Neonatal rat hypoxia-ischemia: Long-term rescue of striatal neurons and motor skills by combined antioxidant-hypothermia treatment

Perinatal hypoxia-ischemia can cause long-term neurological and behavioral disability. Recent multicenter clinical trials suggest that moderate hypothermia, within 6 h of birth, offers significant yet incomplete protection. We investigated the effect of combined treatment with the antioxidant N-tert-butyl-(2-sulfophenyl)-nitrone (S-PBN) and moderate hypothermia on long-term neuronal injury and behavioral disability. S-PBN or its diluent was administered 12-hourly to rats from postnatal day (PN) 7 to 10. On PN8, hypoxia-ischemia was induced. Immediately post-hypoxia, additional S-PBN and 6 h of moderate hypothermia or additional diluent and 6 h of normothermia were administered. At 1 week, and at 11 weeks, after hypoxia-ischemia, the absolute number of surviving medium-spiny neurons was measured in the coded right striatum. In a separate experiment, skilled forepaw ability was investigated in coded 9- to 11-week-old rats. Normal, uninjured animals were also tested for motor skills at 9- to 11-weeks-of-age. The combination of S-PBN and moderate hypothermia provided statistically significant short- and long-term protection of the striatal medium-spiny neurons to normal control levels. This combinatorial treatment also preserved fine motor skills to normal control levels. The impressive histological and functional preservation suggests that S-PBN and moderate hypothermia is a safe and attractive combination therapy for perinatal hypoxia-ischemia.