Isoflurane-Delayed Preconditioning Reduces Immediate Mortality and Improves Striatal Function in Adult Mice After Neonatal Hypoxia–Ischemia

Abstract

Exposure to hypoxia and isoflurane (Iso) before hypoxia-ischemia has been found to be neuroprotective in neonatal rats. We investigated the long-term effects of delayed preconditioning with Iso, hypoxia, or room air on motor and cognitive function in mice that had 65 min of hypoxia-ischemia on postnatal day 10. Nine-day-old C57x129T2 F1 mice received either 1.8% Iso, hypoxic (10% O2 in N2), or sham (room air) preconditioning. The following day, the mice were subjected to permanent right common carotid ligation or sham ligation followed by 65 min of hypoxia, or room air. At 70 days of age, learning was tested using a series of Morris water maze tests. Striatal function was assessed by response to apomorphine injection. Histological analysis was performed on adult brain (P120) sections of striatum and dorsal hippocampus. Iso preconditioning 24 h before severe neonatal hypoxia-ischemia reduced preweaning mortality from 20% to 0% (P < 0.04) and improved striatal function in adult mice, as assessed by circling after apomorphine injection (P < 0.028), but no improvements in performance were noted in the spatial-reference memory water maze tests. Hypoxic preconditioning improved learning relative to the sham-preconditioned group on the hidden maze, but not the more difficult reduced maze test of spatial memory. It had no significant effect on preweaning mortality and apomorphine response. Histologic analysis showed the hippocampus of non-preconditioned and Iso-preconditioned animals to be equally injured. Iso and hypoxia confer selective functional neuroprotection in a delayed preconditioning paradigm in neonatal mice.