Hopkins team investigates oxygen deprivation

A newborn baby can suffer from oxygen deprivation for reasons including a blocked airway and a long or difficult delivery, but no matter the cause, this oxygen deprivation can lead to numerous grave problems, such as impaired mobility or cerebral palsy. Interestingly, these problems seem to preferentially arise in males, as male children have a harder time recovering from oxygen deprivation than female children do.

While this sex bias is well known within the pediatric medical community, researchers have only recently discovered the reason behind this phenomenon. Scientists at the Johns Hopkins Children’s Center have found that estradiol, a sex hormone that binds to estrogen receptors in cells, may be partially responsible for the sex difference in oxygen deprivation recovery.

The team was led by Raul Chavez-Valdez, a neonatologist at the Center. His team, which included Frances Northington, Lee J. Martin, Sheila Razdan and Estelle Gauda, found that estradiol was one cause of the differences in recovery between male and female newborn mice. They also found that neurons in male and female mouse brains suffer from different types of cell death. These specific forms of cell death may the products of pathways that trigger different sex-specific patterns of cell demise. Lastly, the scientists found that although the brains of male mice suffer more damage, they respond better than female brains to therapies that halt cell death.

The investigators have stated that their findings underline the importance of sex-specific research. From what they have discovered, it is apparent that sex-specific differences in cell death appear as early as a few days after birth and likely even before that. Sex differences on the cellular level can play a powerful role in the progress of a disease. Thus, courses of treatment that utilize sex-specific differences can be more effective than those that do not.

The researchers started out by looking at brain-derived neurotrophic factor, or BDNF. BDNF is known for stimulating the growth of neurons in the brain. After newborn mice experienced oxygen deprivation, there was a spike of BDNF in the brain, followed by a large dip 96 hours later. Both male and female mice brains exhibited this spike and dip pattern. However, what the researchers found was that female mouse brains contained a higher number of a certain type of BDNF receptors that promote a milder type of cell death, known as apoptosis. Apoptosis, programmed cell death, is carried out naturally billions of times a day in the body of a human adult. The brains of male mice, though, contained fewer of these receptors, causing their brain cells to bypass apoptosis and begin undergoing necrosis. Necrosis is a type of traumatic cell death, usually seen following cellular injury. During necrosis, cells burst or disintegrate and can cause damage to neighboring cells.

Nectostatin-1, or nec-1, is a molecule that has been shown to halt necrotic cell death in mice. When the scientists treated the oxygen-deprived newborn mice’s brains with this drug, they found that male mice responded better than female mice to the treatment. Ninety-six hours after the oxygen deprivation had occurred, the brains of the male mice had 41 percent more BDNF than that of the female mice.

To determine why this happened, the scientists focused their attention on the sex hormone estradiol. Although estradiol is associated with females, it is also present in small amounts in males. The newborn mice had similar levels of estradiol in their brains, but it seemed to affect them differently. The researchers noted that after treatment with nec-1, the male mice had higher levels of alpha estrogen receptors. These receptors increase cell sensitivity to estradiol, as well as promote BDNF production. The researchers’ conclusion is that nec-1 helps the production of these receptors, increasing the amount of BDNF in the male mice’s brains.

The Neurosciences Intensive Care Surgery team at Johns Hopkins wants to look into the subject further. They are planning to carry out a study on human newborns to track human levels of BDNF in response to brain injury and treatments.

This research was funded by the National Institutes of Health’s National Institute of Child Health and Human Development. The results will appear in the February issue of the journal Neuroscience.