Department of Experimental Medical Science, Lund University, Lund, Sweden.
Brain. 2011 Aug;134(Pt 8):2339-57. doi: 10.1093/brain/awr165. Epub 2011 Jul 19.
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.
血管生成和血脑屏障通透性增加已在帕金森病和左旋多巴诱导的运动障碍的动物模型中报道，但这些现象的意义仍不清楚。本研究使用已验证的左旋多巴诱导的运动障碍大鼠模型表明，慢性左旋多巴治疗可剂量依赖性地诱导基底神经节核中血管内皮生长因子的表达。血管内皮生长因子在血管附近的星形胶质细胞和星形胶质细胞突起中大量表达。当与左旋多巴一起给予时，血管内皮生长因子信号的小分子抑制剂显著减弱了运动障碍的发展，并完全阻断了该治疗引起的血管生成反应和相关的血脑屏障通透性增加。在有运动障碍病史的帕金森病患者的死后基底神经节组织中验证了血管生成和血管内皮生长因子的上调，其表现为微血管密度增加、微血管巢蛋白表达增加和血管内皮生长因子信使核糖核酸的上调。大鼠模型和人类患者中的这些一致发现表明，血管内皮生长因子与左旋多巴诱导的运动障碍的病理生理学有关，并强调微血管区室参与了帕金森病中左旋多巴药物治疗的不良反应。
