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Hypoxic preconditioning failure in aging hippocampal neurons: Impaired gene expression and rescue with intracellular calcium chelation
Author(s) -
Bickler Philip E.,
Fahlman Christian S.,
Gray Jonathan J.
Publication year - 2010
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.22508
Subject(s) - neuroprotection , protein kinase b , biology , microbiology and biotechnology , signal transduction , intracellular , phosphorylation , pi3k/akt/mtor pathway , kinase , calcium in biology , hippocampal formation , pharmacology , endocrinology
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 Ca 2+ 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 [Ca 2+ ] i during HPC occurred in P7–10 HSCs, but [Ca 2+ ] i was persistently increased at 1 and 24 hr after preconditioning in HSCs from 2‐year‐old rats. The intracellular Ca 2+ 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 Ca 2+ homeostasis (excess and sustained increase in [Ca 2+ ] i ) and is a lesion that prevents critical elements of neuroprotective signal transduction. © 2010 Wiley‐Liss, Inc.