Early postnatal inhibition of neurosteroid synthesis changes the later-life adverse outcome of neonatal asphyxia in rats

Birth asphyxia (BA) is a common cause of hypoxic-ischemic encephalopathy (HIE), neonatal seizures, and detrimental neurodevelopment. Brain levels of neurosteroids such as allopregnanolone rise in response to acute hypoxic stress, which is thought to represent an endogenous protective mechanism that reduces excitotoxicity in the developing brain. In the present study, we investigated how inhibition of neurosteroid synthesis by the steroid 5α-reductase inhibitor finasteride affects the adverse outcomes of BA/HIE. Intermittent asphyxia was induced in neonatal rats at postnatal day 11. Finasteride (50 mg/kg) was administered immediately before asphyxia. Behavioral and cognitive tests were performed over the subsequent 14 months, which corresponds to ∼50 % of the lifespan of the outbred rat strain used. In contrast to our expectation, finasteride decreased the severity and duration of the neonatal seizures and did not increase mortality. Subsequent behavioral experiments showed no adverse development of motor function, but finasteride-treated rats exhibited increased anxiety-like behavior in the open field, elevated plus-maze, and light-dark box tests. The increased anxiety-like behavior was correlated with enhanced mossy fiber sprouting in the hippocampal CA3a region. While vehicle-treated post-asphyxial rats showed a serious decline in cognitive functions, this was not observed in the finasteride-treated group. One possible explanation of the latter finding is that a significant loss of CA3c neurons in the dorsal hippocampus was only determined in vehicle-treated but not finasteride-treated post-asphyxial rats. Overall, the present study indicates that the role of neurosteroids in BA and its adverse outcome is much more complex than previously thought.