Laboratory of Molecular and Behavioral Neurobiology, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil.
Graduate Program in Biochemistry and Pharmacology, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil.
Neuromolecular Med. 2018 Mar;20(1):73-82. doi: 10.1007/s12017-018-8476-z. Epub 2018 Jan 13.
The neurotoxin MPTP has long been used to create a mouse model of Parkinson's disease (PD). Indeed, several MPTP analogues have been developed, including 2'-CH-MPTP, which was shown to induce nigrostriatal DA neuronal depletion more potently than MPTP. However, no study on behavioral and molecular alterations in response to 2'-CH-MPTP has been carried out so far. In the present work, 2'-CH-MPTP was administered to mice (2.5, 5.0 and 10 mg/kg per injection, once a day, 5 days) and histological, biochemical, molecular and behavioral alterations were evaluated. We show that, despite a dose-dependent-like pattern observed for nigrostriatal dopaminergic neuronal death and dopamine depletion, dose-specific alterations in dopamine metabolism and in the expression of dopaminergic neurotransmission-associated genes could be related to specific motor deficits elicited by the different doses tested. Interestingly, 2'-CH-MPTP leads to increased DAT and MAO-B transcription, which could explain, respectively, its higher potency and the requirement of higher doses of MAO inhibitors to prevent nigrostriatal neuronal death when compared to MPTP. Also, perturbations in dopamine metabolism as well as possible alterations in dopamine bioavailability in the synaptic cleft were also identified and correlated with strength and ambulation deficits in response to specific doses. Overall, the present work brings new evidence supporting the distinct effects of 2'-CH-MPTP when compared to its analogue MPTP. Moreover, our data highlight the utmost importance of a precise experimental design, as different administration regimens and doses yield different biochemical, molecular and behavioral alterations, which can be explored to study specific aspects of PD.
神经毒素 MPTP 长期以来一直被用于创建帕金森病（PD）的小鼠模型。事实上，已经开发出了几种 MPTP 类似物，包括 2'-CH-MPTP，它被证明比 MPTP 更有效地诱导黑质纹状体 DA 神经元耗竭。然而，迄今为止，尚未针对 2'-CH-MPTP 进行过行为和分子改变的研究。在本工作中，给小鼠注射 2'-CH-MPTP（2.5、5.0 和 10mg/kg/次，每天一次，共 5 天），并评估组织学、生化、分子和行为改变。我们表明，尽管观察到黑质纹状体多巴胺能神经元死亡和多巴胺耗竭呈剂量依赖性模式，但多巴胺代谢和多巴胺能神经传递相关基因表达的剂量特异性改变可能与不同剂量测试引起的特定运动缺陷有关。有趣的是，2'-CH-MPTP 导致 DAT 和 MAO-B 转录增加，这可以分别解释其更高的效力以及与 MPTP 相比，需要更高剂量的 MAO 抑制剂来预防黑质纹状体神经元死亡的原因。此外，还发现了多巴胺代谢的紊乱以及突触间隙中多巴胺生物利用度的可能改变，并与对特定剂量的强度和步态缺陷相关。总体而言，本工作提供了新的证据，支持 2'-CH-MPTP 与类似物 MPTP 相比具有不同的作用。此外，我们的数据强调了精确实验设计的重要性，因为不同的给药方案和剂量会产生不同的生化、分子和行为改变，这些改变可以用来研究 PD 的特定方面。
