Suppression of endogenous PPARγ increases vulnerability to methamphetamine-induced injury in mouse nigrostriatal dopaminergic pathway.
Suppression of endogenous PPARγ increases vulnerability to methamphetamine-induced injury in mouse nigrostriatal dopaminergic pathway.
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DOI：
10.1007/s00213-011-2595-7
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发表时间：
2012-06
影响因子：
3.4
通讯作者：
Wang, Yun
中科院分区：
文献类型：
--
作者：
Yu, Seong-Jin;Airavaara, Mikko;Shen, Hui;Chou, Jenny;Harvey, Brandon K.;Wang, Yun
甲基苯丙胺是一种常见的滥用药物和多巴胺能神经毒素。重复给予高剂量的甲基苯丙胺诱导程序性细胞死亡，抑制多巴胺的释放，并减少自发活动。先前的研究表明，用过氧化物酶体增殖物激活受体γ（PPARγ）激动剂预处理减少甲基苯丙胺诱导的神经变性。本研究的目的是研究内源性过氧化物酶体增殖物激活受体γ在甲基苯丙胺毒性保护中的作用。将编码Cre重组酶基因的腺相关病毒（腺相关病毒）单侧注射到loxP-PPARγ或对照野生型小鼠的左侧黑质中。在病毒注射后1个月，用高剂量的甲基苯丙胺处理动物。行为测试采用旋转棒和旋转计。体内伏安法用于检查多巴胺释放/清除，并在2个月后注射甲基苯丙胺。施用AAV-Cre选择性地去除loxP-PPARγ小鼠中左侧黑质中的PPARγ，但不在野生型小鼠中。接受甲基苯丙胺的loxP-PPARγ/AAV-Cre小鼠在转棒上的时间显着减少，并且使用旋转计显示出同侧旋转增加。loxP-PPARγ/AAV-Cre动物左侧纹状体局部应用KCl诱导的多巴胺释放峰值和多巴胺清除率明显减弱。在接受高剂量甲基苯丙胺的loxP-PPARγ/AAV-Cre小鼠中，与右侧相比，左侧黑质和背侧纹状体的酪氨酸羟化酶免疫反应性降低。过氧化物酶体增殖物激活受体γ的缺乏增加了对高剂量甲基苯丙胺的易感性。内源性过氧化物酶体增殖物激活受体γ可能在降低甲基苯丙胺体内毒性中起重要作用。
Methamphetamine is a commonly abused drug and dopaminergic neurotoxin. Repeated administration of high doses of methamphetamine induces programmed cell death, suppression of dopamine release, and reduction in locomotor activity. Previous studies have shown that pretreatment with Peroxisome Proliferator-Activated Receptor gamma (PPARγ) agonist reduced Methamphetamine -induced neurodegeneration. The purpose of this study was to examine the role of endogenous PPARγ in protecting against methamphetamine toxicity. Adeno-associated virus (AAV) encoding the Cre recombinase gene was unilaterally injected into the left substantia nigra of loxP-PPARγ or control wild type mice. Animals were treated with high doses of methamphetamine 1-month after viral injection. Behavioral tests were examined using Rotarod and rotometer. In vivo voltammetry was used to examine dopamine release/clearance and at 2 months after methamphetamine injection. Administration of AAV-Cre selectively removed PPARγ in left nigra in loxP-PPARγ mice but not in the wild type mice. The loxP-PPARγ/AAV-Cre mice that received methamphetamine showed a significant reduction in time on the rotarod and exhibited increased ipislateral rotation using a rotometer. The peak of dopamine release induced by local application of KCl and the rate of dopamine clearance were significantly attenuated in the left striatum of loxP-PPARγ/AAV-Cre animals. Tyrosine hydroxylase immunoreactivity was reduced in the left, compared to right, nigra and dorsal striatum in loxP-PPARγ/AAV-Cre mice receiving high doses of methamphetamine. A deficiency in PPARγ increases vulnerability to high doses of methamphetamine. Endogenous PPARγ may play an important role in reducing methamphetamine toxicity in vivo.
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影响因子：
64.8
作者：
Jiang, CY;Ting, AT;Seed, B
通讯作者：
Seed, B
影响因子：
2.5
作者：
Fang, Xin;Sugiyama, Kenji;Namba, Hiroki
通讯作者：
Namba, Hiroki
DOI：
10.1073/pnas.2536828100
发表时间：
2003-12-23
影响因子：
11.1
作者：
He, WM;Barak, Y;Evans, RM
通讯作者：
Evans, RM
影响因子：
3.3
作者：
Chou, J.;Luo, Y.;Wang, Y.
通讯作者：
Wang, Y.
影响因子：
16
作者：
Barak, Y;Nelson, MC;Evans, RM
通讯作者：
Evans, RM