Babies born with breathing problems are at risk for brain injury due to hypoxia (oxygen deprivation) and ischemia (restricted blood flow to tissues). Those brain injuries, which occur in 20,000 U.S. newborns each year, can lead to disabilities that range from mild to severe to life-threatening.
Interestingly, clinical studies suggest that female newborns are more resistant to the effects of hypoxia and ischemia—and have better long-term cognitive outcomes—than male newborns with comparable brain injury.
However, the sex-specific mechanisms that protect females from brain injury and/or facilitate better recovery, remain unknown.
Now, new basic research by Pelin Cengiz, MD (Associate Professor, Division of Critical Care) aims to better elucidate the biological basis of this poorly understood phenomenon.
Dr. Cengiz recently received a five-year, $2M grant from the National Institutes of Health’s (NIH) National Institute of Neurological Disorders and Stroke—her first NIH R01 award as a principal investigator—to investigate how estrogen receptor α (ERα) mediates neuroprotective responses in female newborns.
Neuroprotective Responses in the Female Brain
The project builds on her preliminary research, which found that giving mice an investigational agent called 7,8-dihydroxyflavone (7,8-DHF) activated a receptor for brain-derived neurotrophic factor called tyrosine kinase B receptor (TrkB). TrkB, in turn, activated several downstream pathways linked to brain recovery and survival after hypoxia and ischemia. Importantly, these TrkB-mediated neuroprotective responses occurred only in female mice.
The team then investigated sex-differences in neurons in the hippocampus, the part of the brain that regulates memory, emotion regulation and spatial navigation, and found that post-injury ERα signaling was three times higher in the females than the males.
What’s more, when they administered testosterone to the female mice, reducing their hippocampal ERα expression to male levels, the neuroprotective effect of 7,8-DHF was lost. Taken together, these findings strongly suggest that sex differences in outcome after hypoxia-ischemia may be related to increased ERα-dependent neurotrophin signaling in females.
In the new study, Dr. Cengiz’ team will fully evaluate the signaling pathways between ERα and TrkB. Specifically, they aim to determine the role of non-genomic ERα signaling, the epigenetic regulation of ERα expression and the impact of the perinatal hormonal environment on ERα signaling post-injury.
Mitigating Complications in Later Life
Dr. Cengiz hopes that her research will improve understanding of sex differences in outcome after injury in the developing brain, and pave the way for sex-specific therapies to mitigate the negative outcomes of hypoxia- and ischemia-related brain injury.
She explained that newborns with mild or moderate brain injury may not show signs of significant impairment when they are discharged from the NICU. But as their brains develop, those children may present with learning disabilities, seizure disorders or cerebral palsy.
“As a pediatric intensivist, I see the complications from early brain injury,” she reflects. “That’s my motivation for investigating the mechanisms of sex differences in neuroprotection. If we can understand the differences between the male brain and the female brain, we can help improve outcomes for both.”