have long known that oxygen deprivation to the brain around the time of birth
causes worse damage in boys than girls. Now a study
by researchers from the Johns
Hopkins Children’s Center conducted in mice reveals one
possible reason behind this gender disparity and points to gender-specific
mechanisms of brain repair following such injury.
The results of the study, to appear in the
February issue of the journal Neuroscience,
show that inherent differences in the way newborn brains react to the sex
hormone estradiol may be behind the sex-specific response to brain damage and
“Our observations reveal intriguing differences in the way
male and female brains respond to injury following oxygen deprivation and in
the manner in which they recover following such injury,” says lead investigator
Raul Chavez-Valdez, M.D., a neonatologist at the Johns Hopkins Children’s
In addition, the researchers say, neurons in male and
female brains undergo different type of cell death following oxygen deprivation
that may be due to the presence of certain receptors that trigger sex-specific
pathways of cell demise.
Lastly, the scientists say, their results clarify an earlier observation
that the brains of male mice, while sustaining worse damage overall, tend to
respond better to certain types of therapies that halt neuronal cell death.
The findings, Chavez-Valdez says, underscore the need to
explore questions about gender differences in all studies, including those
conducted in animals, infants and children. Answering these questions in this
case could prove to be a stepping stone toward finding precisely targeted,
gender-based therapies to stimulate brain cell preservation and recovery, the
“Our findings show just how important gender-specific
research is. Not only are sex differences a powerful player in the pathology
and course of disease, but our results indicate that such differences begin to
emerge very early in life, in the very first days of birth and, indeed, perhaps
long before that,” says senior study investigator Frances Northington, M.D., a
neonatologist at the Johns Hopkins Children’s Center.
For their experiments, the investigators homed in on a critical
cell repair protein called brain-derived neurotrophic factor (BDNF), known for
its role in stimulating the growth and regeneration of neurons in the brain. Adequate
amounts of this neuron-nurturing protein ensure cell health in areas of the
brain associated with a range of vital functions, such as processing of sensory
information, learning and memory.
Examining tissue from newborn mice with brain injury, the
researchers noticed that following oxygen-deprivation, cells rapidly release
BDNF, causing a spike in its levels, followed by a precipitous dip 96 hours thereafter.
The team observed that BDNF levels in male and female mice followed the same spike-dip
patterns. However, they found a disproportionately higher presence of two BDNF receptors
in the brains of female mice that promote a milder form of cell death after
oxygen deprivation. These receptors, the researchers say, trigger a form of neuronal
death known as apoptosis, a type of programmed cell death. The brains of male
mice, on the other hand, had fewer of these injury-blunting receptors. The scarcity
of such receptors in male mice, the researchers believe, causes neurons in the
male brain to undergo necrosis, a more violent type of cell death marked by
bursting or disintegration of the cell, which can also wreak damage on
When researchers treated brain-injured animals with a
substance called necrostatin-1, or nec-1, previously shown to halt necrotic
cell death in the brains of mice, they noted a markedly different response to
treatment in male and female animals. The brains of male mice had 41 percent
more BDNF than female mice 96 hours after injury. In other words, nec-1 exhibited
sex-specific protective effects. Could sex hormones explain this gender gap?
To answer this question, the researchers turned their
attention to estradiol, the chief female sex hormone, also found in smaller
amounts in males. Newborn male and female mice had similar levels of estradiol
in their brains, the researchers noted, yet, they somehow responded differently
to it. The investigators observed that following treatment with nec-1, the
brain cells of male mice had a higher concentration of a receptor known as alpha
estrogen receptor. Alpha estrogen receptors’ primary role is to increase cell
sensitivity to estradiol, a type of estrogen, but one of its lesser known
actions is to promote BDNF production. Thus, the researchers say, nec-1 appears
to fuel the expression of such receptors in the male brain, which in turn
trigger more BDNF production.
Investigators say the Neurosciences Intensive Care Nursery
team at Johns Hopkins is also planning a study in human newborns to track the behavior
of BDNF in response to brain injury and treatments.
Temporary cutoff of
oxygen to the brain before, during or immediately after birth can cause a range
of neurologic, developmental and learning disorders, including cerebral palsy,
which is believed to occur in one to three out of 1,000 full-term newborns. Newborn boys have a 40 percent greater risk of developing cerebral
palsy following hypoxic brain injury.
The research was funded by the National Institutes of
Health under grant number RO1HD070996. Additional support was provided by the
Sheila S. and Lawrence C. Pakula, M.D., Endowment for Neonatal Research.
The other Johns Hopkins investigators involved in the
study were Lee J. Martin, Ph.D.; Sheila Razdan; and Estelle Gauda, M.D.
Watch Hadley's story of birth-related brain injury and the 'cooling' therapy at Johns Hopkins Children's Center NICU that saved her