Estrogen receptor alpha mediates protection against hypoxic ischemic brain injury in newborn female mice, study shows

Females are preferentially protected from the long-term cognitive impairments caused by low oxygen and blood flow to the brain at birth, or hypoxia ischemia.  A new study led by Pelin Cengiz, MD, professor of pediatrics and Waisman Center investigator, has revealed  that this female-specific neuroprotection is mediated by the activation of the tyrosine kinase B receptor (TrkB) and is dependent on the presence of estrogen receptor alpha (ERα).  The study, published recently in Biology of Sex Differences found that ERα is required for the preservation of recognition and location memories in female adult mice that experienced hypoxia and ischemia as newborns.

Graphs showing study results.
TrkB-mediated sustained neuroprotection is sex-specific and estrogen receptor alpha-dependent in adult mice following neonatal hypoxia ischemia.

In her practice as a pediatric intensivist, Cengiz noticed that even with similar brain injuries, functional outcomes varied from child to child. “So, I began wondering what could be the potential mechanisms of these differences in outcome”, Cengiz says. In the lab, she found that administering a drug that activates TrkB – a kinase receptor involved in cell survival – provides short term protection against hypoxia ischemia in female mice three days after the initial injury, but not in male mice.  Interestingly, these female-specific benefits were not observed in mice that lacked ERα, suggesting that TrkB-mediated protection depends on the expression of ERα.

For Cengiz, the next important question was whether the early benefits from ERα-dependent TrkB activation would be sustained into adulthood.  To answer this, Cengiz used genetically modified mice that lack ERα (knockout mice) and compared them to mice with normal levels of ERα. After exposing both groups of mice to hypoxia ischemia, some mice were treated with a TrkB activating drug called 7,8-DHF some were not. Once the mice reached young adulthood, they underwent a series of memory tests.

Pelin Cengiz speaking with a researcher in her lab
Pelin Cengiz, MD

Cengiz observed that the female mice with normal ERα expression that received 7,8-DHF after hypoxia ischemia showed similar performance on recognition and location memory tests to mice that didn’t experience hypoxia ischemia at all. These neuroprotective effects of 7,8-DHF were not seen in male mice, and they were also absent in the female ERα knockout mice.  This suggests that the ERα is necessary for the long-term TrkB-mediated neuroprotection against hypoxia ischemia.

The results of this study provide new insight into sex-specific protective mechanisms after hypoxia ischemia in newborns. In the future, Cengiz and her team hope to translate these findings to develop novel sex-specific therapies for newborns suffering from hypoxia ischemia.

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