| Autor: |
Xu K; Departments of Physiology and Biophysics, Case Western Reserve University, School of Medicine, Cleveland, OH, USA., Ye L; Departments of Physiology and Biophysics, Case Western Reserve University, School of Medicine, Cleveland, OH, USA., Sharma K; Departments of Physiology and Biophysics, Case Western Reserve University, School of Medicine, Cleveland, OH, USA., Jin Y; Neurosugery and Nutrition, Case Western Reserve University, School of Medicine, Cleveland, OH, USA., Harrison MM; Departments of Physiology and Biophysics, Case Western Reserve University, School of Medicine, Cleveland, OH, USA., Caldwell T; Departments of Physiology and Biophysics, Case Western Reserve University, School of Medicine, Cleveland, OH, USA., Berthiaume JM; Departments of Physiology and Biophysics, Case Western Reserve University, School of Medicine, Cleveland, OH, USA., Luo Y; Neurosugery and Nutrition, Case Western Reserve University, School of Medicine, Cleveland, OH, USA., LaManna JC; Departments of Physiology and Biophysics, Case Western Reserve University, School of Medicine, Cleveland, OH, USA., Puchowicz MA; Nutrition, Case Western Reserve University, School of Medicine, Cleveland, OH, USA. map10@case.edu. |
| Abstrakt: |
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 mm 3 , 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. |
