Vascular endothelial growth factor is upregulated by L-dopa in the parkinsonian brain: implications for the development of dyskinesia.

Ohlin KE, Francardo V, Lindgren HS, Sillivan SE, O'Sullivan SS, Luksik AS, Vassoler FM, Lees AJ, Konradi C, Cenci MA
Brain. 2011 134 (Pt 8): 2339-57

PMID: 21771855 · PMCID: PMC3155708 · DOI:10.1093/brain/awr165

Angiogenesis and increased permeability of the blood-brain barrier have been reported to occur in animal models of Parkinson's disease and l-dopa-induced dyskinesia, but the significance of these phenomena has remained unclear. Using a validated rat model of l-dopa-induced dyskinesia, this study demonstrates that chronic treatment with l-dopa dose dependently induces the expression of vascular endothelial growth factor in the basal ganglia nuclei. Vascular endothelial growth factor was abundantly expressed in astrocytes and astrocytic processes in the proximity of blood vessels. When co-administered with l-dopa, a small molecule inhibitor of vascular endothelial growth factor signalling significantly attenuated the development of dyskinesia and completely blocked the angiogenic response and associated increase in blood-brain barrier permeability induced by the treatment. The occurrence of angiogenesis and vascular endothelial growth factor upregulation was verified in post-mortem basal ganglia tissue from patients with Parkinson's disease with a history of dyskinesia, who exhibited increased microvascular density, microvascular nestin expression and an upregulation of vascular endothelial growth factor messenger ribonucleic acid. These congruent findings in the rat model and human patients indicate that vascular endothelial growth factor is implicated in the pathophysiology of l-dopa-induced dyskinesia and emphasize an involvement of the microvascular compartment in the adverse effects of l-dopa pharmacotherapy in Parkinson's disease.

MeSH Terms (37)

Aged Aged, 80 and over Analysis of Variance Animals Antigens, CD Antigens, Surface Antiparkinson Agents Astrocytes Behavior, Animal Benserazide Blood-Brain Barrier Blood Vessels Brain Bromodeoxyuridine Cell Count Cells, Cultured Disease Models, Animal Dopamine Dose-Response Relationship, Drug Dyskinesia, Drug-Induced Embryo, Mammalian Enzyme-Linked Immunosorbent Assay Enzyme Inhibitors Female Humans Laminin Levodopa Male Neovascularization, Pathologic Nerve Tissue Proteins Parkinsonian Disorders Rats Rats, Sprague-Dawley RNA, Messenger Time Factors Up-Regulation Vascular Endothelial Growth Factor A

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