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The Journal of Neuroscience, September 13, 2006, 26(37):9448-9461; doi:10.1523/JNEUROSCI.0944-06.2006

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Neurobiology of Disease
Endothelial Proliferation and Increased Blood–Brain Barrier Permeability in the Basal Ganglia in a Rat Model of 3,4-Dihydroxyphenyl-L-Alanine-Induced Dyskinesia

Jenny E. Westin,^1 * Hanna S. Lindgren,^1 * Jonathan Gardi,³ Jens Randel Nyengaard,³ Patrik Brundin,² Paul Mohapel,² and M. Angela Cenci¹

¹Basal Ganglia Unit and ²Neuronal Survival Unit, Department of Experimental Medical Science, Lund University, S-221 84 Lund, Sweden, and ³Stereology and Electron Microscopy Research Laboratory and Centre of Research in Membrane-receptor in Neurological Disease, Aarhus University, DK-8000 Aarhus, Denmark

Correspondence should be addressed to M. Angela Cenci, Basal Ganglia Pathophysiology Unit, Biomedical Center F11, 221 84 Lund, Sweden. Email: angela.cenci_nilsson{at}med.lu.se

3,4-Dihydroxyphenyl-L-alanine (L-DOPA)-induced dyskinesia is associated with molecular and synaptic plasticity in the basal ganglia, but the occurrence of structural remodeling through cell genesis has not been explored. In this study, rats with 6-hydroxydopamine lesions received injections of the thymidine analog 5-bromo-2'-deoxyuridine (BrdU) concomitantly with L-DOPA for 2 weeks. A large number of BrdU-positive cells were found in the striatum and its output structures (globus pallidus, entopeduncular nucleus, and substantia nigra pars reticulata) in L-DOPA-treated rats that had developed dyskinesia. The vast majority (60–80%) of the newborn cells stained positively for endothelial markers. This endothelial proliferation was associated with an upregulation of immature endothelial markers (nestin) and a downregulation of endothelial barrier antigen on blood vessel walls. In addition, dyskinetic rats exhibited a significant increase in total blood vessel length and a visible extravasation of serum albumin in the two structures in which endothelial proliferation was most pronounced (substantia nigra pars reticulata and entopeduncular nucleus). The present study provides the first evidence of angiogenesis and blood–brain barrier dysfunction in an experimental model of L-DOPA-induced dyskinesia. These microvascular changes are likely to affect the kinetics of L-DOPA entry into the brain, favoring the occurrence of motor complications.

Key words: 6-OHDA; angiogenesis; blood–brain barrier; basal ganglia; BrdU; dyskinesia; Parkinson’s disease; proliferation

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Received March 3, 2006; revised July 9, 2006; accepted July 27, 2006.

Correspondence should be addressed to M. Angela Cenci, Basal Ganglia Pathophysiology Unit, Biomedical Center F11, 221 84 Lund, Sweden. Email: angela.cenci_nilsson{at}med.lu.se

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