Metabolic changes detected by proton magnetic resonance spectroscopy in vivo and in vitro in a murin model of Parkinson's disease, the MPTP-intoxicated mouse
Metabolic changes detected by proton magnetic resonance spectroscopy in vivo and in vitro in a murin model of Parkinson's disease, the MPTP-intoxicated mouse
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DOI：
10.1111/j.1471-4159.2007.05185.x
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发表时间：
2008-05-01
影响因子：
4.7
通讯作者：
Durif, Franck
中科院分区：
文献类型：
--
作者：
Chassain, Carine;Bielicki, Guy;Durif, Franck
帕金森氏病是一种神经退行性疾病，其特征在于黑质背侧部多巴胺能神经元的进行性损失，其投射到纹状体。本研究的目的是使用质子H-1磁共振波谱（MRS）分析帕金森病小鼠模型中多巴胺耗竭对代谢物数量的体内和体外后果。对对照小鼠（n = 7）和MPTP中毒小鼠（n = 7）进行研究。所有实验均在9.4T下进行。对于体内MRS采集，将小鼠麻醉并小心地放置在动物处理系统上，其中头部以用于激发和信号接收的鸟笼线圈为中心。在以纹状体为中心的体素（8 μ L）中采集光谱，应用点分辨光谱序列（TR = 4000 ms，TE = 8.8 ms）。在体内MRS采集后，处死小鼠;通过对黑质黑质部的酪氨酸羟化酶免疫标记和对小鼠脑前部的高氯酸提取物进行体外MRS采集来验证成功的损伤。使用标准单脉冲实验获得体外光谱。使用JMRUI（里昂，法国）根据纹状体体内和高氯酸提取物体外获得的H-1光谱测定代谢物的绝对浓度。谷氨酸（Glu），谷氨酰胺（Gln），和GABA的浓度在体内获得的MPTP损伤小鼠纹状体显着增加（Glu：15.5 +/- 2.5 vs. 12.9 +/- 1.0 mmol/L，p < 0.05; Gln：2.3 +/- 0.9 vs. 1.8 +/- 0.6 mmol/L，p < 0.05; GABA：2.3 +/- 0.9 vs. 1.3 +/- 0.6 mmol/L，p < 0.05）。体外结果证实了这些结果，Glu（10.9 +/- 2.5 vs. 7.9 +/- 1.7 μ mol/g，p < 0.05）、Gln（6.8 +/- 2.9 vs. 4.3 +/- 1.0 μ mol/g，p < 0.05）和GABA（2.9 +/- 0.9 vs. 1.5 +/- 0.4 μ mol/g，p < 0.01）。本研究强烈支持多巴胺能去神经支配后纹状体GABA水平增加的多巴胺能皮质-纹状体通路假说的过度活跃。它进一步显示纹状体Gln浓度的增加，可能作为纹状体多巴胺耗尽后保护神经元免受Glu兴奋性毒性损伤的策略。
Parkinson's disease is a neurodegenerative disorder characterized by the progressive loss of the dopaminergic neurons in the substantia nigra pars compacta, which project to the striatum. The aim of this study was to analyze in vivo and in vitro consequences of dopamine depletion on amount of metabolites in a mouse model of Parkinson's disease using proton H-1 magnetic resonance spectroscopy (MRS). The study was performed on control mice (n = 7) and MPTP-intoxicated mice (n = 7). All the experiments were performed at 9.4 T. For in vivo MRS acquisitions, mice were anesthetized and carefully placed on an animal handling system with the head centered in birdcage coil used for both excitation and signal reception. Spectra were acquired in a voxel (8 mu L) centered in the striatum, applying a point-resolved spectroscopy sequence (TR = 4000 ms, TE = 8.8 ms). After in vivo MRS acquisitions, mice were killed; successful lesion verified by tyrosine hydroxylase immunolabeling on the substantia nigra pars compacta and in vitro MRS acquisitions performed on perchloric extracts of anterior part of mice brains. In vitro spectra were acquired using a standard one-pulse experiment. The absolute concentrations of metabolites were determined using JMRUI (Lyon, France) from H-1 spectra obtained in vivo on striatum and in vitro on perchloric extracts. Glutamate (Glu), glutamine (Gln), and GABA concentrations obtained in vivo were significantly increased in striatum of MPTP-lesioned mice (Glu: 15.5 +/- 2.5 vs. 12.9 +/- 1.0 mmol/L, p < 0.05; Gln: 2.3 +/- 0.9 vs. 1.8 +/- 0.6 mmol/L, p < 0.05; GABA: 2.3 +/- 0.9 vs. 1.3 +/- 0.6 mmol/L, p < 0.05). The in vitro results confirmed these results, Glu (10.9 +/- 2.5 vs. 7.9 +/- 1.7 mu mol/g, p < 0.05), Gln (6.8 +/- 2.9 vs. 4.3 +/- 1.0 mu mol/g, p < 0.05), and GABA (2.9 +/- 0.9 vs. 1.5 +/- 0.4 mu mol/g, p < 0.01). The present study strongly supports a hyperactivity of the glutamatergic cortico-striatal pathway hypothesis after dopaminergic denervation in association with an increase of striatal GABA levels. It further shows an increased of striatal Gln concentrations, perhaps as a strategy to protect neurons from Glu excitotoxic injury after striatal dopamine depletion.