关键词: 孕期用药安全, 地塞米松, 海马, 神经元, 突触损伤

Abstract:

Dexamethasone is a glucocorticoid drug with various pharmacological effects such as anti-inflammatory and immunosuppressive effects. It is widely used in multiple departments to treat multiple autoimmune diseases. Dexamethasone is often used during pregnancy to promote lung maturation in preterm infants and prevent fetal respiratory distress syndrome. Current epidemiological and experimental studies have shown that dexamethasone exposure during pregnancy could lead to an increased risk of cartilage and kidney damage in the offspring. This study investigated the effects of prenatal dexamethasone exposure （PDE） on the proliferation of fetal hippocampal neurons and the formation of synaptic plasticity in the fetal hippocampus. Wistar rats were injected subcutaneously with dexamethasone （0.2 mg·kg^-1·d^-1） at mid-to-late gestation， and the control group was treated with isodose 0.9% sodium chloride solution. The hippocampus of GD20 offspring was collected and examined for morphology and functions related to hippocampal neuron proliferation and synaptic plasticity formation by real-time fluorescence quantitative PCR and Western blot. We further examined adaptor protein containing pH domain， PTB domain， and leucine zipper motif 1 （APPL1）. Restlts showed that， compared with the blank control group， the specific indexes of Ki67， proliferating cell nuclear antigen （PCNA）， synaptic fusion protein （syntaxin）， and 25 kD synaptic-associated protein （SNAP25） in PDE fetal hippocampus were significantly reduced， suggesting that PDE inhibited neural proliferation， synaptic development， and other functions in the fetal hippocampus. Western blot showed significant downregulation of postsynaptic dense protein 95 （PSD95） in the PDE group， confirming that PDE could lead to impaired synaptic plasticity in the offspring hippocampus. APPL1 results showed that APPL1 expression was down-regulated in the hippocampus of PDE offspring， so it was hypothesized that PDE might affect hippocampal synaptic plasticity in offspring by regulating APPL1 expression. The study suggested that PDE is developmentally toxic to the hippocampus and can reduce hippocampal neurons' proliferation and impaired synaptic plasticity. This study provided the experimental and theoretical basis for guiding the rational use of drugs during pregnancy and effectively assessing the risk of hippocampal developmental toxicity in fetuses.

Key words: drug safety during pregnancy, dexamethasone, hippocampus, neuron, synaptic injury