Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5800, USA.
Department of Radiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Mol Neurobiol. 2021 Nov;58(11):5703-5721. doi: 10.1007/s12035-021-02508-5. Epub 2021 Aug 14.
Dolutegravir (DTG) is a first-line antiretroviral drug (ARV) used in combination therapy for the treatment of human immunodeficiency virus type-1 (HIV-1) infection. The drug is effective, safe, and well tolerated. Nonetheless, concerns have recently emerged for its usage in pregnant women or those of child-bearing age. Notably, DTG-based ARV regimens have been linked to birth defects seen as a consequence of periconceptional usages. To this end, uncovering an underlying mechanism for DTG-associated adverse fetal development outcomes has gained clinical and basic research interest. We now report that DTG inhibits matrix metalloproteinases (MMPs) activities that could affect fetal neurodevelopment. DTG is a broad-spectrum MMPs inhibitor and binds to Zn at the enzyme's catalytic domain. Studies performed in pregnant mice show that DTG readily reaches the fetal central nervous system during gestation and inhibits MMP activity. Postnatal screenings of brain health in mice pups identified neuroinflammation and neuronal impairment. These abnormalities persist as a consequence of in utero DTG exposure. We conclude that DTG inhibition of MMPs activities during gestation has the potential to affect prenatal and postnatal neurodevelopment.
多替拉韦（DTG）是一种一线抗逆转录病毒药物（ARV），用于治疗人类免疫缺陷病毒 1 型（HIV-1）感染的联合疗法。该药疗效确切、安全性高、耐受性良好。然而，最近人们对其在孕妇或育龄妇女中的应用产生了担忧。值得注意的是，基于 DTG 的 ARV 方案与围孕期使用相关的出生缺陷有关。为此，揭示 DTG 相关不良胎儿发育结局的潜在机制引起了临床和基础研究的兴趣。我们现在报告 DTG 抑制基质金属蛋白酶（MMPs）的活性，这可能会影响胎儿的神经发育。DTG 是一种广谱 MMPs 抑制剂，与酶的催化结构域中的 Zn 结合。在妊娠小鼠中进行的研究表明，DTG 在妊娠期间很容易到达胎儿中枢神经系统，并抑制 MMP 活性。对小鼠幼仔大脑健康的产后筛查发现了神经炎症和神经元损伤。由于宫内暴露于 DTG，这些异常持续存在。我们得出结论，DTG 在妊娠期间抑制 MMPs 活性有可能影响产前和产后的神经发育。
