Pre-eclampsia: new therapeutic prospects

France – French researchers have discovered a new treatment aimed at restoring nitric oxide (NO) production. The results, tested in two rodent models, enable the treatment of pre-eclampsia, a disease of the placenta that can lead to fatal complications. Dr. Milia Ricketi and the Dr. Daniel WeimannTwo authors of an article published in Redox Biology describe possible applications of their research to Medscape.

Preeclampsia is a condition that affects the placenta during pregnancy. “This is a fatal disease,” emphasizes her Dr. Miria Ricchetti, head of molecular mechanisms in the Pasteur Institute’s Pathological and Physiological Aging Unit. “Pre-eclampsia, in its most classical definition, is characterized by appearance. de novo The two main symptoms of the earliest second trimester of pregnancy: arterial hypertension >140/90 mm Hg and proteinuria >300 mg/L,” said Cochin Institute investigator and principal investigator at INSERM. One Dr. Daniel Vaiman added: of a team working on reproductive biology.

long term impact

Pre-eclampsia affects 2-8% of pregnant women worldwide and is responsible for more than 50,000 maternal deaths each year. In addition to hypertension and proteinuria, pre-eclampsia can lead to placental and maternal tissue coagulation abnormalities, liver syndrome (HELLP), maternal cardiovascular abnormalities, brain injury, and eclampsia. In the fetus, one-third of preeclampsia causes growth retardation. These effects are long-lasting through lasting changes in the endothelium, the cell layer that lines all blood vessels, at the maternal cardiovascular, renal, brain and liver level for years and decades after conception. affects the

Limitations of prophylactic aspirin intake

The current recommended treatment for pre-eclampsia is aspirin prophylaxis by at-risk patients. Although this treatment is effective in reducing the procoagulant state of the placenta, reducing inflammation, and partially relieving the vascular network, it shows its limitations. lancet showed an aspirin benefit of approximately 10% (Askie et al, 2007). This modest benefit can only be clearly explained from a 2010 study (Bujold et al, 2010). A meta-analysis of this study showed that aspirin administered to women before 16 weeks’ gestation induced a dramatic reduction in risk divided by 10 depending on the type of pre-eclampsia. After a week, the treatment was ineffective. So if you wait for symptoms to appear (as little as about 20 weeks) to give aspirin, the drug doesn’t work,” explains Dr. Vaiman. As a result, “In France, prophylactic aspirin is given to women who have had their first pre-eclamptic pregnancy, and it certainly reduces the incidence of the second complication. It occurs during pregnancy, so we have to be aware that the population that can be treated is limited,” he points out.

Restores nitric oxide production

Thanks to the collaboration of Institut Pasteur, Inserm and CNRS, French researchers have discovered a new treatment for treating pre-eclampsia. They were interested in specific aspects of this disease. “We realized that a deficiency in nitric oxide (NO), a molecule that enables vasodilation, can lead to pre-eclampsia syndrome,” he explains Dr. Ricchetti.

NO is produced by a family of enzymes, nitric oxide synthase (NOS). Finding a way to restore placental NO production via NOS may be a new therapeutic approach to effectively treat pre-eclampsia. “When working with my group, Dr. Laurent Chatelet took advantage of the characteristics of nitric oxide synthase, and the fact that, especially when they are assisted by their natural cofactor, BH4, they function in two ways. (or tetrahydrobiopterin, a cofactor that stabilizes the NOS enzyme), they produce NO, but when unbound (lack of BH4), NO and reactive oxygen species ( In the latter case, in addition to reducing the amount of NO, NO and ROS combine to produce peroxynitrite, a highly toxic molecule at the root of so-called nitrosative stress. It’s possible,” explains Dr. Richetti. NO is trapped and becomes insufficient to ensure endothelial health and pre-eclamptic pathology to begin.

Finding a way to restore placental NO production via NOS may be a new therapeutic approach to effectively treat pre-eclampsia.

Preclinical administration of BH4

To “force” the enzyme to produce more NO, the researchers administered BH4 to a cellular model of trophoblast cells (placental cells) and then to pregnant mice and rats. “We have demonstrated in these models a reduction in the detrimental effects of NO deficiency. It allowed us to organize and manage the function of the web to bring in oxygen, nutrients and other elements essential for fetal development,” she adds. Furthermore, administration of her BH4 in two preclinical rodent models allowed restoration of placental and fetal weights. At the maternal level, in mice, treatment with BH4 was also able to correct cardiac hypertrophy induced by blood pressure, excess protein in the urine, and cardiovascular abnormalities, particularly hypertension. , suggesting that the treatment is effective in counteracting the long-term effects of pre-eclampsia on the mother.

“We propose that BH4 can be used therapeutically alone or in combination with aspirin, because in this article we demonstrated that the two molecules function in completely independent pathways,” Dr. Ricchetti summarizes. .

It is suggested that BH4 can be used therapeutically alone or in combination with aspirin.
Dr. Milia Ricketi

“The current challenge is getting this drug approved in pregnant women,” said Dr. Vaiman. “This is a drug already used in phenylketonuria. There are no serious side effects mentioned, but the disease is rare enough to prove the molecule’s harmlessness to pregnant women.” There is no hindsight,” he warns.

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