Ischemic preconditioning with a ketogenic diet improves brain ischemic tolerance through increased extracellular adenosine levels and hypoxia-inducible factors

Brain Res. 2017 Jul 15;1667:11-18. doi: 10.1016/j.brainres.2017.04.010. Epub 2017 Apr 18.


Ischemic tolerance reduces brain damage and neurological dysfunction after brain ischemia. A ketogenic diet (KD) has disease-modifying effects in several neurodegenerative disorders. In this study, we fed mice with a KD for three weeks and performed reversible middle cerebral artery occlusion (MCAO) in the animals. KD-fed mice had a significantly reduced infarct volume, increased regional cerebral blood flow (rCBF) and extracellular adenosine levels in both the ischemic and the reperfusion phases. In vitro and in vivo experiments revealed that the KD-induced neuroprotection was mediated through the adenosine A1 receptor. The KD increased Akt and ERK1/2 phosphorylation via A1R activation. Besides, the KD also upregulated robustly HIF-1α/HIF-2α and HIF regulated genes, such as VEGF and EPO. A three-week preconditioning period with a KD improved ischemic tolerance in mice with MCAO. The underlying mechanisms might include elevated extracellular adenosine levels, and increased Akt and ERK1/2 phosphorylation via A1 adenosine receptor activation, together with upregulated HIFs and HIF-regulated genes.

Keywords: Adenosine; Hypoxia-inducible factors (HIFs); Ischemic stroke; Ischemic tolerance; Ketogenic diet (KD).

MeSH terms

  • Adenosine / metabolism*
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Brain / blood supply
  • Brain / metabolism*
  • Brain / pathology
  • Brain Ischemia / metabolism*
  • Brain Ischemia / pathology
  • Brain Ischemia / therapy*
  • Cell Line, Tumor
  • Cerebrovascular Circulation / physiology
  • Diet, Ketogenic*
  • Disease Models, Animal
  • Extracellular Space / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Ischemic Preconditioning*
  • MAP Kinase Signaling System / physiology
  • Male
  • Mice, Inbred BALB C
  • Neuroprotection / physiology
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Random Allocation
  • Receptor, Adenosine A1 / metabolism
  • Vascular Endothelial Growth Factor A / metabolism


  • Basic Helix-Loop-Helix Transcription Factors
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Receptor, Adenosine A1
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • endothelial PAS domain-containing protein 1
  • Proto-Oncogene Proteins c-akt
  • Adenosine