Abstract
Male neonate brains are more susceptible to the effects of perinatal asphyxia resulting in hypoxia and ischemia (HI)-related brain injury. The relative resistance of female neonatal brains to adverse consequences of HI suggests that there are sex-specific mechanisms that afford females greater neuroprotection and/or facilitates recovery post-HI. We hypothesized that HI preferentially induces estrogen receptor α (ERα) expression in female neonatal hippocampi and that ERα is coupled to Src family kinase (SFK) activation that in turn augments phosphorylation of the TrkB and thereby results in decreased apoptosis. After inducing the Vannucci’s HI model on P9 (C57BL/6J) mice, female and male ERα wild-type (ERα+/+) or ERα null mutant (ERα−/−) mice received vehicle control or the selective TrkB agonist 7,8-dihydroxyflavone (7,8-DHF). Hippocampi were collected for analysis of mRNA of ERα and BDNF, protein levels of ERα, p-TrkB, p-src, and cleaved caspase 3 (c-caspase-3) post-HI. Our results demonstrate that: (1) HI differentially induces ERα expression in the hippocampus of the female versus male neonate, (2) src and TrkB phosphorylation post-HI is greater in females than in males after 7,8-DHF therapy, (3) src and TrkB phosphorylation post-HI depend on the presence of ERα, and (4) TrkB agonist therapy decreases the c-caspase-3 only in ERα+/+ female mice hippocampus. Together, these observations provide evidence that female-specific induction of ERα expression confers neuroprotection with TrkB agonist therapy via SFK activation and account for improved functional outcomes in female neonates post-HI.
Highlights
Perinatal asphyxia resulting in hypoxia-ischemia (HI)related brain injury leads to severe, life-long morbidities in thousands of neonates and children born in the U.S each year (Ferriero, 2004; Nelson and Lynch, 2004; Drobyshevsky et al, 2007; Hill and Fitch, 2012)
Our studies confirm the validity of four key elements of this hypothesis, namely that: (1) HI differentially induces ER␣ expression in the hippocampus of the female versus male neonate, (2) src and TrkB phosphorylation post-HI is greater in females than in males after 7,8-DHF therapy, (3) src and TrkB phosphorylation post-HI depend upon the presence of ER␣, (4) TrkB agonist therapy decreases the c-caspase-3 only in estrogen receptor ␣ (ER␣)ϩ/ϩ female mice hippocampus (Fig. 9)
We report here that ER␣ expression is upregulated in the ischemic neonatal hippocampus in a sexually differentiated manner, with greater ER␣ mRNA and protein expression occurring in the female versus male neonate, in a manner similar to that previously reported in adult rodents at the ischemia site after middle cerebral artery occlusion (MCAO) (Westberry et al, 2010)
Summary
Perinatal asphyxia resulting in hypoxia-ischemia (HI)related brain injury leads to severe, life-long morbidities in thousands of neonates and children born in the U.S each year (Ferriero, 2004; Nelson and Lynch, 2004; Drobyshevsky et al, 2007; Hill and Fitch, 2012). Clinical studies indicate that male neonate brains are more susceptible to the effects of perinatal asphyxia (Vannucci and Hurn, 2009; Hill and Fitch, 2012) resulting in greater longterm cognitive deficits compared with females with comparable brain injury (Marlow et al, 2005; Tioseco et al, 2006; Hill and Fitch, 2012). The relative resistance of female neonatal brain to adverse consequences of HI suggests that there are sexspecific mechanisms that afford females greater neuroprotection and/or facilitates recovery post-HI (Rutter et al, 2003; Hill and Fitch, 2012). Understanding these mechanisms will help identify sex-specific therapeutic interventions following perinatal HI and lead to better neurological outcomes
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
