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.
Hobbs
Catherine E
CE
Department of Anatomy and Structural Biology, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand.
Oorschot
Dorothy E
DE
D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology*; D007036:Hypothermia, Induced; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology / Q000628:therapy*; D008297:Male; D009048:Motor Skills / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000975:Antioxidants; D001557:Benzenesulfonates; C094272:N-tert-butyl-(2-sulfophenyl)nitrone