Bonn. Brain damage from lack of oxygen at birth is one of the leading causes of death in newborns worldwide. For a therapy, researchers from the University Hospital Bonn (UKB) and the German Center for Neurodegenerative Diseases (DZNE) have tested possible treatment options with 25 different active ingredients. Seven substances proved to be more effective than the standard therapy of artificial cooling, reports the DZNE in a statement.
In order to counteract the damage, therapeutic hypothermia has so far been used. The body temperature of the newborn is lowered to around 33°C for several days and then gradually increased again. “By cooling down, your metabolism slows down and you give your brain a chance to regenerate. This increases the chances of survival and reduces the risk of long-term effects,” Professor Hemmen Sabir from the UKB is quoted as saying in the statement.
Therapeutic hypothermia does not work for many children
The senior physician in the neonatology and pediatric intensive care department continues: “Although the procedure is established in industrialized nations, around 40 percent of the children treated do not benefit from it. And in developing countries, the success rate is much lower.”
Reasons for the low effectiveness in developing countries could be that the newborns there have worse conditions than in the industrialized countries due to the health condition of their mothers and possibly unnoticed infections. There is an urgent need for alternative therapies.
25 substances tested under identical conditions
A research team led by Sabir therefore wanted to test a whole range of active ingredients under identical conditions. Based on studies by other research groups, they identified 25 promising substances, which they then tested in animal models (laboratory rats) in conditions of oxygen deficiency. The animals were treated for up to six days: depending on the active substance and its conditions of use, which were derived from previous studies (Sci Rep 2023; 13, 9467).
A first dose of some active ingredients was administered shortly before the oxygen deficiency. “In human terms, this means that these active ingredients are administered to the mother shortly before or during birth, for example if there are obvious risks or complications,” says Sabir. “However, only substances that penetrate the placenta and can therefore pass from the mother’s bloodstream to the unborn child are suitable for this. We virtually simulated this situation in our study.”
Caffeine was the most effective
Seven days after the oxygen deprivation, the animals’ brains were examined for damage. “Treatment with caffeine was the most effective, the loss of brain matter was the lowest in this case and also significantly lower than with cold therapy,” says Sabir. “Caffeine is known to have anti-inflammatory effects. Our study shows that caffeine is also extremely neuroprotective.”
Six other active ingredients also performed better than the standard therapy. These were melatonin, allopurinol, clemastine, beta-hydroxybutyrate (BHB), the sonic hedgehog agonist (SAG), and omegaven. Among the seven particularly effective agents are those that were administered before the lack of oxygen – such as caffeine – as well as those that were only used afterwards.
Starting point for follow-up studies
“The advantage of drug treatment is that it does not require complex medical equipment. Moreover, if caffeine turns out to be the drug of choice, we would have an active ingredient that is cheap and readily available. This form of therapy would be particularly suitable for developing countries. But of course it could also be used in industrialized nations if it is superior to cooling therapy,” Sabir said in the statement.
Before testing on humans, however, additional studies in animal models are required. In addition, the mode of action of the various substances must be examined more closely in order to identify the best possible active ingredient or possible combinations. The Bonn researchers are in contact with international partners. “If further laboratory studies are positive, I am confident that we can expect human clinical trials very soon,” says Sabir. (eb/ice)
The study was funded by the Bill and Melinda Gates Foundation.