation in the brain may be one of the major determinants of the functional outcome after intrastriatal DA cell grafts. Here, we report that in animals subjected to an intrastriatal 6-hydroxydopamine lesion of the striatal dopaminergic afferent, the integrity of the host dopaminergic innervation outside the areas innervated by the graft is critical for optimal function of DA neurons placed in the striatum. Established graft-induced functional recovery, as assessed in the stepping and cylinder tests, was compromised in animals in which the dopaminergic lesion was extended to include also the medial and ventral striatum as well as the cortical and limbic DA projections. Poor clinical outcome after transplantation may, thus, at least in part, be caused by dopaminergic denervation in areas outside the graft-innervated territories, and similarly beneficial effects initially observed in patients may regress if the degeneration of the host extrastriatal DA projection systems proceeds with advancing disease. This would have two implications: first, patients with advanced disease involving the ventral striatum and/or nonstriatal DA projections would be unlikely to respond well to intrastriatal DA grafts and, second, to retain the full benefit of the grafts, progression of the disease should be avoided by, for example, combining cell therapy with a neuroprotective approach.

Functional Convergence of Dopaminergic and Cholinergic Input Is Critical for Hippocampus-Dependent Working Memory

“…The dorsal tips of the mammillary and interfascicular nuclei defined the ventral border, and the ventral tip of the red nucleus was used as the exclusion border dorsally. The THϩ cells in the VTA were counted from the rostral SN until the end of pars reticulata, thus excluding the THϩ neurons in the retrorubral area from the analysis (Maingay et al, 2006;Breysse et al, 2007).…”

From bench to bed: the potential of stem cells for the treatment of Parkinson’s disease

“…In the first reported double-blind trial, younger patients (less than 60 years old) exhibited a better response to the grafts than older subjects (Freed et al 2001). Recent animal experimental studies (Breysse et al 2007) and these clinical data indicate that more severe pathology at baseline reduces the chances of a successful outcome after transplantation. Several surgical aspects have also varied between studies, e.g., tissue preparation, number of cells transplanted, graft implantation techniques, and immunosuppression regimens.…”

Brain Repair: The Role of Endogenous and Transplanted Neural Stem Cells

“…In primary neurodegeneration, transplantation should be performed at the beginning of the neurodegenerative process in order to limit the cascade of events leading to the degeneration of other cell populations. Data clearly show that transplanted NPCs acquire an appropriate terminally differentiated fate and integrate functionally in the host tissue (Goldman, 2005;Breysse et al, 2007;Lindvall and Kokaia, 2010), an event particularly evident when there is a partial preservation of the neuronal circuits' cyto-architecture (Shihabuddin et al, 1996). On the other hand, while early transplantation is recommended in degenerative diseases, in primary inflammatory disorders (e.g.…”