Early minocycline treatment prevents a decrease in striatal dopamine in an SIV model of HIV-associated neurological disease.
Early minocycline treatment prevents a decrease in striatal dopamine in an SIV model of HIV-associated neurological disease.
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DOI：
10.1007/s11481-011-9332-1
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发表时间：
2012-06
期刊：
影响因子：
--
通讯作者：
Zink MC
中科院分区：
文献类型：
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作者：
Meulendyke KA;Pletnikov MV;Engle EL;Tarwater PM;Graham DR;Zink MC
HIV感染者，即使接受抗逆转录病毒治疗，也经常表现出认知、行为和运动异常，并且多巴胺（DA）水平降低。米诺环素可预防SIV模型中的脑炎和神经退行性变，这表明它也可预防黑质纹状体多巴胺能系统功能障碍。使用SIV/猕猴模型的HIV相关的中枢神经系统疾病，我们证明了纹状体水平的DA显着降低猕猴感染后期和代谢产物DOPAC的水平也往往较低。DA水平下降超过其代谢产物，表明DA生产或catalysts的失调。米诺环素治疗开始于接种后12天，但不是21天防止纹状体DA损失。DA下降不是由于多巴胺能投射到基底神经节的直接损失，因为米诺环素处理和未处理的猕猴之间的酪氨酸羟化酶、多巴胺转运蛋白、囊泡单胺转运蛋白2或突触素没有差异。SIV感染的猕猴有显着较高的单胺氧化酶（MAO）活性比未感染的猕猴，虽然MAO活性不受米诺环素。氧化/亚硝化应激通过硝基酪氨酸染色在深层白色物质中进行检查，并且与未处理的猕猴相比，在SIV感染的米诺环素处理的猕猴中较低。这些数据表明，米诺环素，具有抗氧化活性，具有保护作用，DA稳态时，在适当的时间给药SIV神经发病机制。
HIV-infected individuals, even with antiretroviral therapy, often display cognitive, behavioral and motor abnormalities and have decreased dopamine (DA) levels. Minocycline prevents encephalitis and neurodegeneration in SIV models, suggesting that it might also protect against nigrostriatal dopaminergic system dysfunction. Using an SIV/macaque model of HIV-associated CNS disease, we demonstrated that striatal levels of DA were significantly lower in macaques late in infection and that levels of the metabolite DOPAC also tended to be lower. DA levels declined more than its metabolites, indicating a dysregulation of DA production or catabolism. Minocycline treatment beginning at 12 but not 21 days postinoculation prevented striatal DA loss. DA decline was not due to direct loss of dopaminergic projections to the basal ganglia as there was no difference in tyrosine hydroxylase, dopamine transporter, vesicular monoamine transporter 2 or synaptophysin between minocycline-treated and untreated macaques. SIV-infected macaques had significantly higher monoamine oxidase (MAO) activity than uninfected macaques, although MAO activity was not affected by minocycline. Oxidative/nitrosative stress was examined by nitrotyrosine staining in the deep white matter and was lower in SIV-infected, minocycline-treated macaques compared with untreated macaques. These data suggest that minocycline, which has antioxidant activity, has a protective effect on DA homeostasis when administered at an appropriate time in SIV neuropathogenesis.