Methamphetamine augment HIV-1 Tat mediated memory deficits by altering the expression of synaptic proteins and neurotrophic factors.
Methamphetamine augment HIV-1 Tat mediated memory deficits by altering the expression of synaptic proteins and neurotrophic factors.
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DOI：
10.1016/j.bbi.2018.04.018
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发表时间：
2018-07
期刊：
影响因子：
--
通讯作者：
Kumar A
中科院分区：
文献类型：
--
作者：
Nookala AR;Schwartz DC;Chaudhari NS;Glazyrin A;Stephens EB;Berman NEJ;Kumar A
甲基苯丙胺（METH）滥用在HIV-1感染者中很常见，已被证明会影响HIV的复制和发病机制。这些HIV-1感染者还表现出更大的神经元损伤和更高的认知能力下降。HIV-1蛋白，特别是gp 120和HIV-1达特，早期已被证明会影响神经认知。HIV-1达特是HIV-1复制早期释放的一种病毒蛋白，通过多种机制促进HIV相关的神经毒性，包括产生促炎细胞因子、活性氧和神经可塑性失调。然而，METH和HIV-1达特对神经认知的联合作用及其对神经可塑性机制的潜在作用在很大程度上仍然未知。因此，本研究利用多西环素（DOX）诱导的HIV-1达特（1-86）转基因小鼠，研究METH和HIV-1达特对行为和神经可塑性标志物表达的联合作用。通过RT-PCR证实达特在这些小鼠的各个脑区域中的表达。在7天的时间内向小鼠施用递增剂量的METH（0.1mg/kg至6 mg/kg，i.p），然后每天两次施用6 mg/kg，i.p METH，持续四周。给药3周后，分别进行Y迷宫和Morris水迷宫试验以确定达特和METH对工作记忆和空间记忆的影响。与对照组相比，给予METH的达特小鼠的工作记忆显著降低。此外，在施用METH的Tat-Tg小鼠中也观察到空间记忆的显著缺陷。突触素1、突触体素、Arg3.1、PSD-95和BDNF在不同脑区的蛋白表达也显著减少。在用METH处理的HIV-1达特小鼠中，钙调蛋白激酶II（CaMK II）（突触树突完整性的标志物）的表达水平也显著降低。总之，这些数据表明，METH通过减少突触前和突触后蛋白和神经可塑性标记物的表达来增强HIV-1 Tat诱导的记忆缺陷，从而为HIV感染的安非他明使用者神经认知障碍背后的分子机制提供了新的见解。
Methamphetamine (METH) abuse is common among individuals infected with HIV-1 and has been shown to affect HIV replication and pathogenesis. These HIV-1 infected individuals also exhibit greater neuronal injury and higher cognitive decline. HIV-1 proteins, specifically gp120 and HIV-1 Tat, have been earlier shown to affect neurocognition. HIV-1 Tat, a viral protein released early during HIV-1 replication, contributes to HIV-associated neurotoxicity through various mechanisms including production of pro-inflammatory cytokines, reactive oxygen species and dysregulation of neuroplasticity. However, the combined effect of METH and HIV-1 Tat on neurocognition and its potential effect on neuroplasticity mechanisms remains largely unknown. Therefore, the present study was undertaken to investigate the combined effect of METH and HIV-1 Tat on behavior and on the expression of neuroplasticity markers by utilizing Doxycycline (DOX)-inducible HIV-1 Tat (1-86) transgenic mice. Expression of Tat in various brain regions of these mice was confirmed by RT-PCR. The mice were administered with an escalating dose of METH (0.1 mg/kg to 6 mg/kg, i.p) over a 7-day period, followed by 6 mg/kg, i.p METH twice a day for four weeks. After three weeks of METH administration, Y maze and Morris water maze assays were performed to determine the effect of Tat and METH on working and spatial memory, respectively. Compared with controls, working memory was significantly decreased in Tat mice that were administered METH. Moreover, significant deficits in spatial memory were also observed in Tat-Tg mice that were administered METH. A significant reduction in the protein expressions of synapsin 1, synaptophysin, Arg3.1, PSD-95, and BDNF in different brain regions were also observed. Expression levels of Calmodulin kinase II (CaMKII), a marker of synaptodendritic integrity, were also significantly decreased in HIV-1 Tat mice that were treated with METH. Together, this data suggests that METH enhances HIV-1 Tat-induced memory deficits by reducing the expression of pre- and postsynaptic proteins and neuroplasticity markers, thus providing novel insights into the molecular mechanisms behind neurocognitive impairments in HIV-infected amphetamine users.
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影响因子：
5.3
作者：
Boger, Heather A.;Middaugh, Lawrence D.;McGinty, Jacqueline F.
通讯作者：
McGinty, Jacqueline F.
影响因子：
64.5
作者：
BEACH, ME;HAWKINS, RD;MAYFORD, M
通讯作者：
MAYFORD, M
影响因子：
7.6
作者：
Belcher, AM;O'Dell, SJ;Marshall, JF
通讯作者：
Marshall, JF
DOI：
10.1017/s1355617797004517
发表时间：
1997-09-01
影响因子：
2.6
作者：
Bartok, John A.;Martin, Eileen M.;Harrow, Martin
通讯作者：
Harrow, Martin
影响因子：
7.6
作者：
Ares-Santos, Sara;Granado, Noelia;Moratalla, Rosario
通讯作者：
Moratalla, Rosario