A gene-focused approach can help prevent or repair neonatal brain injuries

The results of a new preclinical study are published in Journal of Neurology help pave the way for better understanding, prevention, and recovery of neonatal brain injuries. During pregnancy, the fetus usually grows in low oxygen conditions. When babies are born prematurely, there is a sharp transition to a high-oxygen environment that may be higher than the baby can tolerate. These premature babies often need support to breathe because their lungs are underdeveloped. If the oxygen they receive is too high, oxygen-free radicals can form and cause cell death.

Premature babies have underdeveloped antioxidant defenses that prevent or delay certain types of cell damage under normal conditions. In high oxygen environments, these underdeveloped defenses cannot fully protect against oxidative stress by damaging various areas of the brain without available treatments or preventative measures.

Experts at Children’s National Hospital found that oxidative stress activates the enzyme glucose metabolism, GSK3β, altering the development of hippocampal interneurons and impairing learning and memory, according to previous studies.clinical trial. The researchers also inhibited GSK3β in hippocampal interneurons, eliminating these cellular and cognitive deficits.

“I’m thrilled that we’ve found a defect in a specific cell population in the hippocampus to develop memory,” said Vittorio Gala, Ph.D., interim chief researcher and interim director of the Children’s National Research Institute and principal researcher at the Center for Intellectual and deviations in the development of the District of Columbia. “I didn’t think we would be able to do this at an advanced level by discovering cell populations sensitive to oxidative stress and its main signaling pathway and molecular mechanism».

The role of oxidative stress in hippocampal development as well as GSK3β’s involvement oxidative stress-induced neurodevelopmental disorders and cognitive deficits, both have been unexplored so far. Goldstein et al. suggest that the study paves the way for this area as a viable approach to maximal functional recovery after neonatal brain injury.

To better understand the mechanisms underlying neonatal brain injury, the researchers mimicked brain injury by causing high oxygen levels in a preclinical model for a short time. These searches have led to the discovery of the basis of cognitive deficits, including the pathophysiology and molecular mechanisms of oxidative damage in the developing hippocampus.

Once they determined what caused the cell damage, the researchers used a gene-based approach to reduce GSK3β levels in cells that express POMC or interneurons that express Gad2. By regulating GSK3β levels in interneurons, but not in POMC-expressing cells, inhibitory neurotransmission was significantly improved, and memory deficits due to high oxygen levels were eliminated.