Knockdown of glucose-6-phosphate dehydrogenase (G6PD) following cerebral ischemic reperfusion: the pros and cons

Neurochem Int. 2012 Jul;61(2):146-55. doi: 10.1016/j.neuint.2012.05.003. Epub 2012 May 8.


NADPH derived from glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway, has been implicated not only to promote reduced glutathione (GSH) but also enhance oxidative stress in specific cellular conditions. In this study, the effects of G6PD antisense oligodeoxynucleotides (AS-ODNs) was examined on the CA1 pyramidal neurons following transient cerebral ischemia. Specifically knockdown of G6PD protein expression in hippocampus CA1 subregion at early reperfusion period (1-24 h) with a strategy to pre-treated G6PD AS-ODNs significantly reduced G6PD activity and NADPH level, an effect correlated with attenuation of NADPH oxidase activation and superoxide anion production. Concomitantly, pre-treatment of G6PD AS-ODNs markedly reduced oxidative DNA damage and the delayed neuronal cell death in rat hippocampal CA1 region induced by global cerebral ischemia. By contrast, knockdown of G6PD protein at late reperfusion period (48-96 h) increased oxidative DNA damage and exacerbated the ischemia-induced neuronal cell death in hippocampal CA1 region, an effect associated with reduced NADPH level and GSH/GSSG ratio. These findings indicate that G6PD not only plays a role in oxidative neuronal damage but also a neuroprotective role during different ischemic reperfusion period. Therefore, G6PD mediated oxidative response and redox regulation in the hippocampal CA1 act as the two sides of the same coin and may represent two potential applications of G6PD during different stage of cerebral ischemic reperfusion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • CA1 Region, Hippocampal / cytology
  • CA1 Region, Hippocampal / drug effects
  • Cell Death / drug effects
  • Cerebrovascular Disorders / therapy*
  • DNA Damage
  • Glucosephosphate Dehydrogenase / antagonists & inhibitors*
  • Glucosephosphate Dehydrogenase / genetics*
  • Glutathione / metabolism
  • Heart Arrest / pathology
  • Immunohistochemistry
  • Male
  • NADP / metabolism
  • NADPH Oxidases / metabolism
  • Nerve Tissue Proteins / metabolism
  • Neurons / drug effects
  • Neurons / pathology
  • Oligodeoxyribonucleotides, Antisense / therapeutic use*
  • Oxidative Stress / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury / therapy*
  • Superoxides / metabolism


  • Nerve Tissue Proteins
  • Oligodeoxyribonucleotides, Antisense
  • Superoxides
  • NADP
  • Glucosephosphate Dehydrogenase
  • NADPH Oxidases
  • Glutathione