在帕金森病的MPTP小鼠模型中，多巴胺转运体的针孔单光子发射计算机断层显像成像与多巴胺转运体免疫组化分析相关。

Pinhole SPECT imaging of dopamine transporters correlates with dopamine transporter immunohistochemical analysis in the MPTP mouse model of Parkinson's disease.

作者信息

Andringa Gerda, Drukarch Benjamin, Bol John G J M, de Bruin Kora, Sorman Karolina, Habraken Jan B A, Booij Jan

机构信息

Department of Medical Pharmacology, VU University Medical Center, Institute for Clinical and Experimental Neurosciences (ICEN), Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.

出版信息

Neuroimage. 2005 Jul 15;26(4):1150-8. doi: 10.1016/j.neuroimage.2005.03.034.

DOI:10.1016/j.neuroimage.2005.03.034

PMID:15908232

Abstract

The in vivo analysis of dopaminergic degeneration in animal models of Parkinson's disease (PD), using pinhole single photon emission computed tomography (SPECT), ideally should afford a serial study design, enabling the analysis of the degenerative process as well as the potential neuroprotective and/or restorative properties of drugs over time in living animals. Previously, we demonstrated that striatal dopamine transporter (DAT) levels in rats could be analyzed reproducibly, using pinhole SPECT with the DAT probe [(123)I]N-omega-fluoropropyl-2beta-carbomethoxy-3beta-{4-iodophenyl}nortropane (FP-CIT). However, the capacity of this approach to accurately detect a range of striatal DAT levels in the most widely used animal model of PD, i.e., the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse, remains to be determined. For this purpose, various levels of DAT were induced by treating c57BL/6J mice for 1, 3, or 5 days with MPTP (25 mg/kg ip), respectively. [(123)I]FP-CIT SPECT scans were performed 5 days after the last MPTP injection. Mice were perfused 6 days after the last MPTP injection, and the SPECT data were compared to ex vivo striatal and nigral DAT levels as measured by immunohistochemistry within the same animals. The analysis of striatal DAT levels using SPECT and DAT immunohistochemistry yielded highly comparable results on the percentage of DAT reduction in each MPTP group. The in vivo data showed a decrease of specific striatal to non-specific binding ratios by 59%, 82%, and 76% in mice treated for 1, 3, and 5 days, respectively. Moreover, a strong, positive correlation was observed between the in vivo and ex vivo parameters. The present study provides the first evidence that [(123)I]FP-CIT pinhole SPECT allows the accurate detection of a range of striatal DAT (i.e., losses of approximately 60-80%) levels in mice. Since such large dopaminergic lesions could be detected, this SPECT method may at least be useful for analyzing neuroprotective treatment with a clear-cut positive (i.e., complete protection) or negative (i.e., not any protection) effect. Whether this method is also useful for analyzing more subtle effects of neuroprotective treatment (partial protection) remains to be established, by studying mice with small dopaminergic lesions.

摘要

在帕金森病（PD）动物模型中，使用针孔单光子发射计算机断层扫描（SPECT）对多巴胺能神经元变性进行体内分析，理想情况下应采用系列研究设计，以便能够分析变性过程以及随着时间推移药物在活体动物中的潜在神经保护和/或恢复特性。此前，我们证明使用针孔SPECT和多巴胺转运体（DAT）探针[（123）I]N-ω-氟丙基-2β-甲氧基羰基-3β-{4-碘苯基}去甲托烷（FP-CIT），可以对大鼠纹状体中的DAT水平进行可重复分析。然而，在最常用的PD动物模型即1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）处理的小鼠中，这种方法准确检测一系列纹状体DAT水平的能力仍有待确定。为此，分别用MPTP（25mg/kg腹腔注射）处理c57BL/6J小鼠1、3或5天，诱导出不同水平的DAT。在最后一次MPTP注射后5天进行[（123）I]FP-CIT SPECT扫描。在最后一次MPTP注射后6天对小鼠进行灌注，并将SPECT数据与同一动物体内通过免疫组织化学测量的纹状体和黑质DAT水平进行比较。使用SPECT和DAT免疫组织化学分析纹状体DAT水平，在每个MPTP组中DAT减少的百分比方面产生了高度可比的结果。体内数据显示，分别接受1、3和5天治疗的小鼠中，纹状体特异性与非特异性结合率分别降低了59%、82%和76%。此外，在体内和体外参数之间观察到了很强的正相关性。本研究提供了首个证据，即[（123）I]FP-CIT针孔SPECT能够准确检测小鼠中一系列纹状体DAT水平（即损失约60 - 80%）。由于能够检测到如此大的多巴胺能损伤，这种SPECT方法至少可能有助于分析具有明确阳性（即完全保护）或阴性（即无任何保护）效果的神经保护治疗。通过研究具有小多巴胺能损伤的小鼠，该方法是否也有助于分析神经保护治疗的更细微效果（部分保护）仍有待确定。