Portland VA Medical Center, Portland, OR 97239, USA.
Neuroscience. 2011 May 19;182:203-7. doi: 10.1016/j.neuroscience.2011.03.015. Epub 2011 Mar 21.
We have previously reported that a progressively increased dose of MPTP over the course of 4 weeks induces the gradual impairment of the nigrostriatal dopamine (DA) pathway and several behaviors [Goldberg et al. (in press) Neuroscience]. To our knowledge, this is the first report of specific behavioral deficits correlated with discrete thresholds of DA loss in this pathway. In that study, MPTP was administered 5 d/wk, with behavioral and tissue analysis being carried out 3 days following the final injection at each dose. However, in order to better represent long-term progressive neurodegeneration the present study introduced a washout period of 10 days between each increased dose of MPTP. This implementation also controlled for any transient de-activation of tyrosine hydroxylase (TH), the enzyme that catalyzes synthesis of DA, caused by MPTP-induced oxidative stress which has been suggested following acute administration of the toxin [Smeyne and Jackson-Lewis (2005) Brian Res Mol Brain Res 134:57-66]. Additionally, by the end of the previous study, there was an ultimate decrease of 62% in the mean number of TH-labeled neurons/section in the substantia nigra pars compacta (SNpc) and a 74% decrease in caudate putamen (CPu) TH optical density with continuous MPTP. In the present study, we find that the washout periods lead to a final 79% decrease in the mean number of TH-labeled SNpc neurons/section, and a similar 74% decrease in CPu TH following the 32 mg/kg MPTP dose. Additionally, a dose-dependent decrease was observed in the mean number of SNpc TH-ir neurons/section in the current study which was not seen in the continuous MPTP protocol. These results suggest that a washout period following each increased MPTP dose allows for observation of continued cell death that might occur during the week following MPTP administration, and for therapeutic interventions to be applied at any of several stages during progressive neurodegeneration.
我们之前曾报道过，在 4 周的时间内逐渐增加 MPTP 的剂量会导致黑质纹状体多巴胺（DA）通路逐渐受损，以及几种行为出现问题[Goldberg 等人（即将发表）神经科学]。据我们所知，这是首次报道在该通路中，特定的行为缺陷与 DA 损失的离散阈值相关。在那项研究中，MPTP 每周给药 5 天，在每个剂量的最后一次注射后 3 天进行行为和组织分析。然而，为了更好地代表长期进行性神经退行性变，本研究在每个增加的 MPTP 剂量之间引入了 10 天的洗脱期。这种实施方式还控制了 MPTP 诱导的氧化应激对酪氨酸羟化酶（TH）的任何瞬时去激活作用，TH 是催化 DA 合成的酶，在毒素急性给药后已经提出了这种作用[ Smeyne 和 Jackson-Lewis（2005）Brian Res Mol Brain Res 134：57-66]。此外，在之前的研究结束时，在黑质致密部（SNpc）中，TH 标记神经元/节的平均数量最终减少了 62%，纹状体（CPu）TH 光密度减少了 74%，而连续的 MPTP 则减少了 74%。在本研究中，我们发现洗脱期导致 SNpc 中 TH 标记神经元/节的平均数量最终减少了 79%，并且在 32mg/kg MPTP 剂量下，CPu 中的 TH 也减少了 74%。此外，在当前研究中观察到 SNpc TH-ir 神经元/节的平均数量呈剂量依赖性下降，而在连续 MPTP 方案中则没有观察到这种情况。这些结果表明，在每个增加的 MPTP 剂量后进行洗脱期，可以观察到在 MPTP 给药后一周内可能发生的持续细胞死亡，并可以在进行性神经退行性变的任何几个阶段应用治疗干预措施。
