Neocortical pCREB and BDNF expression under different modes of hypobaric hypoxia: Role in brain hypoxic tolerance in rats

Preconditioning with repetitive mild hypobaric hypoxia is known to increase tolerance of susceptible brain neurons to severe hypoxia, whereas a single trial of mild hypoxia has been ineffective. In the present study, the effects of three-trial and one-trial hypobaric preconditioning on the expression of the protective transcription factor phosphorylated CREB (pCREB) and neurotrophin BDNF, before and after severe hypobaric hypoxia, have been comparatively studied in the neocortex of rats. As revealed by quantitative immunocytochemistry, the severe hypobaric hypoxia (180 Torr, 3 h) substantially down-regulated the levels of pCREB and BDNF in cortical neurons assessed 24 h after the treatment. One trial of mild hypoxia (360 Torr, 2 h) also reduced by half the number of BDNF-expressing cells, but had no effect on pCREB expression in the neocortex. In contrast, the exposure to three trials of mild hypoxia at 24 h intervals considerably up-regulated pCREB and BDNF levels in the neocortex of rats. Only preconditioning by three trials of mild hypoxia (360 Torr, 2 h, 24 h intervals), but not a single trial preconditioning, was neuroprotective significantly enhancing the pCREB and BDNF neuronal expression in response to severe hypoxic challenge. The results of the present study indicate that development of the neuronal hypoxic tolerance induced by the three-trial mild hypoxic preconditioning is apparently associated with activation of CREB and BDNF expression.