Didanosine causes sensory neuropathy in an HIV/AIDS animal model: impaired mitochondrial and neurotrophic factor gene expression.
Didanosine causes sensory neuropathy in an HIV/AIDS animal model: impaired mitochondrial and neurotrophic factor gene expression.
复制标题
去羟肌苷会导致 HIV/AIDS 动物模型感觉神经病变：线粒体和神经营养因子基因表达受损。
DOI：
10.1093/brain/awm148
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Power,Christopher
中科院分区：
文献类型：
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作者：
Zhu,Yu;Antony,JosephM;Martinez,JoseA;Glerum,DMoira;Brussee,Valentine;Hoke,Ahmet;Zochodne,Douglas;Power,Christopher
抗逆转录病毒中毒性神经病（Antiretroviral toxic neuropathy，ATN）是HIV/AIDS患者常见的周围神经病，其发病机制尚不清楚。事实上，目前还没有评估逆转录病毒感染和抗逆转录病毒治疗之间相互作用的ATN模型。在此，我们开发了由去羟肌苷（ddI）诱导的ATN的vivomodels慢病毒，猫免疫缺陷病毒（FIV）感染后，使我们能够解决的工作假设，ddI介导ATN通过线粒体损伤神经元。我们研究了FIV感染和未感染的动物或背根神经节（DRG）培养物的神经元形态学，神经行为测试，病毒载量，线粒体和神经营养因子基因表达后，DDI治疗。ddI可引起培养的猫DRG神经元损伤（P< 0.05），并伴有病毒复制减少，线粒体细胞色素氧化酶亚基I（mtCOX I）基因和神经营养因子脑源性神经营养因子（BDNF）表达减少。事实上，BDNF治疗逆转了FIV感染引起的神经元损伤（P< 0.05），体内FIV感染显示对有害刺激的退缩潜伏期延迟，ddI治疗加重了这种延迟。FIV感染后神经末梢的表皮密度降低（P< 0.05），ddI处理后更明显。尽管ddI处理的动物血液中的病毒复制受到抑制（P< 0.05），但ddI对相同动物DRG中病毒丰度的影响有限。ddI可降低FIV感染动物DRG神经元mtCOX I的表达（P< 0.05）。FIV感染后，DDI可下调DRG雪旺细胞BDNF的表达。因此，在FIV感染期间，ddI治疗导致了有助于ATN发展的附加致病效应，这与神经元的线粒体损伤和DRG中Schwann细胞的BDNF产生减少有关，突出了抗逆转录病毒药物可能在HIV感染患者中具有的会聚致病效应。
Antiretroviral toxic neuropathy (ATN) has become a common peripheral neuropathy among HIV/AIDS patients, for which the underlying pathogenesis is uncertain. Indeed, no models exist for ATN that assess the interaction between retroviral infection and antiretroviral therapy. Herein, we developedex vivoandin vivomodels of ATN induced by didanosine (ddI) following infection by the lentivirus, feline immunodeficiency virus (FIV), permitting us to address the working hypothesis that ddI mediates ATN through mitochondrial injury in neurons. We investigated neuronal morphology, neurobehavioural testing, viral load, mitochondrial and neurotrophic factor gene expression after ddI treatment of FIV-infected and uninfected animals or dorsal root ganglia (DRG) cultures. ddI caused concentration-dependent neuronal injury in cultured feline DRGs (P< 0.05), together with reduced viral replication and diminished expression of mitochondrial cytochromeCoxidase subunit I gene (mtCOX I) and the neurotrophin, brain-derived neurotrophic factor (BDNF). Indeed, BDNF treatment reversed neuronal injury caused by FIV infection in the presence or absence of ddI exposure (P< 0.05).In vivoFIV infection revealed delays in withdrawal latency to a noxious stimulus, which were exacerbated by ddI treatment. Epidermal density of nerve endings was reduced after FIV infection (P< 0.05), especially with ddI treatment. Although viral replication in blood was suppressed in ddI-treated animals (P< 0.05), ddI had a limited effect on viral abundance in DRGs of the same animals. ddI decreased mtCOX I expression in DRG neurons of FIV-infected animals (P< 0.05). BDNF expression was downregulated by ddI in DRG Schwann cells following FIV infection. Thus, ddI treatment during FIV infection resulted in additive pathogenic effects contributing to the development of ATN, which was associated with mitochondrial injury on neurons and reduced BDNF production by Schwann cells in DRGs, highlighting the convergent pathogenic effects that antiretroviral drugs might have in patients with HIV infection.