Department of Pathology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-0609, USA.
J Neuroimmune Pharmacol. 2012 Sep;7(3):686-700. doi: 10.1007/s11481-012-9345-4. Epub 2012 Mar 6.
Changes in synapse structure occur in frontal neocortex with HIV encephalitis (HIVE) and may contribute to HIV-associated neurocognitive disorders (HAND). A postmortem survey was conducted to determine if mRNAs involved in synaptic transmission are perturbed in dorsolateral prefrontal cortex (DLPFC) in subjects with HIVE or HAND. Expression of the opioid neurotransmitter preproenkephalin mRNA (PENK) was significantly decreased in a sampling of 446 brain specimens from HIV-1 infected people compared to 67 HIV negative subjects. Decreased DLPFC PENK was most evident in subjects with HIVE and/or increased expression of interferon regulatory factor 1 mRNA (IRF1). Type 2 dopamine receptor mRNA (DRD2L) was decreased significantly, but not in the same set of subjects with PENK dysregulation. DRD2L downregulation occurred primarily in the subjects without HIVE or neurocognitive impairment. Subjects with neurocognitive impairment often failed to significantly downregulate DRD2L and had abnormally high IRF1 expression.
Dysregulation of synaptic preproenkephalin and DRD2L in frontal neocortex can occur with and without neurocognitive impairment in HIV-infected people. Downregulation of DRD2L in the prefrontal cortex was associated with more favorable neuropsychological and neuropathological outcomes; the failure to downregulate DRD2L was significantly less favorable. PENK downregulation was related neuropathologically to HIVE, but was not related to neuropsychological outcome independently. Emulating endogenous synaptic plasticity pharmacodynamically could enhance synaptic accommodation and improve neuropsychological and neuropathological outcomes in HIV/AIDS.
在 HIV 脑炎（HIVE）和额皮质的突触结构发生变化，并可能有助于 HIV 相关的神经认知障碍（HAND）。进行了一项尸检调查，以确定是否在 HIVE 或 HAND 患者的背外侧前额叶皮层（DLPFC）中干扰涉及突触传递的 mRNA。与 67 名 HIV 阴性对照相比，在从 HIV-1 感染者的 446 个脑标本中取样，阿片类神经递质前强啡肽原 mRNA（PENK）的表达显著降低。在具有 HIVE 和/或干扰素调节因子 1 mRNA（IRF1）表达增加的患者中，DLPFC PENK 的减少最为明显。2 型多巴胺受体 mRNA（DRD2L）显著降低，但在 PENK 失调的相同组中并未降低。DRD2L 的下调主要发生在没有 HIVE 或神经认知障碍的患者中。有神经认知障碍的患者通常不能显著下调 DRD2L，并具有异常高的 IRF1 表达。
在 HIV 感染者中，即使没有神经认知障碍，也会出现前脑皮质突触前强啡肽原和 DRD2L 的失调。在额叶皮层中下调 DRD2L 与更好的神经心理学和神经病理学结果相关；未能下调 DRD2L 则明显不利。PENK 的下调与 HIVE 在神经病理学上有关，但与神经心理学结果无关。在药理学上模拟内源性突触可塑性可以增强突触适应能力，改善 HIV/AIDS 的神经心理学和神经病理学结果。
