Long-term exposure of mice to nucleoside analogues disrupts mitochondrial DNA maintenance in cortical neurons.
Long-term exposure of mice to nucleoside analogues disrupts mitochondrial DNA maintenance in cortical neurons.
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小鼠长期接触核苷类似物会破坏皮质神经元线粒体 DNA 的维持
DOI：
10.1371/journal.pone.0085637
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Chen D
中科院分区：
文献类型：
--
作者：
Zhang Y;Song F;Gao Z;Ding W;Qiao L;Yang S;Chen X;Jin R;Chen D
核苷类似物逆转录酶抑制剂（NRTI）是高效抗逆转录病毒治疗（HAART）的重要组成部分，被广泛用于抑制HIV复制。长期暴露于NRTIs可导致线粒体毒性，表现为脂肪萎缩、乳酸酸中毒、心肌病和肌病以及多发性神经病变。但NRTIs的脑神经毒性尚不清楚，部分原因是血脑屏障（BBB）的限制和中枢神经系统（CNS）复杂的微环境。在本研究中，Balb/c小鼠每天腹腔注射50 mg/kg司他夫定（D4T）、100 mg/kg齐多夫定（AZT）、50 mg/kg拉米夫定（3TC）或50 mg/kg二丹参（DDI），每周5天，连续1或4个月，培养原代皮质神经元，暴露于25µM D4T、50µM AZT、25µM 3TC或25µM DDI中7天。然后，用激光捕获显微解剖法从小鼠大脑皮层组织中捕获单个神经元。采用实时荧光定量PCR检测原代培养的皮质神经元、捕获的神经元或神经胶质细胞、脑组织、肝脏和肌肉组织的线粒体DNA （mtDNA）水平。数据显示，在暴露于nrti的培养神经元和nrti治疗一个月的小鼠大脑中，mtDNA均未丢失。在四个月的NRTIs治疗中，即使肝脏（除了3TC）和肌肉的mtDNA水平显著降低，脑mtDNA水平仍保持不变。然而，从mtDNA未改变的大脑中捕获的神经元中，mtDNA缺失率明显更高。这些结果表明，长期暴露于NRTIs可导致小鼠皮质神经元mtDNA缺失。
Nucleoside analogue reverse transcriptase inhibitor (NRTI), an integral component of highly active antiretroviral therapy (HAART), was widely used to inhibit HIV replication. Long-term exposure to NRTIs can result in mitochondrial toxicity which manifests as lipoatrophy, lactic acidosis, cardiomyopathy and myopathy, as well as polyneuropathy. But the cerebral neurotoxicity of NRTIs is still not well known partly due to the restriction of blood-brain barrier (BBB) and the complex microenvironment of the central nervous system (CNS). In this study, the Balb/c mice were administered 50 mg/kg stavudine (D4T), 100 mg/kg zidovudine (AZT), 50 mg/kg lamivudine (3TC) or 50 mg/kg didanosine (DDI) per day by intraperitoneal injection, five days per week for one or four months, and primary cortical neurons were cultured and exposed to 25 µM D4T, 50 µM AZT, 25 µM 3TC or 25 µM DDI for seven days. Then, single neuron was captured from mouse cerebral cortical tissues by laser capture microdissection. Mitochondrial DNA (mtDNA) levels of the primary cultured cortical neurons, and captured neurons or glial cells, and the tissues of brains and livers and muscles were analyzed by relative quantitative real-time PCR. The data showed that mtDNA did not lose in both NRTIs exposed cultured neurons and one month NRTIs treated mouse brains. In four months NRTIs treated mice, brain mtDNA levels remained unchanged even if the mtDNA levels of liver (except for 3TC) and muscle significantly decreased. However, mtDNA deletion was significantly higher in the captured neurons from mtDNA unchanged brains. These results suggest that long-term exposure to NRTIs can result in mtDNA deletion in mouse cortical neurons.
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影响因子：
3.2
作者：
Heaton, Robert K.;Franklin, Donald R.;Ellis, Ronald J.;McCutchan, J. Allen;Letendre, Scott L.;LeBlanc, Shannon;Corkran, Stephanie H.;Duarte, Nichole A.;Clifford, David B.;Woods, Steven P.;Collier, Ann C.;Marra, Christina M.;Morgello, Susan;Mindt, Monica Rivera;Taylor, Michael J.;Marcotte, Thomas D.;Atkinson, J. Hampton;Wolfson, Tanya;Gelman, Benjamin B.;McArthur, Justin C.;Simpson, David M.;Abramson, Ian;Gamst, Anthony;Fennema-Notestine, Christine;Jernigan, Terry L.;Wong, Joseph;Grant, Igor
通讯作者：
Grant, Igor
影响因子：
6
作者：
Rook, MS;Delach, SM;Wolfe, JL
通讯作者：
Wolfe, JL
影响因子：
3.2
作者：
Kohler, James J.;Hosseini, Seyed H.;Lewis, William
通讯作者：
Lewis, William
DOI：
10.1007/978-1-61779-163-5_22
发表时间：
2011-01-01
期刊：
LASER CAPTURE MICRODISSECTION: METHODS AND PROTOCOLS, SECOND EDITION
影响因子：
--
作者：
Kohler, James J.;Hosseini, Seyed H.
通讯作者：
Hosseini, Seyed H.
DOI：
10.1097/00042560-200109010-00004
发表时间：
2001-09-01
期刊：
JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES
影响因子：
--
作者：
Tozzi, V;Balestra, T;Ippolito, G
通讯作者：
Ippolito, G