Pyridostigmine Attenuated Placental Ischemia-Upregulated Paraventricular Nucleus TLR4-Associated Hypertension in...

Preeclampsia (PE) is a pregnancy-specific hypertension with signs of other organ dysfunction. Despite its unclear mechanism, current data suggest the role of neuroinflammation in blood pressure dysregulation in PE. Considering the role of toll-like receptor 4 (TLR4) in various inflammatory conditions, we hypothesized that centrally expressed TLR4 may promote PE and that its inhibition, with pyridostigmine (PYR), may attenuate this condition in rats. Changes in TLR4 expression in the paraventricular nucleus (PVN) of reduced uterine perfusion pressure (RUPP) were assessed, as well as TLR4 sensitivity. The effect of PYR, at an oral dose of 20 mg/kg/day, on TLR4 signaling in RUPP or lipopolysaccharides (LPS, 5 µg/kg)-infused pregnant rats was assessed. On gestation day 19, mean arterial pressure (MAP) was recorded under urethane anesthesia, and PVN samples were collected and subsequently processed. Placental ischemia increased MAP (p < 0.05), TLR4 expression (p < 0.05) in RUPP, and TLR4 sensitivity in RUPP + LPS rats. LPS infusion elevated MAP to a greater extent in RUPP (37.1 ± 3.5 mmHg) compared to Sham (13.2 ± 6.5 mmHg) (p < 0.01) after 1 h. Such an effect of LPS was associated with increased expression of c-Fos (p < 0.01) in the PVN. PYR significantly reduced MAP in RUPP and LPS-treated dams, as well as TLR4 signaling proteins, ROS, TNF-α, and IL-1β in the PVN. In conclusion, placental ischemia-increased MAP is associated with high TLR4 expression in the PVN and increased TLR4 sensitivity, and PYR could attenuate TLR4 signaling in the PVN, thereby reducing blood pressure.