Activation of the neuroprotective ERK signaling pathway by fructose-1,6-bisphosphate during hypoxia involves intracellular Ca2+and phospholipase C

  • Fahlman C
  • Bickler P
  • Sullivan B
 et al. 
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Abstract

The mechanism of the neuroprotective action of the glycolytic pathway intermediate fructose-1,6-bisphosphate (FBP) may involve activation of a phospholipase-C (PLC) dependent MAP kinase signaling pathway. In this study, we determined whether FBP's capacity to decrease delayed cell death in hippocampal slice cultures is dependent on PLC signaling or activation of the intracellular Ca2+-MEK/ERK neuroprotective signaling cascade. FBP (3.5 mM) reduced delayed death from oxygen/glucose deprivation in CA1, CA3 and dentate neurons in slice cultures. The phospholipase-C inhibitor U73122 and the MEK1/2 inhibitor U0126 prevented this protection. In hippocampal and cortical neurons, FBP increased phospho-ERK1/2 (p42/44) immunostaining during hypoxic, but not normoxic conditions. Increased phospho-ERK immunostaining was dependent on PLC and also on MEK 1/2, an upstream regulator of ERK. Further, we found that FBP enhancement of phospho-ERK immunostaining depended on [Ca2+]i: PLC inhibition and the IP3receptor blocker xestospongin C prevented FBP from increasing [Ca2+]iand increasing phospho-ERK levels. However, while FBP-induced increases in [Ca2+]iwere blocked by xestospongin and a PLC inhibitor, [Ca2+]iincreases induced by the neuroprotective growth factor BDNF were not prevented. We conclude that during hypoxia FBP initiates a series of neuroprotective signals which include PLC activation, small increases in [Ca2+]i, and increased activity of the MEK/ERK signaling pathway. © 2002 Elsevier Science B.V. All rights reserved.

Author-supplied keywords

  • 6-bisphosphate
  • Brain injury
  • CA1 neuron
  • Calcium
  • Fructose-1
  • Hypoxia
  • Ischemia

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Authors

  • C. S. Fahlman

  • P. E. Bickler

  • Breandan Sullivan

  • G. A. Gregory

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