Reducing long-term complications in infants born prematurely

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Some GnRH neurons (green) express NOS1 (red) during their migration from the nos
Some GnRH neurons (green) express NOS1 (red) during their migration from the nose to the brain during fetal life. GnRH + NOS1 double-labeled cells are shown in yellow. Vincent Prévot/Inserm

Children born prematurely have a higher risk of suffering from cognitive and sensory disorders but also infertility in adulthood. In a new study, a team of researchers from Inserm, the University Hospital of Lille and the University of Lille, within the Lille Neuroscience and Cognition Laboratory, raises interesting avenues to improve their prognosis. While working on a rare disease called congenital hypogonadotropic hypogonadism, the scientists discovered the key role of an enzyme and the therapeutic potential of the neurotransmitter it synthesizes - nitric oxide - to reduce the risk of long-term complications in cases of prematurity. The findings are described in Science Translational Medicine. The research team has also launched a clinical trial at the University Hospital of Lille in partnership with a hospital in Athens (Greece) to go further and measure the effect of nitric oxide in premature infants.

Congenital hypogonadotropic hypogonadism is a rare disease characterized by delayed puberty or complete absence of puberty in adolescence, resulting in infertility. Some forms of the disease are due to a defect in the production of the hormone GnRH, which is produced in the brain and remotely controls the development and function of the male and female gonads via various intermediaries.

The team of Vincent Prévot, Inserm research director, is a specialist in the dialogue between the brain and the rest of the body.

The scientists were interested in a neurotransmitter that regulates the activity of GnRH neurons, nitric oxide, and more specifically in the enzyme that synthesizes it, called NOS1. " Nitric oxide suppresses the electrical activity of GnRH neurons and modulates the release of this hormone, so it could not be excluded that a defect in the functioning of NOS1 is at the origin of congenital hypogonadotropic hypogonadism", explains Vincent Prévot, principal coordinator of this study.

To go further, his team collaborated with a laboratory in Lausanne, Switzerland, that had a cohort of 341 patients with the disease. Using DNA samples, they looked for the presence of rare mutations in the gene encoding the NOS1 enzyme and found five different ones that could explain the disease. In addition to fertility problems, some of the individuals concerned had sensory and cognitive problems (loss of hearing or smell or intellectual disability).

An application in the context of prematurity?

The next step in the study was to develop a NOS1-deficient mouse model [1] to better understand the role of this enzyme. The researchers found puberty problems, as well as sensory and neurological alterations, as observed in humans with congenital hypogonadotropic hypogonadism. They also found an exacerbation of minipuberty in these animals. Minipuberty occurs in all mammals just after birth (between one and three months in humans), and triggers an initial activation by the brain of the axis controlling reproduction before "true" puberty in adolescence.

Here, the researchers found that the sex hormone spike associated with this minipuberty was twice as large in NOS1-deficient mice. "This was intriguing to us because infants born prematurely also frequently exhibit more intense minipuberty than normal. And the greater the prematurity, the greater the risk of neurosensory and mental complications in adulthood," said Konstantina Chachlaki, an Inserm researcher and first author of the study.

Based on these observations, the researchers tested the administration of nitric oxide in NOS1-deficient mice just after birth, during the period of minipuberty. They then observed the reversal of all the symptoms developed by these mice: the puberty problems and the sensory and neurological disorders disappeared and this, in the long term, for the rest of their lives.

A clinical trial underway

These promising results could lead to improved management of premature infants. It turns out that nitric oxide is also administered to certain children born prematurely to facilitate the opening of the bronchial tubes in the event of respiratory difficulties.

"Faced with this concordance of observations and practices, we decided to set up a clinical trial to test the effect of nitric oxide in premature infants by studying reproductive and neurosensory parameters," explain Vincent Prévot and Konstantina Chachlaki, who are jointly coordinating the European project miniNo dedicated to studying the role of minipuberty in prematurely born children. "The administration of nitric oxide at birth could reduce the risk of reproductive, sensory and intellectual complications in children born prematurely. This is what we will try to verify after making these surprising findings in mice," they continue.

The miniNO trial was launched at the Lille University Hospital in partnership with a hospital in Athens, Greece. The objective is to verify whether children receiving this treatment have a normal minipuberty and then puberty and whether they develop fewer sensory and neurological complications, compared to premature children who did not receive nitric oxide at birth. The objective of the clinical trial is to include 120 patients at the two sites over 24 months (Athens and Lille).

[1] That is, in which the gene coding for the NOS1 enzyme was inactivated.

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