Intermittent hypoxia induces time-dependent changes in the protein kinase B signaling pathway in the hippocampal CA1 region of the rat

Neurobiol Dis. 2003 Dec;14(3):440-6. doi: 10.1016/j.nbd.2003.08.004.


Intermittent hypoxia (IH) during sleep induces temporally defined increases in apoptosis within vulnerable brain regions such as the hippocampal CA1 region in rats. Protein kinase B (AKT) has emerged as major signal transduction protein underlying inhibition of apoptosis and consequent increases in cell survival. Sprague Dawley adult male rats were exposed during sleep to IH or to normoxia (RA) for periods ranging from 0 to 30 days, and expression of total and phosphorylated AKT, of forkhead family members FKHR and FKHRL1, and of glycogen synthase kinase 3beta (GSK3beta) was assessed. Decreases in phosphorylation occurred as early as 1 h IH exposure, reached a nadir at 6 h-3 days, and then progressively returned to baseline levels at 14-30 days. Phosphorylated AKT and GSK3beta were intensely expressed and highly colocalized within neuronal cells (Neu-N positive) in the CA1 region. Thus, IH induces time-dependent biphasic changes in AKT survival pathways within the CA1 region that are temporally correlated with the initial increases and subsequent decreases in neuronal apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Cell Survival / physiology
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Down-Regulation / physiology
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Hippocampus / enzymology*
  • Hippocampus / pathology
  • Hippocampus / physiopathology
  • Hypoxia, Brain / enzymology*
  • Hypoxia, Brain / pathology
  • Hypoxia, Brain / physiopathology
  • Male
  • Nerve Degeneration / enzymology*
  • Nerve Degeneration / physiopathology
  • Nerve Tissue Proteins*
  • Phosphorylation
  • Protein Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Rats, Sprague-Dawley
  • Reaction Time
  • Signal Transduction / physiology
  • Sleep Apnea Syndromes / enzymology*
  • Sleep Apnea Syndromes / pathology
  • Sleep Apnea Syndromes / physiopathology
  • Time Factors
  • Transcription Factors / metabolism


  • DNA-Binding Proteins
  • FOXO3 protein, rat
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins
  • Transcription Factors
  • Foxo1 protein, rat
  • Akt1 protein, rat
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, rat
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3