Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden.
Neuroimage. 2012 May 15;61(1):228-39. doi: 10.1016/j.neuroimage.2012.02.066. Epub 2012 Mar 3.
Large increases in regional cerebral blood flow (rCBF) have been measured in patients with Parkinson's disease (PD) following the administration of L-DOPA, but the underlying mechanisms have remained unknown. In this study, rats with unilateral 6-hydroxydopamine (6-OHDA) lesions were used to compare patterns of rCBF and regional cerebral glucose utilisation (rCGU) in chronically L-DOPA-treated subjects following a final injection of L-DOPA or saline. The same animal model was used to the leakage of a blood-brain barrier (BBB) tracer molecule at 60 min vs. 24h following the last L-DOPA injection of a chronic treatment. All the parameters under investigation were examined with brain autoradiography following intravenous injections of specific radiotracers in awake animals ([14C]-iodoantipyrine for rCBF, [14C]-2-deoxyglucose for rCGU, and [14C]-α-aminoisobutyric acid for BBB leakage). Significant changes in rCBF and rCGU on the side ipsilateral to the 6-OHDA lesion relative to the non-lesioned side were seen at 60 min ("ON") but not 24h ("OFF") following L-DOPA administration. These changes were not seen in sham-operated rats. In the output nuclei of the basal ganglia (the entopeduncular nucleus and the substantia nigra pars reticulata) both rCBF and rCGU were elevated both in acutely L-DOPA-treated rats and chronically L-DOPA-treated rats displaying dyskinesia, but did not change significantly in chronically L-DOPA-treated non-dyskinetic cases. Acutely and chronically L-DOPA-treated rats with dyskinesia exhibited increases in rCBF "ON L-DOPA" also in the motor cortex, the striatum, and the globus pallidus, but the corresponding changes in rCGU did not show the same direction, magnitude, and/or relative group differences. The uptake of a BBB tracer (studied in the striatum and the substantia nigra reticulata in chronically L-DOPA treated rats) was significantly higher ON vs. OFF L-DOPA. The present results are the first to show that the administration of L-DOPA is followed by transient and robust increases in rCBF in the dopamine-denervated basal ganglia. This effect occurs already upon acute L-DOPA treatment and persists upon repeated drug administration in animals that develop dyskinesia. Increases in rCBF ON L-DOPA are not necessarily accompanied by enhanced glucose utilisation in the affected regions, pointing to altered mechanisms of neurovascular coupling. Finally, our results show that increases in rCBF ON L-DOPA may be accompanied by BBB hyperpermeability in the most affected regions.
在接受左旋多巴治疗后，帕金森病（PD）患者的局部脑血流（rCBF）大量增加，但潜在机制仍不清楚。在这项研究中，使用单侧 6-羟多巴胺（6-OHDA）损伤的大鼠来比较慢性左旋多巴治疗后，最后一次左旋多巴或生理盐水注射后 rCBF 和局部脑葡萄糖利用（rCGU）的模式。相同的动物模型用于在慢性治疗的最后一次左旋多巴注射后 60 分钟与 24 小时比较血脑屏障（BBB）示踪剂分子的渗漏。在清醒动物静脉注射特定放射性示踪剂后，通过脑自动放射显影检查所有研究参数（[14C]-碘安替比林用于 rCBF、[14C]-2-脱氧葡萄糖用于 rCGU、和[14C]-α-氨基异丁酸用于 BBB 渗漏）。与非损伤侧相比，在接受 L-DOPA 治疗后 60 分钟（“ON”）而不是 24 小时（“OFF”），在 6-OHDA 损伤的对侧出现 rCBF 和 rCGU 的显著变化。在假手术大鼠中未观察到这些变化。在基底神经节的输出核（红核苍白球和黑质网状部）中，急性和慢性左旋多巴治疗的大鼠均表现出运动障碍，rCBF 和 rCGU 均升高，但在慢性左旋多巴治疗的非运动障碍病例中无明显变化。急性和慢性左旋多巴治疗的运动障碍大鼠在运动皮层、纹状体和苍白球中也表现出 rCBF“ON L-DOPA”的增加，但 rCGU 的相应变化并未显示出相同的方向、幅度和/或相对组差异。BBB 示踪剂（在慢性左旋多巴治疗大鼠的纹状体和黑质网状部研究）的摄取在 ON 与 OFF L-DOPA 之间显著增加。本研究结果首次表明，左旋多巴的给药后会导致多巴胺去神经的基底神经节中 rCBF 的短暂和强烈增加。这种效应在急性左旋多巴治疗时已经发生，并在动物出现运动障碍时在反复药物治疗后持续存在。L-DOPA 给药时 rCBF 的增加不一定伴有受影响区域葡萄糖利用的增强，这表明神经血管耦联的机制发生改变。最后，我们的结果表明，L-DOPA 给药时 rCBF 的增加可能伴有最受影响区域的 BBB 通透性增加。
