Preeclampsia is a serious complication of pregnancy and there is no medical treatment. Metformin has been identified in laboratory studies and a clinical trial as a potential treatment for preeclampsia [1]. Here in, we explore its potential mechanism of action in treating preeclampsia.
We have previously shown metformin likely reduces sFlt-1, an antiangiogenic molecule upregulated in preeclampsia, by inhibiting complex I of the electron transport chain [2, 3]. In treating trophoblasts with metformin (1-5mM) we showed a reduction in sFlt-1 secretion (p<0.001). We rescued sFlt-1 secretion by adding succinate, a substrate for complex II, which switches the electron transport chain on in the presence of metformin [3].
Metformin is known to upregulate AMP activated protein kinase (AMPK) in the liver. AMPK is a regulator of energy homeostasis that coordinates metabolic function and mitochondrial dynamics. We discovered that AMPK protein was higher in metformin (1-5mM) treated trophoblasts (n=5, p<0.05). Similarly, AMPK is increased in placentas from patients with preterm preeclampsia treated with metformin, compared to placebo (n=21, p<0.01).
Reactive oxygen species (ROS) are upregulated in preeclampsia. In other fields metformin increases ROS. Reassuringly, we demonstrated treating trophoblasts with metformin (1-2mM) significantly reduced ROS under both normoxic (n=5, p<0.01) and hypoxic conditions (n=5, p<0.01), compared to vehicle treated controls (as determined by DCFDA kit).
We have shown metformin likely has pleiotropic effects in trophoblasts to quench preeclampsia. It inhibits complex I of the mitochondrial electron transport chain reducing sFlt-1 secretion. It upregulates AMPK, the master regulator of cellular metabolism. It also reduces reactive oxygen species. By understanding its mechanism of action we might develop targeted therapies which may be more efficacious at treating preeclampsia.