Effects of retinoic acid receptor α modulators on developmental ethanol-induced neurodegeneration and neuroinflammation.
Effects of retinoic acid receptor α modulators on developmental ethanol-induced neurodegeneration and neuroinflammation.
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DOI：
10.3389/fnins.2023.1170259
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发表时间：
2023
影响因子：
4.3
通讯作者：
Das, Bhaskar C.
中科院分区：
文献类型：
--
作者：
Saito, Mariko;Subbanna, Shivakumar;Zhang, Xiuli;Canals-Baker, Stefanie;Smiley, John F.;Wilson, Donald A.;Das, Bhaskar C.
关键词：
新生小鼠的乙醇暴露诱导急性神经变性，随后是长期的胶质细胞活化和GABA能细胞缺陷沿着行为异常，提供了胎儿酒精谱系障碍（FASD）的妊娠晚期模型。维甲酸（RA）是维生素A的活性形式，调节RA响应基因的转录，并在胚胎及其中枢神经系统的发育中发挥重要作用。乙醇已被证明会干扰发育中的大脑中的RA代谢和信号传导，这可能是导致FASD的乙醇毒性的原因。使用RA受体α（RARα）特异性激动剂和拮抗剂，我们研究了RA/RARα信号传导如何影响乙醇给药新生小鼠引起的吞噬细胞和星形胶质细胞的急性和长期神经变性和激活。我们发现，在出生后第7天（P7）小鼠注射乙醇前30分钟给予RARα拮抗剂（BT382），可部分阻断急性神经变性以及同一脑区CD 68阳性吞噬细胞的升高。虽然RARα激动剂（BT 75）不影响急性神经退行性变，但在乙醇给药之前或之后给予BT 75可改善某些脑区的长期星形胶质细胞活化和GABA能细胞缺陷。我们的研究使用Nkx2.1-Cre; Ai 9小鼠，其中皮质和海马中的主要GABA能神经元及其祖细胞用组成型表达的tdTomato荧光蛋白标记，表明持久的GABA能细胞缺陷主要由P7乙醇诱导的初始神经变性引起。然而，通过后乙醇BT 75处理部分减少了延长的GABA能细胞缺陷和神经胶质活化，这表明，除了初始细胞死亡之外，还可能存在延迟的细胞死亡或GABA能细胞的发育紊乱，这部分地被BT 75挽救。由于RARα激动剂（包括BT 75）已显示具有抗炎作用，因此BT 75可通过减少胶质细胞活化/神经炎症来挽救GABA能细胞缺陷。
Ethanol exposure in neonatal mice induces acute neurodegeneration followed by long-lasting glial activation and GABAergic cell deficits along with behavioral abnormalities, providing a third trimester model of fetal alcohol spectrum disorders (FASD). Retinoic acid (RA), the active form of vitamin A, regulates transcription of RA-responsive genes and plays essential roles in the development of embryos and their CNS. Ethanol has been shown to disturb RA metabolism and signaling in the developing brain, which may be a cause of ethanol toxicity leading to FASD. Using an agonist and an antagonist specific to RA receptor α (RARα), we studied how RA/RARα signaling affects acute and long-lasting neurodegeneration and activation of phagocytic cells and astrocytes caused by ethanol administered to neonatal mice. We found that an RARα antagonist (BT382) administered 30 min before ethanol injection into postnatal day 7 (P7) mice partially blocked acute neurodegeneration as well as elevation of CD68-positive phagocytic cells in the same brain area. While an RARα agonist (BT75) did not affect acute neurodegeneration, BT75 given either before or after ethanol administration ameliorated long-lasting astrocyte activation and GABAergic cell deficits in certain brain regions. Our studies using Nkx2.1-Cre;Ai9 mice, in which major GABAergic neurons and their progenitors in the cortex and the hippocampus are labeled with constitutively expressed tdTomato fluorescent protein, indicate that the long-lasting GABAergic cell deficits are mainly caused by P7 ethanol-induced initial neurodegeneration. However, the partial reduction of prolonged GABAergic cell deficits and glial activation by post-ethanol BT75 treatment suggests that, in addition to the initial cell death, there may be delayed cell death or disturbed development of GABAergic cells, which is partially rescued by BT75. Since RARα agonists including BT75 have been shown to exert anti-inflammatory effects, BT75 may rescue GABAergic cell deficits by reducing glial activation/neuroinflammation.
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