Hypoxic-ischemic tolerance in newborn rat brain

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Understanding the endogenous neuroprotective mechanism is important for the prevention and treatment of hypoxic-ischemic brain damage in fetus and neonate, a major cause of childhood handicaps. We found the sublethal hypoxic or hypoerthermic preconditioning of 7-day-old rats reduced the severity of brain injury produced by subsequent hypoxic-ischemic stress. We named this phenomenon "hypoxic-ichemic tolerance" (Ota et al. Am J Obstet Gynecol 1998 ; 179 : 1075-8, Ota et al. Journal of SGI 2000 ; 102-5).Hyperhtermia-induced hypoxic-ischemic tolerance was observed at 6, 12, and 24 hours but not at 48 and 72 hours after hyperthermic preconditioning. Heat shock protein 72 expression in the vascular endothelial cells, rather than in the glial or neuronal cells, was most strongly associated with hypoxic-ischemic tolerance. Hyperhtermic preconditioning prevents disruption of blood-brain barrier, resulting in amelioration of hypoxic-ischemic neuronal damage. Taking all above mentioned results into account, "hypoxic-ischemic tolerance" seems to associate with the endothelial functional change in immature brain.As another endogenous protection mechanism, we started to investigate the role of neurotrophic factors. Cerebrospinal fluid concentration of nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 was measured in normal developing rat from birth to postnatal day 21 by enzyme-linked immunosorbent assay. Expression of glial cell line-derived neurotrophic factor(GDNF) in developing rat brain from postnatal day 1 to 21 was examined immunocytochemiscally. GDNF injecting into brain parenchyma provided remarkable protection against ischemic-hypoxic-induced brain damage in 7-day-old rats in a dose-dependent manner.