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Diet-Induced Ketosis Protects Against Focal Cerebral Ischemia in Mouse

  • Kui Xu
  • Lena Ye
  • Katyayini Sharma
  • Yongming Jin
  • Matthew M. Harrison
  • Tylor Caldwell
  • Jessica M. Berthiaume
  • Yu Luo
  • Joseph C. LaManna
  • Michelle A. PuchowiczEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 977)

Abstract

Over the past decade we have consistently shown that ketosis is neuroprotective against ischemic insults in rats. We reported that diet-induced ketotic rats had a significant reduction in infarct volume when subjected to middle cerebral artery occlusion (MCAO), and improved survival and recovery after cardiac arrest and resuscitation. The neuroprotective mechanisms of ketosis (via ketogenic diet; KG) include (i) ketones are alternate energy substrates that can restore energy balance when glucose metabolism is deficient and (ii) ketones modulate cell-signalling pathways that are cytoprotective. We investigated the effects of diet-induced ketosis following transient focal cerebral ischemia in mice. The correlation between levels of ketosis and hypoxic inducible factor-1alpha (HIF-1α), AKT (also known as protein kinase B or PKB) and 5′ AMP-activated protein kinase (AMPK) were determined. Mice were fed with KG diet or standard lab-chow (STD) diet for 4 weeks. For the MCAO group, mice underwent 60 min of MCAO and total brain infarct volumes were evaluated 48 h after reperfusion. In a separate group of mice, brain tissue metabolites, levels of HIF-1α, phosphorylated AKT (pAKT), and AMPK were measured. After feeding a KG diet, levels of blood ketone bodies (beta-hydroxyburyrate, BHB) were increased. There was a proportional decrease in infarct volumes with increased blood BHB levels (KG vs STD; 4.2 ± 0.6 vs 7.8 ± 2.2 mm3, mean ± SEM). A positive correlation was also observed with HIF-1α and pAKT relative to blood BHB levels. Our results showed that chronic ketosis can be induced in mice by KG diet and was neuroprotective against focal cerebral ischemia in a concentration dependent manner. Potential mechanisms include upregulation of cytoprotective pathways such as those associated with HIF-1α, pAKT and AMPK.

Keywords

Ketogenic diet Ischemia-reperfusion injury HIF-1α, AKT Neuroprotection. 

Notes

Acknowledgments

This study was supported by NIH grant R01 HL 092933-01A1.

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Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Kui Xu
    • 1
  • Lena Ye
    • 1
  • Katyayini Sharma
    • 1
  • Yongming Jin
    • 2
  • Matthew M. Harrison
    • 1
  • Tylor Caldwell
    • 1
  • Jessica M. Berthiaume
    • 1
  • Yu Luo
    • 2
  • Joseph C. LaManna
    • 1
  • Michelle A. Puchowicz
    • 3
    Email author
  1. 1.Departments of Physiology and BiophysicsCase Western Reserve University, School of MedicineClevelandUSA
  2. 2.Neurosugery and NutritionCase Western Reserve University, School of MedicineClevelandUSA
  3. 3.NutritionCase Western Reserve University, School of MedicineClevelandUSA

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