Hypoxic preconditioning in the immature rat has been shown to reduce the brain damage resulting from a subsequent hypoxic-ischemic (H/I) insult. The mechanism underlying the neuroprotective effect has not yet been determined. To investigate this, Wistar rat pups were
subjected to 8% oxygen and 37°C for 2.5 hours on postnatal day 6 (P6); littermates were maintained in room air. All pups were returned to their dams. On P7, preconditioned (PC) and control (N) pups were subjected to H/I according to our standard protocol, i.e. ligation of the right carotid artery, 4 hour of recovery with the dam, prewarming to 37°C for 20 minutes, followed by 2.5 hours of 8% oxygen. For glycolytic and high energy metabolite analysis, PC and N H/I pups were quick-frozen in liquid N2 at 0, 4 and 24 hours of recovery. Neuropathologic analysis was performed at P30. Brain damage was scored from 0-4, depending on the extent of atrophy - infarction of the ipsilateral (ipsi) hemisphere. Brains of PC pups showed less damage than N(PC= 2.5 ± 0.4; N= 4.0 ± 0.0, p<0.001), confirming significant protection. Brain glucose, lactate, pyruvate, ATP and P≈Cr at 0 and 4 hours of recovery were not different between PC and N pups. At 24 hours, ATP and P≈Cr levels in the ipsi hemisphere of N pups were uniformly reduced, demonstrating a secondary decline in energy potential, consistnet with neuronal loss. Although this was also true of ≈ 50% of PC pups, ATP and P≈Cr values in the other PC pups were increased to normal, indicating neuronal recovery. The results of this study indicate the hypoxic preconditioning in the immature rat affects a post-ischemic event resulting in reduced neuronal injury. This suggests the induction of a neuroprotective factor(s) as a result of the prior hypoxic stress.
