TrkB Agonist Treatment Decreases Hippocampal Testosterone Contents in a Sex-Dependent Manner Following Neonatal Hypoxia and Ischemia

Hypoxia-ischemia (HI)-related brain injury impacts millions of neonates worldwide. Male neonates are two times more susceptible to developing HI. We have previously reported that the administration of the neurotrophin receptor tyrosine kinase B (TrkB) agonist 7,8-dihydroxyflavone (DHF) following neonatal HI increases hippocampal TrkB phosphorylation and improves hippocampal-dependent learning and memory in early adult life only in females. We hypothesize that sex differences in HI outcomes are due to alterations in neonatal hippocampal steroid content, mainly the neural testosterone. At postnatal day 9, <i>C57BL/6J</i> mice underwent sham and Vannucci's HI surgeries and were treated either with DHF or vehicle control. Hippocampi and plasma were collected on days 1 and 3 post-HI and liquid chromatography tandem mass spectrometry was used to determine the testosterone (T), estradiol (E₂), progesterone (P₄), and corticosterone (CORT) contents in these samples. All hippocampal steroid contents were at least 10-fold higher than in plasma, suggesting neural synthesis. Males had higher hippocampal T content than females at 3 days post-HI. Treatment with DHF reduced T in the female hippocampi at 3 days post-HI, but not in males. These findings suggest that the neuroprotective effect of DHF in females may be mediated, at least in part, through the reduction in hippocampal T following HI.