Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience, Radboud University, Nijmegen, The Netherlands.
Department of General Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
Biochem Pharmacol. 2020 Aug;178:114050. doi: 10.1016/j.bcp.2020.114050. Epub 2020 May 22.
Efavirenz (EFV) is used for antiretroviral treatment of HIV infection, and successfully inhibits viral replication and mother-to-child transmission of HIV during pregnancy and childbirth. Unfortunately, the drug induces neuropsychiatric symptoms such as anxiety and depressed mood and potentially affects cognitive performance. EFV acts on, among others, the serotonin transporter and serotonin receptors that are expressed in the developing brain. Yet, how perinatal EFV exposure affects brain cytoarchitecture remains unclear. Here, we exposed pregnant and lactating rats to EFV, and examined in the medial prefrontal cortex (mPFC) of their adult offspring the effects of the maternal EFV exposure on cortical architecture. We observed a significant decrease in the number of cells, mainly mature neurons, in the infra/prelimbic and cingulate cortices of adult offspring. Next, we found an altered cortical cytoarchitecture characterized by a significant reduction in deep- and superficial-layer cells. This was accompanied by a sharp increase in programmed cell death, as we identified a significantly higher number of cleaved Caspase-3-positive cells. Finally, the serotonergic and dopaminergic innervation of the mPFC subdomains was increased. Thus, the perinatal exposure to EFV provoked in the mPFC of adult offspring cell death, significant changes in cytoarchitecture, and disturbances in serotonergic and dopaminergic innervation. Our results are important in the light of EFV treatment of HIV-positive pregnant women, and its effect on brain development and cognitive behavior.
依非韦伦（EFV）用于治疗人类免疫缺陷病毒（HIV）感染的抗逆转录病毒治疗，并且在怀孕期间和分娩期间成功抑制 HIV 的病毒复制和母婴传播。不幸的是，该药物会引起神经精神症状，如焦虑和抑郁情绪，并可能影响认知表现。EFV 作用于在发育中的大脑中表达的 5-羟色胺转运体和 5-羟色胺受体等。然而，围产期 EFV 暴露如何影响大脑细胞结构仍不清楚。在这里，我们使怀孕和哺乳期大鼠接触 EFV，并在其成年后代的内侧前额叶皮层（mPFC）中检查母体 EFV 暴露对皮质结构的影响。我们观察到成年后代的下额前皮质和扣带皮质中的细胞数量（主要是成熟神经元）显着减少。接下来，我们发现皮质细胞结构发生了改变，其特征是深层和浅层细胞数量显着减少。这伴随着程序性细胞死亡的急剧增加，因为我们发现 Caspase-3 阳性细胞的数量明显增加。最后，mPFC 亚区的 5-羟色胺能和多巴胺能神经支配增加。因此，围产期接触 EFV 会导致成年后代 mPFC 中的细胞死亡、细胞结构发生重大变化以及 5-羟色胺能和多巴胺能神经支配紊乱。鉴于 EFV 治疗 HIV 阳性孕妇及其对大脑发育和认知行为的影响，我们的研究结果非常重要。
