Single low doses of MPTP decrease tyrosine hydroxylase expression in the absence of overt neuron loss.
Single low doses of MPTP decrease tyrosine hydroxylase expression in the absence of overt neuron loss.
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DOI：
10.1016/j.neuro.2017.03.008
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发表时间：
2017-05
期刊：
影响因子：
3.4
通讯作者：
Richardson JR
中科院分区：
文献类型：
--
作者：
Alam G;Edler M;Burchfield S;Richardson JR
帕金森病（Parkinson's disease，PD）是第二常见的年龄相关性神经退行性疾病。1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）是一种原型神经毒剂，用于小鼠中模拟PD病理学的主要特征，包括纹状体多巴胺耗竭和黑质背侧部（SNc）中的多巴胺神经元丢失。在文献中，有几个涉及多剂量MPTP的实验范例，用于引起多巴胺神经元损失。然而，最近的一项研究报告说，单次低剂量导致多巴胺神经元的显著损失。在这里，我们确定了一个单一的三个剂量的MPTP（0.1，2和20毫克/公斤）的多巴胺神经元，标记的酪氨酸羟化酶（TH+），和神经元总数（尼氏+）在SNC使用无偏体视学计数的一个腹膜内注射的效果。数据显示，仅在用20 mg/kg MPTP处理的组中，SNc（TH+和Nissl+−）中的神经元显著损失。低剂量MPTP（0.1和2 mg/kg）处理组仅表现出TH+神经元的显著损失，而不是TH+和Nissl+。纹状体多巴胺水平在2和20 mg/kg MPTP处理组中降低，纹状体末端标记物包括TH和多巴胺转运蛋白（DAT）仅在20 mg/kg MPTP处理组中降低。这些数据表明，较低剂量的MPTP可能导致TH表达的损失，而不是SN中实际的多巴胺神经元损失。这一发现加强了在确定多巴胺神经元损失时测量总神经元数量沿着TH+细胞的需要。
Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a prototypical neurotoxicant used in mice to mimic primary features of PD pathology including striatal dopamine depletion and dopamine neuron loss in the substantia nigra pars compacta (SNc). In the literature, there are several experimental paradigms involving multiple doses of MPTP that are used to elicit dopamine neuron loss. However, a recent study reported that a single low dose caused significant loss of dopamine neurons. Here, we determined the effect of a single intraperitoneal injection of one of three doses of MPTP (0.1, 2 and 20 mg/kg) on dopamine neurons, labeled by tyrosine hydroxylase (TH+), and total neuron number (Nissl+) in the SNc using unbiased stereological counting. Data reveal a significant loss of neurons in the SNc (TH+ and Nissl+−) only in the group treated with 20 mg/kg MPTP. Groups treated with lower dose of MPTP (0.1 and 2 mg/kg) only showed significant loss of TH+ neurons rather than TH+ and Nissl+. Striatal dopamine levels were decreased in the groups treated with 2 and 20 mg/kg MPTP and striatal terminal markers including, TH and the dopamine transporter (DAT), were only decreased in the groups treated with 20 mg/kg MPTP. These data demonstrate that lower doses of MPTP likely result in loss of TH expression rather than actual dopamine neuron loss in the SN. This finding reinforces the need to measure both total neuron number along with TH+ cells in determining dopamine neuron loss.