Hypoxic preconditioning reduces hypoxic-ischemic injury in newborn piglet brain

Perinatal hypoxic-ischemic brain injury is a major cause of learning disabilities, cerebral palsy, epilepsy and death. At present, there are no therapies available to protect the infant brain from perinatal insults. However, powerful endogenous pathways exist to control central nervous system (CNS) cell death. These pathways are exploited in a phenomenon known as hypoxic preconditioning in which neurons exposed to non injurious hypoxic challenge are subsequently provided profound resistance. In this study we investigated the effects of moderate hypoxia on neuronal death following subsequent severe hypoxic-ischemic insult in various brain regions, using a newborn piglet model of cerebral hypoxia-ischemia. Piglets were divided into 4 groups: control normoxic group; hypoxic-preconditioned (PC) group; hypoxic-ischemic (H/I) group; and hypoxic preconditioned + hypoxic-ischemic (PC+H/I) group. The piglets in all these four groups were recovered for 3 or 7 days. Microscopic examination of the brains stained with H&E and Nissl from piglets subjected to 3h of PC alone did not reveal any histological damage. In the severe insult group (H/I), the combination of hypoxia and ischemia resulted in predominant neuronal loss in cerebral cortex and pyramidal neurons of CA1 and dentate gyrus region of hippocampus with recovery periods of 3 or 7 days. The striatum, thalamus and cerebellum were also affected. On the other hand, hypoxic preconditioning performed 24h before hypoxic-ischemic injury exhibited significant protection in the CA1 region of the hippocampus, the cerebral cortex, striatum and the thalamus. The present study demonstrated that hypoxic preconditioning induces 'ischemic tolerance' phenomenon in the newborn piglet brain.