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The Journal of Neuroscience, May 30, 2007, 27(22):5849-5856; doi:10.1523/JNEUROSCI.0626-07.2007
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Neurobiology of Disease
The Functional Impact of the Intrastriatal Dopamine Neuron Grafts in Parkinsonian Rats Is Reduced with Advancing Disease
Nathalie Breysse,1,2 Thomas Carlsson,1 Christian Winkler,1,3 Anders Björklund,2 andDeniz Kirik1 1Central Nervous System Disease Modeling Unit and 2Neurobiology Unit, Section for Neuroscience, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden, and 3Department of Neurology, Hannover Medical School, 30625 Hannover, Germany
Correspondence should be addressed to Dr. Deniz Kirik, Wallenberg Neuroscience Center, Biomedical Center A11, 221 84 Lund, Sweden. Email: Deniz.Kirik{at}med.lu.se
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.
Key words: Parkinson's disease; cell transplantation; dopamine; functional recovery; motor behavior; stereology
Received Feb. 12, 2007; revised April 16, 2007; accepted April 17, 2007.
Correspondence should be addressed to Dr. Deniz Kirik, Wallenberg Neuroscience Center, Biomedical Center A11, 221 84 Lund, Sweden. Email: Deniz.Kirik{at}med.lu.se
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