Hormone-like therapy NF-1 shows promise in ICP mouse study
Treatment reduces injury to placenta
Nesfatin-1 (NF-1), a hormone-like molecule that may ease cellular stress, reduced injury to the placenta in a mouse model of intrahepatic cholestasis of pregnancy (ICP), a study reported.
NF-1 also reduced markers of oxidative stress — a process in which unstable molecules damage cells — and decreased concentrations of molecules called glucocorticoids in the placenta, stress hormones that can affect fetal growth and development. This double action may help maintain fetal health during ICP, the researchers said.
“These results suggest that NF-1 may serve as a potential therapeutic agent for managing ICP and related stress-induced pregnancy complications by modulating [glucocorticoid] metabolism and mitigating [oxidative stress],” the team wrote.
The study, “Nesfatin-1 Reduces Cholic Acid-Induced Intrahepatic Cholestasis of Pregnancy by Regulating the General Control Nonderepressible 2/Eukaryotic Initiation Factor 2α Pathway,” was published in Chemical Biology & Drug Design.
Oxidative stress and ICP
Cholestasis occurs when bile, a digestive fluid, flows slowly or stops in the liver. This can lead to liver damage and symptoms like itching and fatigue.
ICP is a specific type of cholestasis that develops late in pregnancy, potentially putting the mother and fetus at risk. In addition to damaging the liver, ICP can damage the placenta, an organ that supplies nutrients and protection to the fetus. The placental environment, including the activity of glucocorticoids, needs to stay balanced to support a healthy fetus.
Although the exact causes of ICP aren’t fully understood, oxidative stress may play a role. As bile acids build up in the liver, they can increase the production of unstable molecules known as reactive oxygen species. This oxidative stress may damage liver and placental cells, potentially affecting pregnancy outcomes. Oxidative stress “provides a theoretical basis for developing new biomarkers and targeted therapeutic strategies for ICP,” the researchers wrote.
The team examined the effects of NF-1, a small protein (peptide) with hormone-like activity that participates in several physiological processes, including regulating oxidative stress. They hypothesized that NF-1 could mitigate damage to the placenta from oxidative stress and glucocorticoid imbalances.
To test this hypothesis, the researchers used a mouse model of ICP. During gestation, pregnant mice received oral doses of cholic acid (CA), a type of bile acid in later stages of pregnancy. Some of these animals also received injections of NF-1 into their abdominal cavities.
ICP mice showed high levels of bile acids in their blood and scratching behavior, suggesting itchiness. Their placentas had significantly lower weight than control (healthy) animals and significantly elevated glucocorticoid levels.
However, these effects were mitigated in mice treated with NF-1. Maternal bile acid levels, scratching behavior, and placental glucocorticoid levels decreased, while placental weight increased. “NF-1 effectively alleviates ICP-related placental dysfunction and associated symptoms by reducing glucocorticoid levels,” the researchers wrote.
Next, the team investigated the mechanisms by which NF-1 produced these effects. They looked at 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), a protein that helps inactivate glucocorticoids.
In the placentas of pregnant ICP mice, 11beta-HSD2 levels were significantly lower than in untreated mice. In the mice that also received NF-1, however, there was significantly more 11beta-HSD2. This suggests that NF-1 restored 11beta-HSD2 expression, “thereby enhancing the inactivation of glucocorticoids in the placenta,” the researchers wrote.
As expected, ICP mice had significantly elevated levels of oxidative stress markers in the placenta. Treatment with NF-1 not only lowered the levels of these markers: It also suppressed the activation of a molecular signaling pathway called GCN2/eIF2alpha, which helps cells respond to oxidative stress.
The team confirmed their findings using cells derived from human placentas and treated with halofuginone, a compound that activates GCN2/eIF2alpha signaling. Exposure to halofuginone diminished the beneficial effects of NF-1 on 11beta-HSD2, overriding any potential suppression by NF-1. The results suggest that NF-1’s positive impact is mediated, at least in part, through its regulation of the GCN2/eIF2alpha pathway.
Together, the results show signs that NF-1 may help treat ICP, with potential positive effects for both the mother and the fetus, the researchers said. “Ultimately, clinical trials and larger preclinical models are essential to validate NF-1’s safety and efficacy,” they concluded.
