Reduced vesicular storage of dopamine exacerbates methamphetamine-induced neurodegeneration and astrogliosis.
Reduced vesicular storage of dopamine exacerbates methamphetamine-induced neurodegeneration and astrogliosis.
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DOI：
10.1111/j.1471-4159.2008.05568.x
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发表时间：
2008-09
影响因子：
4.7
通讯作者：
Miller GW
中科院分区：
文献类型：
--
作者：
Guillot TS;Shepherd KR;Richardson JR;Wang MZ;Li Y;Emson PC;Miller GW
囊泡单胺转运蛋白2 （VMAT2）控制多巴胺（DA）进入囊泡，从而决定突触特性，如数量大小、受体敏感性以及囊泡和胞质DA浓度。适当的DA区隔化的损害被认为是DA神经元对氧化损伤和变性的敏感性的基础。众所周知，DA可以在细胞质中自动氧化形成醌和其他氧化物质，这种氧化应激的产生被认为是甲基苯丙胺（METH）暴露后DA末端丢失的关键因素。使用突变小鼠（VMAT2 LO），只有5-10%的VMAT2在野生型动物中表达，我们发现VMAT2是纹状体中甲基苯甲胺毒性的主要决定因素。在甲基安非他明暴露后，VMAT2 LO小鼠表现出多巴胺转运体和酪氨酸羟化酶（TH）的加剧损失，以及星形胶质细胞增生和蛋白质羰基形成的增强。更重要的是，冰毒后，VMAT2 LO小鼠纹状体中出现大量亲银沉积，表明VMAT2是冰毒诱导的神经退行性变的调节剂。在基础温度或冰毒诱导的热疗没有任何显著差异的情况下，VMAT2 LO中冰毒神经毒性增加。此外，与野生型培养物相比，VMAT2 LO小鼠的中脑原代培养物在冰毒暴露后显示出更多的氧化应激产生和更大的TH阳性过程损失。VMAT2 LO小鼠和培养物中神经毒性标志物升高表明，储存DA的能力决定了甲基苯丙胺给药后氧化应激和神经变性的程度。
The vesicular monoamine transporter 2 (VMAT2) controls the loading of dopamine (DA) into vesicles and therefore determines synaptic properties such as quantal size, receptor sensitivity, and vesicular and cytosolic DA concentration. Impairment of proper DA compartmentalization is postulated to underlie the sensitivity of DA neurons to oxidative damage and degeneration. It is known that DA can auto-oxidize in the cytosol to form quinones and other oxidative species and that this production of oxidative stress is thought to be a critical factor in DA terminal loss after methamphetamine (METH) exposure. Using a mutant strain of mice (VMAT2 LO), which have only 5–10% of the VMAT2 expressed by wild-type animals, we show that VMAT2 is a major determinant of METH toxicity in the striatum. Subsequent to METH exposure, the VMAT2 LO mice show an exacerbated loss of dopamine transporter and tyrosine hydroxylase (TH), as well as enhanced astrogliosis and protein carbonyl formation. More importantly, VMAT2 LO mice show massive argyrophilic deposits in the striatum after METH, indicating that VMAT2 is a regulator of METH-induced neurodegeneration. The increased METH neurotoxicity in VMAT2 LO occurs in the absence of any significant difference in basal temperature or METH-induced hyperthermia. Furthermore, primary midbrain cultures from VMAT2 LO mice show more oxidative stress generation and a greater loss of TH positive processes than wild-type cultures after METH exposure. Elevated markers of neurotoxicity in VMAT2 LO mice and cultures suggest that the capacity to store DA determines the amount of oxidative stress and neurodegeneration after METH administration.
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影响因子：
16.2
作者：
Fon, EA;Pothos, EN;Edwards, RH
通讯作者：
Edwards, RH
影响因子：
2.9
作者：
AXT, KJ;COMMINS, DL;SEIDEN, LS
通讯作者：
SEIDEN, LS
DOI：
10.1196/annals.1344.053
发表时间：
2005-01-01
期刊：
NEUROPROTECTIVE AGENTS
影响因子：
--
作者：
Ali, SF;Imam, SZ;Itzhak, Y
通讯作者：
Itzhak, Y
影响因子：
3.9
作者：
Gasnier, B
通讯作者：
Gasnier, B
影响因子：
4.7
作者：
Gluck, MR;Moy, LY;Sonsalla, PK
通讯作者：
Sonsalla, PK