ITAB, G D'Annunzio University, Chieti, Italy.
PLoS One. 2013;8(2):e56501. doi: 10.1371/journal.pone.0056501. Epub 2013 Feb 19.
Systemic administration of a Synthetic Proteasome Inhibitor (PSI) in rats has been described as able to provide a model of Parkinson's disease (PD), characterized by behavioral and biochemical modifications, including loss of dopaminergic neurons in the substantia nigra (SN), as assessed by post-mortem studies. With the present study we aimed to assess in-vivo by Magnetic Resonance (MR) possible morphological and metabolic changes in the nigro-striatal pathway of PSI-treated rats. 10 animals were subcutaneously injected with PSI 6.0 mg/kg dissolved in DMSO 100%. Injections were made thrice weekly over the course of two weeks. 5 more animals injected with DMSO 100% with the same protocol served as controls. The animals underwent MR sessions before and at four weeks after the end of treatment with either PSI or vehicle. MR Imaging was performed to measure SN volume and Proton MR Spectroscopy ((1)H-MRS) was performed to measure metabolites changes at the striatum. Animals were also assessed for motor function at baseline and at 4 and 6 weeks after treatment. Dopamine and dopamine metabolite levels were measured in the striata at 6 weeks after treatment. PSI-treated animals showed volumetric reduction of the SN (p<0.02) at 4 weeks after treatment as compared to baseline. Immunofluorescence analysis confirmed MRI changes in SN showing a reduction of tyrosine hydroxylase expression as compared to neuron-specific enolase expression. A reduction of N-acetyl-aspartate/total creatine ratio (p = 0.05) and an increase of glutamate-glutamine-γ amminobutirrate/total creatine were found at spectroscopy (p = 0.03). At 6 weeks after treatment, PSI-treated rats also showed motor dysfunction compared to baseline (p = 0.02), accompanied by dopamine level reduction in the striatum (p = 0.02). Treatment with PSI produced morphological and metabolic modifications of the nigro-striatal pathway, accompanied by motor dysfunction. MR demonstrated to be a powerful mean to assess in-vivo the nigro-striatal pathway morphology and metabolism in the PSI-based PD animal model.
系统给予合成蛋白酶体抑制剂（PSI）在大鼠被描述为能够提供帕金森病（PD）模型，其特征为行为和生化修饰，包括死后研究评估的黑质（SN）中多巴胺能神经元的丧失。本研究旨在通过磁共振（MR）评估 PSI 处理大鼠黑质纹状体通路的形态和代谢变化。10 只动物接受皮下注射溶解于 DMSO 100%中的 PSI 6.0mg/kg。每周注射 3 次，共两周。5 只注射 DMSO 100%且具有相同方案的动物作为对照。动物在接受 PSI 或载体治疗前后以及治疗结束后 4 周进行 MR 检查。MR 成像用于测量 SN 体积，质子磁共振波谱（1H-MRS）用于测量纹状体代谢物变化。动物还在治疗前和治疗后 4 周和 6 周进行运动功能评估。治疗后 6 周测量纹状体中的多巴胺和多巴胺代谢物水平。与基线相比，PSI 处理动物在治疗后 4 周 SN 体积减少（p<0.02）。免疫荧光分析证实了 SN 中的 MRI 变化，与神经元特异性烯醇化酶表达相比，酪氨酸羟化酶表达减少。在光谱中发现 N-乙酰天冬氨酸/总肌酸的比率降低（p = 0.05）和谷氨酸-谷氨酰胺-γ 氨基丁酸/总肌酸的增加（p = 0.03）。在治疗后 6 周，与基线相比，PSI 处理的大鼠也表现出运动功能障碍（p = 0.02），同时纹状体中的多巴胺水平降低（p = 0.02）。PSI 治疗导致黑质纹状体通路的形态和代谢改变，伴有运动功能障碍。MR 证明是评估基于 PSI 的 PD 动物模型中黑质纹状体通路形态和代谢的有力手段。
