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N-乙酰半胱氨酸可预防 EAAC1-/- 小鼠多巴胺能神经元的丢失。

N-acetylcysteine prevents loss of dopaminergic neurons in the EAAC1-/- mouse.

机构信息

Department of Neurology, University of California, San Francisco, San Francisco Veterans Affairs Medical Center, USA.

出版信息

Ann Neurol. 2011 Mar;69(3):509-20. doi: 10.1002/ana.22162. Epub 2010 Nov 23.

DOI:10.1002/ana.22162
PMID:21446024
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4096233/
Abstract

OBJECTIVE

Dopaminergic neuronal death in Parkinson's disease (PD) is accompanied by oxidative stress and preceded by glutathione depletion. The development of disease-modifying therapies for PD has been hindered by a paucity of animal models that mimic these features and demonstrate an age-related progression. The EAAC1(-/-) mouse may be useful in this regard, because EAAC1(-/-) mouse neurons have impaired neuronal cysteine uptake, resulting in reduced neuronal glutathione content and chronic oxidative stress. Here we aimed to (1) characterize the age-related changes in nigral dopaminergic neurons in the EAAC1(-/-) mouse, and (2) use the EAAC1(-/-) mouse to evaluate N-acetylcysteine, a membrane-permeable cysteine pro-drug, as a potential disease-modifying intervention for PD.

METHODS

Wild-type mice, EAAC1(-/-) mice, and EAAC1(-/-) mice chronically treated with N-acetylcysteine were evaluated at serial time points for evidence of oxidative stress, dopaminergic cell death, and motor abnormalities.

RESULTS

EAAC1(-/-) mice showed age-dependent loss of dopaminergic neurons in the substantia nigra pars compacta, with more than 40% of these neurons lost by age 12 months. This neuronal loss was accompanied by increased nitrotyrosine formation, nitrosylated α-synuclein, and microglial activation. These changes were substantially reduced in mice that received N-acetylcysteine.

INTERPRETATION

These findings suggest that the EAAC1(-/-) mouse may be a useful model of the chronic neuronal oxidative stress that occurs in PD. The salutary effects of N-acetylcysteine in this mouse model provide an impetus for clinical evaluation of glutathione repletion in PD.

摘要

目的

帕金森病 (PD) 中的多巴胺能神经元死亡伴随着氧化应激，并且在谷胱甘肽耗竭之前发生。由于缺乏模拟这些特征并表现出与年龄相关进展的动物模型，因此 PD 的疾病修饰疗法的发展受到了阻碍。EAAC1(-/-) 小鼠在这方面可能很有用，因为 EAAC1(-/-) 小鼠神经元的神经元半胱氨酸摄取受损，导致神经元谷胱甘肽含量降低和慢性氧化应激。在这里，我们旨在 (1) 描述 EAAC1(-/-) 小鼠黑质多巴胺能神经元的年龄相关变化，(2) 使用 EAAC1(-/-) 小鼠来评估 N-乙酰半胱氨酸，一种膜通透性半胱氨酸前药，作为 PD 的潜在疾病修饰干预措施。

方法

在连续时间点评估野生型小鼠、EAAC1(-/-) 小鼠和慢性给予 N-乙酰半胱氨酸的 EAAC1(-/-) 小鼠，以评估氧化应激、多巴胺能细胞死亡和运动异常的证据。

结果

EAAC1(-/-) 小鼠表现出黑质致密部多巴胺能神经元的年龄依赖性丧失，这些神经元中有超过 40%在 12 个月时丧失。这种神经元丧失伴随着硝基酪氨酸形成、硝化 α-突触核蛋白和小胶质细胞激活的增加。接受 N-乙酰半胱氨酸的小鼠这些变化明显减少。

解释

这些发现表明，EAAC1(-/-) 小鼠可能是 PD 中发生的慢性神经元氧化应激的有用模型。N-乙酰半胱氨酸在这种小鼠模型中的有益作用为 PD 中谷胱甘肽补充的临床评估提供了动力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6536/4096233/a6c81eed1e27/nihms587949f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6536/4096233/7ab1824151bb/nihms587949f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6536/4096233/053cd85b9e24/nihms587949f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6536/4096233/f945650955e1/nihms587949f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6536/4096233/abaf4bcc81e0/nihms587949f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6536/4096233/dfa356c42afd/nihms587949f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6536/4096233/3d265d8a8a43/nihms587949f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6536/4096233/a6c81eed1e27/nihms587949f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6536/4096233/7ab1824151bb/nihms587949f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6536/4096233/053cd85b9e24/nihms587949f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6536/4096233/f945650955e1/nihms587949f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6536/4096233/abaf4bcc81e0/nihms587949f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6536/4096233/dfa356c42afd/nihms587949f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6536/4096233/3d265d8a8a43/nihms587949f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6536/4096233/a6c81eed1e27/nihms587949f7.jpg

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