• ischemia;
  • hypoxia;
  • ischemic tolerance;
  • hippocampus;
  • aging


Hypoxic preconditioning in the brain (HPC), a phenomenon whereby noninjurious hypoxia induces resistance to cell death following ischemia, requires the expression of specific genes. Declines in signal transduction pathway activity with aging may decrease the genomic response to HPC and limit its neuroprotective efficacy. To test this, we determined how signal transduction gene expression, intracellular Ca2+ levels, and phosphorylation of the survival-associated kinase Akt differ in hippocampal slice cultures (HSCs) made from postnatal day 7–10 (P7–10) and 2-year-old rats following HPC. HPC neuroprotection decreased with increasing source animal age, and HPC could not be demonstrated in HCSs made from animals >6 months of age, despite adjusting the duration of hypoxic exposure. Preconditioning protection required the survival kinase Akt in P10 hippocampal slices cultures. In P9 cultures, HPC increased Akt phosphorylation and the expression of prosurvival genes, including Bcl-2, heat shock proteins, protein kinases, c-jun, and NfκB. Lack of increased Akt phosphorylation and a greatly diminished signaling pathway gene response were found in HSCs from aging animals. Moderate and transient increases in [Ca2+]i during HPC occurred in P7–10 HSCs, but [Ca2+]i was persistently increased at 1 and 24 hr after preconditioning in HSCs from 2-year-old rats. The intracellular Ca2+ chelator BAPTA-AM facilitated HPC neuroprotection in 2-year-old HSCs and restored the pattern of post-HPC gene expression seen in immature animals. We conclude that age-related loss of preconditioning may be due to altered intracellular Ca2+ homeostasis (excess and sustained increase in [Ca2+]i) and is a lesion that prevents critical elements of neuroprotective signal transduction. © 2010 Wiley-Liss, Inc.