Long-lasting transcriptional refractoriness triggered by a single exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine.
Long-lasting transcriptional refractoriness triggered by a single exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine.
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DOI：
10.1016/j.neuroscience.2012.03.047
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发表时间：
2012-07-12
期刊：
影响因子：
3.3
通讯作者：
Morgan, J. I.
中科院分区：
文献类型：
--
作者：
Pattarini, R.;Rong, Y.;Shepherd, K. R.;Jiao, Y.;Qu, C.;Smeyne, R. J.;Morgan, J. I.
帕金森病（PD）是一种进行性神经退行性疾病，其病因被认为具有环境（毒素）和遗传贡献。神经毒素1-甲基-4-苯基-1，2，3，6-四氢嘧啶（MPTP）可诱导PD的病理特征，包括黑质多巴胺能神经元的丢失和纹状体多巴胺（DA）耗竭。我们以前描述了纹状体的转录反应后，急性MPTP管理MPTP敏感的C57 BL/6 J小鼠。我们确定了三个不同的阶段：早期（5小时），中期（24小时）和晚期（72小时），并报告说，中期和晚期的反应是不存在的MPTP耐药的Swiss-Webster（SWR）小鼠。在这里，我们发现，C57 BL/6 J小鼠用单次40 mg/kg剂量的MPTP预处理，9天后用4 × 20 mg/kg MPTP处理，显示出与MPTP耐药的SWR小鼠相似的纹状体转录反应，即强烈的急性反应，但没有中期或晚期反应。转录不应性取决于引发激发的剂量，低至10 mg/kg MPTP有效，并且可以持续超过28天。SWR小鼠的引发对其随后用MPTP攻击的反应没有影响。我们还报告说，百草枯，另一种自由基生产者，也electrically纹状体转录的改变，但这些在很大程度上是不同的MPTP引发的。百草枯引起的变化也不受百草枯引发的影响。然而，百草枯和MPTP都不会引起交叉衰减。因此，暴露于特定的毒素触发了纹状体中不同的转录反应，这些反应受到先前暴露于相同毒素的影响。这里描述的MPTP不应期延长可以在分子水平上解释不同MPTP给药方案之间报告的差异，并可能对我们理解环境毒素暴露与PD之间的关系产生影响。
Parkinson’s disease (PD) is a progressive neurodegenerative disorder whose etiology is thought to have environmental (toxin) and genetic contributions. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine (MPTP) induces pathological features of PD including loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and striatal dopamine (DA) depletion. We previously described the striatal transcriptional response following acute MPTP administration in MPTP-sensitive C57BL/6J mice. We identified three distinct phases: early (5h), intermediate (24 h) and late (72 h) and reported that the intermediate and late responses were absent in MPTP-resistant Swiss-Webster (SWR) mice. Here we show that C57BL/6J mice pre-treated with a single 40 mg/kg dose of MPTP and treated 9 days later with 4 × 20 mg/kg MPTP, display a striatal transcriptional response similar to that of MPTP-resistant SWR mice i.e. a robust acute response but no intermediate or late response. Transcriptional refractoriness is dependent upon the dose of the priming challenge with as little as 10 mg/kg MPTP being effective and can persist for more than 28 days. Priming of SWR mice has no effect on their response to subsequent challenge with MPTP. We also report that paraquat, another free radical producer, also elicits striatal transcriptional alterations but these are largely distinct from those triggered by MPTP. Paraquat-induced changes are also refractory to priming with paraquat. However neither paraquat nor MPTP elicit cross-attenuation. Thus exposure to specific toxins triggers distinct transcriptional responses in striatum that are influenced by prior exposure to the same toxin. The prolonged refractory period described here for MPTP could explain at the molecular level the reported discrepancies between different MPTP administration regimens and may have implications for our understanding of the relationship between environmental toxin exposure and PD.
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影响因子：
10.4
作者：
Brown TP;Rumsby PC;Capleton AC;Rushton L;Levy LS
通讯作者：
Levy LS
影响因子：
3.4
作者：
Fernandez-Gonzalez, A;Pérez-Otaño, I;Morgan, JI
通讯作者：
Morgan, JI
影响因子：
10.4
作者：
Gatto, Nicole M.;Cockburn, Myles;Ritz, Beate
通讯作者：
Ritz, Beate
影响因子：
3
作者：
Bazzu, Gianfranco;Calia, Giammario;Miele, Egidio
通讯作者：
Miele, Egidio
DOI：
10.1016/1055-8330(95)90015-2
发表时间：
1995-09-01
期刊：
NEURODEGENERATION
影响因子：
--
作者：
JACKSONLEWIS, V;JAKOWEC, M;PRZEDBORSKI, S
通讯作者：
PRZEDBORSKI, S