European journal of pharmacology · 2026
Combined treatment with metformin and melatonin improves placental mitochondrial function via the AMPK/SIRT3 pathway in an LPS-induced model of preeclampsia.
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Zhou Zhen, Bao Yongfen, Li Rongjie, Yang Rui, Peng Qingyu, Lu Tianci, Wang Binyu, Zhang Ming, Xu Jie, Xiang Ying, Shan Shigang, Huang Liqiong
Аннотация
BACKGROUND: Preeclampsia (PE) is a severe hypertensive disorder in pregnancy, and disruption of placental energy homeostasis, particularly mitochondrial dysfunction, plays a critical role in its pathogenesis. Melatonin (MEL) and Metformin (MET), an effect associated through the AMP-activated protein kinase/Sirtuin 3 (AMPK/SIRT3) signaling pathway. However, the precise mechanisms remain unclear.
MATERIALS AND METHODS: The PE rat model was established in Sprague-Dawley (SD) rats by lipopolysaccharide (LPS) injection after confirmation of pregnancy. Pathological changes, protein expression, inflammatory and angiogenic factors, and mitochondrial status in placental tissue and HTR-8/SVneo trophoblasts were assessed by histology, immunohistochemistry, Western blotting, ELISA, RT-qPCR, reactive oxygen species (ROS) detection, transmission electron microscopy, and measurements of mitochondrial membrane potential and cytosolic calcium.
RESULTS: Both MEL and MET individually activated the AMPK/SIRT3 signaling pathway, thereby enhancing mitochondrial function and placental energy homeostasis, while attenuating LPS-induced oxidative stress and inflammatory damage in placental tissue and trophoblast cells.
CONCLUSIONS: MEL and MET, when administered together, improve placental mitochondrial dysfunction and inflammatory injury in PE, which is associated with activation of the AMPK/SIRT3 signaling pathway, suggesting a potential therapeutic strategy for preeclampsia using clinically available agents.
MATERIALS AND METHODS: The PE rat model was established in Sprague-Dawley (SD) rats by lipopolysaccharide (LPS) injection after confirmation of pregnancy. Pathological changes, protein expression, inflammatory and angiogenic factors, and mitochondrial status in placental tissue and HTR-8/SVneo trophoblasts were assessed by histology, immunohistochemistry, Western blotting, ELISA, RT-qPCR, reactive oxygen species (ROS) detection, transmission electron microscopy, and measurements of mitochondrial membrane potential and cytosolic calcium.
RESULTS: Both MEL and MET individually activated the AMPK/SIRT3 signaling pathway, thereby enhancing mitochondrial function and placental energy homeostasis, while attenuating LPS-induced oxidative stress and inflammatory damage in placental tissue and trophoblast cells.
CONCLUSIONS: MEL and MET, when administered together, improve placental mitochondrial dysfunction and inflammatory injury in PE, which is associated with activation of the AMPK/SIRT3 signaling pathway, suggesting a potential therapeutic strategy for preeclampsia using clinically available agents.