title: Vascular endothelial growth factor is upregulated by L-dopa in the parkinsonian brain: implications for the development of dyskinesia.
abstract: 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.
authors.affiliation: Department of Experimental Medical Science, Lund University, Lund, Sweden. elisabet.ohlin@med.lu.se
authors.forename: K Elisabet
authors.initials: KE
authors.lastname: Ohlin
authors.forename: Veronica
authors.initials: V
authors.lastname: Francardo
authors.forename: Hanna S
authors.initials: HS
authors.lastname: Lindgren
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Sillivan
authors.forename: Sean S
authors.initials: SS
authors.lastname: O'Sullivan
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Luksik
authors.forename: Fair M
authors.initials: FM
authors.lastname: Vassoler
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lees
authors.forename: Christine
authors.initials: C
authors.lastname: Konradi
authors.forename: M Angela
authors.initials: MA
authors.lastname: Cenci
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000954:Antigens, Surface / Q000378:metabolism; D000978:Antiparkinson Agents / Q000009:adverse effects*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001545:Benserazide / Q000009:adverse effects; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology; D001921:Brain / Q000166:cytology / Q000187:drug effects*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007797:Laminin / Q000378:metabolism; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000188:drug therapy; D009419:Nerve Tissue Proteins / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D000954:Antigens, Surface; D000978:Antiparkinson Agents; D004791:Enzyme Inhibitors; D007797:Laminin; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C114781:endothelial barrier antigen, rat; D007980:Levodopa; D001545:Benserazide; D001973:Bromodeoxyuridine; D004298:Dopamine