Combined treatment with steroids and statins could reduce ‘accelerated aging’ in premature babies, study in rats suggests

Cambridge scientists gave newborn rats, which are naturally born prematurely, a combination of glucocorticoid steroids and statin therapy. The results, published today in Hypertension, show that the combined treatment led to the elimination of the negative effects of steroids on the cardiovascular system, while maintaining their positive effects on the developing respiratory system.

Premature birth (before 37 weeks) is one of the leading causes of death in perinatal medicine today. In high-income countries, one in ten babies are born prematurely; this can rise to almost 40% in low- and middle-income countries.

Premature babies are extremely vulnerable because they miss a crucial final stage of development in which the hormone cortisol is exponentially produced and released into the unborn baby’s blood. Cortisol is essential for the maturation of organs and systems necessary to keep the baby alive after birth.

In the lungs, for example, cortisol ensures that they become more elastic. This allows the lungs to expand so that the baby can take his first breath. Without cortisol, newborns’ lungs would be too stiff, which leads to Respiratory Distress Syndrome (RDS) and can be fatal.

The established clinical treatment for any pregnancy at risk of preterm delivery is glucocorticoid therapy, administered via the mother before the birth of the baby and/or directly to the baby after birth. These synthetic steroids mimic natural cortisol by accelerating the development of organs – including the lungs – meaning the premature baby has a much greater chance of survival.

Lead author Professor Dino Giussani from the Department of Physiology, Development and Neuroscience at the University of Cambridge said: “Glucocorticoids are clearly a lifesaver, but the problem with steroids is that they accelerate steroid maturation. all organs. This is beneficial for the baby’s lungs, but it can be harmful to the heart and circulatory system; it looks like accelerated aging.”

An earlier clinical study by Professor Paul Leeson’s laboratory at the University of Oxford found that people exposed to glucocorticoid therapy as unborn babies, through their mothers, showed measures of cardiovascular health typical of people ten years older.

Cambridge researcher Dr. Andrew Kane, involved in the rat research, thought that this accelerated aging could be the result of steroids causing oxidative stress. Steroids lead to an imbalance of molecules known as free radicals, resulting in a reduction in nitric oxide. Nitric oxide is very beneficial for the cardiovascular system: it increases blood flow and has antioxidant and anti-inflammatory properties.

To test whether a nitric oxide deficiency could be the cause of the adverse cardiovascular side effects associated with glucocorticoid therapy, the researchers combined steroid treatment with statins, which are commonly used to lower cholesterol and are known to increase nitric oxide.

Researchers gave the synthetic steroid dexamethasone, combined with the statin pravastatin, to rat pups. There were three other groups: one received only dexamethasone, one received only pravastatin, and a control group received saline. Measurements of respiratory and cardiovascular function were then taken when the rats had grown into ‘infancy’.

The Cambridge scientists found that steroids had adverse effects on the heart and blood vessels, and on molecular indices linked to cardiovascular problems. But when statins were given at the same time, the rats were protected from these effects. Crucially, the statins had no effect whatsoever on the beneficial effects of steroids on the respiratory system.

“Our discovery suggests that combined treatment with glucocorticoids and statins may be safer than glucocorticoids alone for the treatment of premature infants,” said Professor Giussani.

“Goods not say to stop using glucocorticoids because they are clearly a life-saving treatment. We say against that improve this therapy – to refine it — we could combine it with statins. This gives us the best of both worlds: we can retain the benefits of steroids on the developing lungs, but eliminate the adverse side effects on the developing heart and circulatory system, making therapy much safer for the treatment of preterm labor. .”

The team plans to replicate the experiment in sheep, which have similar physiology to humans, before conducting clinical trials on humans.

The research was funded by the British Heart Foundation and the Research Council for Biotechnology and Biological Sciences (BBSRC). Dr. Andrew Kane was supported by the Frank Edward Elmore Fund and the James Baird Fund.