TIGAR contributes to ischemic tolerance induced by cerebral preconditioning through scavenging of reactive oxygen species and inhibition of apoptosis

Sci Rep. 2016 Jun 3;6:27096. doi: 10.1038/srep27096.


Previous study showed that TIGAR (TP53-induced glycolysis and apoptosis regulator) protected ischemic brain injury via enhancing pentose phosphate pathway (PPP) flux and preserving mitochondria function. This study was aimed to study the role of TIGAR in cerebral preconditioning. The ischemic preconditioning (IPC) and isoflurane preconditioning (ISO) models were established in primary cultured cortical neurons and in mice. Both IPC and ISO increased TIGAR expression in cortical neurons. Preconditioning might upregulate TIGAR through SP1 transcription factor. Lentivirus mediated knockdown of TIGAR significantly abolished the ischemic tolerance induced by IPC and ISO. ISO also increased TIGAR in mouse cortex and hippocampus and alleviated subsequent brain ischemia-reperfusion injury, while the ischemic tolerance induced by ISO was eliminated with TIGAR knockdown in mouse brain. ISO increased the production of NADPH and glutathione (GSH), and scavenged reactive oxygen species (ROS), while TIGAR knockdown decreased GSH and NADPH production and increased the level of ROS. Supplementation of ROS scavenger NAC and PPP product NADPH effectively rescue the neuronal injury caused by TIGAR deficiency. Notably, TIGAR knockdown inhibited ISO-induced anti-apoptotic effects in cortical neurons. These results suggest that TIGAR participates in the cerebral preconditioning through reduction of ROS and subsequent cell apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis Regulatory Proteins
  • Brain Ischemia / genetics*
  • Brain Ischemia / metabolism
  • Brain Ischemia / pathology
  • Brain Ischemia / prevention & control
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism*
  • Cerebral Cortex / pathology
  • Gene Expression Regulation
  • Glutathione / metabolism
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Hippocampus / pathology
  • Ischemic Preconditioning*
  • Isoflurane / pharmacology
  • Lentivirus / genetics
  • Lentivirus / metabolism
  • Male
  • Mice
  • Mice, Inbred ICR
  • NADP / metabolism
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Phosphoric Monoester Hydrolases
  • Primary Cell Culture
  • Proteins / antagonists & inhibitors
  • Proteins / genetics*
  • Proteins / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Reactive Oxygen Species / antagonists & inhibitors
  • Reactive Oxygen Species / metabolism
  • Reperfusion Injury / genetics*
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / pathology
  • Reperfusion Injury / prevention & control
  • Signal Transduction
  • Sp1 Transcription Factor / genetics
  • Sp1 Transcription Factor / metabolism


  • Apoptosis Regulatory Proteins
  • Proteins
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Sp1 Transcription Factor
  • NADP
  • Isoflurane
  • Phosphoric Monoester Hydrolases
  • TIGAR protein, mouse
  • Glutathione