Department of Neurology, Philipps University, D-35033 Marburg, Germany.
Neuroimage. 2013 Oct 1;79:191-200. doi: 10.1016/j.neuroimage.2013.04.076. Epub 2013 Apr 28.
A previous clinical trial studied the effect of long-term treatment with levodopa (LD) or the dopamine agonist pramipexole (PPX) on disease progression in Parkinson disease using SPECT with the dopamine transporter (DAT)-radioligand [(123)I]β-CIT as surrogate marker. [(123)I]β-CIT binding declined to significantly lower levels in patients receiving LD compared to PPX. However, the interpretation of this difference as LD-induced neurotoxicity, PPX-induced neuroprotection/-regeneration, or only drug-induced regulatory changes of DAT-availability remained controversial. To address this question experimentally, we induced a subtotal lesion of the substantia nigra in mice by bilateral injection of the neurotoxin 6-hydroxydopamine. After 4 weeks, mice were treated for 20 weeks orally with LD (100mg/kg/day) or PPX (3mg/kg/day), or water (vehicle) only. The integrity of nigrostriatal projections was assessed by repeated [(123)I]FP-CIT SPECT in vivo and by immunostaining for DAT and the dopamine-synthesizing enzyme tyrosine hydroxylase (TH) after sacrifice. In sham-lesioned mice, we found that both LD and PPX treatment significantly decreased the striatal FP-CIT binding (LD: -21%; PPX: -14%) and TH-immunoreactivity (LD: -42%; PPX: -45%), but increased DAT-immunoreactivity (LD: +42%; PPX: +33%) compared to controls without dopaminergic treatment. In 6-hydroxydopamine-lesioned mice, however, neither LD nor PPX significantly influenced the stably reduced FP-CIT SPECT signal (LD: -66%; PPX: -66%; controls -66%), TH-immunoreactivity (LD: -70%; PPX: -72%; controls: -77%) and DAT-immunoreactivity (LD: -70%; PPX: -75%; controls: -75%) in the striatum or the number of TH-positive cells in the substantia nigra (LD: -88%; PPX: -88%; controls: -86%), compared to lesioned mice without dopaminergic treatment. In conclusion, chronic dopaminergic stimulation with LD or PPX induced similar adaptive presynaptic changes in healthy mice, but no discernible changes in severely lesioned mice. These findings allow to more reliably interpret the results from clinical trials using neuroimaging of DAT as surrogate parameter.
先前的临床试验研究了使用多巴胺转运体（DAT）放射性配体[(123)I]β-CIT 作为替代标志物，长期使用左旋多巴（LD）或多巴胺激动剂普拉克索（PPX）治疗对帕金森病疾病进展的影响。与 PPX 相比，接受 LD 治疗的患者的[(123)I]β-CIT 结合显著降低至更低水平。然而，将这种差异解释为 LD 诱导的神经毒性、PPX 诱导的神经保护/再生，或仅为药物诱导的 DAT 可用性的调节变化，仍然存在争议。为了在实验中解决这个问题，我们通过双侧注射神经毒素 6-羟多巴胺在小鼠中诱导了黑质的亚全损伤。4 周后，小鼠连续 20 周口服 LD（100mg/kg/天）或 PPX（3mg/kg/天）或仅用水（载体）治疗。通过重复体内[(123)I]FP-CIT SPECT 评估黑质纹状体投射的完整性，并在牺牲后通过 DAT 和多巴胺合成酶酪氨酸羟化酶（TH）的免疫染色进行评估。在假损伤小鼠中，我们发现 LD 和 PPX 治疗都显著降低了纹状体 FP-CIT 结合（LD：-21%；PPX：-14%）和 TH-免疫反应性（LD：-42%；PPX：-45%），但与未经多巴胺治疗的对照组相比，DAT-免疫反应性增加（LD：+42%；PPX：+33%）。然而，在 6-羟多巴胺损伤的小鼠中，LD 或 PPX 均未显著影响稳定降低的 FP-CIT SPECT 信号（LD：-66%；PPX：-66%；对照组：-66%）、TH-免疫反应性（LD：-70%；PPX：-72%；对照组：-77%）和纹状体中的 DAT-免疫反应性（LD：-70%；PPX：-75%；对照组：-75%）或黑质中 TH 阳性细胞的数量（LD：-88%；PPX：-88%；对照组：-86%），与未经多巴胺治疗的损伤小鼠相比。总之，在健康小鼠中，LD 或 PPX 进行慢性多巴胺刺激诱导了类似的适应性突触前变化，但在严重损伤的小鼠中没有明显变化。这些发现使得使用 DAT 作为替代参数进行神经影像学研究的临床试验结果的解释更加可靠。
