Ketones Suppress Brain Glucose Consumption

Glucose is the main energy substrate in brain but in certain circumstances such as prolonged fasting and the suckling period alternative substrates can be used such as the ketone bodies (KB), beta-hydroxybutyrate (BHB), and acetoacetate. It has been shown that KB prevent neuronal death induced during energy limiting conditions and excitotoxicity. The protective effect of KB has been mainly attributed to the improvement of mitochondrial function. In the present study, we have investigated the protective effect of D-BHB against neuronal death induced by severe noncoma hypoglycemia in the rat in vivo and by glucose deprivation (GD) in cortical cultures. Results show that systemic administration of D-BHB reduces reactive oxygen species (ROS) production in distinct cortical areas and subregions of the hippocampus and efficiently prevents neuronal death in the cortex of hypoglycemic animals. In vitro results show that D-BHB stimulates ATP production and reduces ROS levels, while the nonphysiologic isomer of BHB, L-BHB, has no effect on energy production but reduces ROS levels. Data suggest that protection by BHB, not only results from its metabolic action but is also related to its capability to reduce ROS, rendering this KB as a suitable candidate for the treatment of ischemic and traumatic injury. INTRODUCTIONGlucose is the main energy source in brain. However, under certain conditions other energy substrates such as the ketone bodies (KB), acetoacetate (AcAc), and β-hydroxybutyrate (BHB) can be used by brain, including the suckling period, 1,2 prolonged fasting, 3 and the ketogenic diet; 4 all these situations are associated with increased KB levels in blood. Several studies have shown that KB can protect the brain against damage associated with diverse neurotoxic insults such as hypoxia, 5 ischemia, 6-8 hypoglycemia, 9,10 and excitotoxicity. 11,12 In addition, the ketogenic diet has been used for a long time for the treatment of refractory epilepsy. 4,13,14 The protective effect of KB has been mostly attributed to their conversion to AcetylCoA improving mitochondrial metabolism and preserving energy levels. [15][16][17] However, studies suggest that besides providing energy to neurons, KB reduce the production of reactive oxygen species (ROS) contributing to their protective effect. It has been observed in vitro that AcAc reduces ROS levels induced by glutamate exposure and glycolysis inhibition in cultured neurons, 12,16 and previous in vivo studies have shown that BHB decreases hypoglycemia and glutamate-mediated lipoperoxidation in the rat brain. 10,18 The mechanism underlying the reduction of ROS by BHB has not been elucidated but we have previously reported that KB display a scavenging action of ROS, in particular of the hydoxyl radical ( • OH). 10 The physiologic and the

Section: Discussionmentioning

confidence: 99%

Protection of Hypoglycemia-Induced Neuronal Death by β-Hydroxybutyrate Involves the Preservation of Energy Levels and Decreased Production of Reactive Oxygen Species

Julio-Amilpas

Montiel

Soto‐Tinoco

et al. 2015

“…For instance, during starvation the brain utilizes acetoacetate and hydroxybutyrate. 21,22 Our GC-MS experimental methods evaluated the oxidative contribution for glucose relative to total CAC flux. Our study shows that propofol compared with isoflurane shifts the oxidative preference from glucose to an alternate, unlabeled substrate.…”

Section: Discussionmentioning

confidence: 99%

Propofol Compared with Isoflurane Inhibits Mitochondrial Metabolism in Immature Swine Cerebral Cortex

Kajimoto

Atkinson

Ledee

et al. 2014

Anesthetics used in infants and children are implicated in the development of neurocognitive disorders. Although propofol induces neuroapoptosis in developing brain, the underlying mechanisms require elucidation and may have an energetic basis. We studied substrate utilization in immature swine anesthetized with either propofol or isoflurane for 4 hours. Piglets were infused with 13-Carbon-labeled glucose and leucine in the common carotid artery to assess citric acid cycle (CAC) metabolism in the parietal cortex. The anesthetics produced similar systemic hemodynamics and cerebral oxygen saturation by near-infrared spectroscopy. Compared with isoflurane, propofol depleted ATP and glycogen stores. Propofol decreased pools of the CAC intermediates, citrate, and a-ketoglutarate, while markedly increasing succinate along with decreasing mitochondrial complex II activity. Propofol also inhibited acetyl-CoA entry into the CAC through pyruvate dehydrogenase, while promoting glycolytic flux with marked lactate accumulation. Although oxygen supply appeared similar between the anesthetic groups, propofol yielded a metabolic phenotype that resembled a hypoxic state. Propofol impairs substrate flux through the CAC in the immature cerebral cortex. These impairments occurred without systemic metabolic perturbations that typically accompany propofol infusion syndrome. These metabolic abnormalities may have a role in the neurotoxity observed with propofol in the vulnerable immature brain.

“…18,19 Neuroprotection by ketosis is thought to be associated with improved mitochondrial function, decreased reactive oxygen species, apoptotic and inflammatory mediators, and protective pathways. 9,20 In the last few decades, the 2-deoxy-D-glucose or positron emission tomography (PET) approaches have been applied to ketotic studies, in both animal, 18,[21][22][23] and humans. 2,5,24,25 Reports of altered CMR glc as a result of short-term fasting [3][4][5][6][7] or acute infusions of ketone bodies 25,26 had generated discrepancies.…”

Section: Introductionmentioning

confidence: 99%

Ketosis Proportionately Spares Glucose Utilization in Brain

Zhang

Kuang

et al. 2013

Self Cite

The brain is dependent on glucose as a primary energy substrate, but is capable of utilizing ketones such as b-hydroxybutyrate and acetoacetate, as occurs with fasting, starvation, or chronic feeding of a ketogenic diet. The relationship between changes in cerebral metabolic rates of glucose (CMR glc ) and degree or duration of ketosis remains uncertain. To investigate if CMR glc decreases with chronic ketosis, 2-[18 F]fluoro-2-deoxy-D-glucose in combination with positron emission tomography, was applied in anesthetized young adult rats fed 3 weeks of either standard or ketogenic diets. Cerebral metabolic rates of glucose (mmol/min per 100 g) was determined in the cerebral cortex and cerebellum using Gjedde-Patlak analysis. The average CMR glc significantly decreased in the cerebral cortex (23.0 ± 4.9 versus 32.9 ± 4.7) and cerebellum (29.3 ± 8.6 versus 41.2 ± 6.4) with increased plasma ketone bodies in the ketotic rats compared with standard diet group. The reduction of CMR glc in both brain regions correlates linearly by B9% for each 1 mmol/L increase of total plasma ketone bodies (0.3 to 6.3 mmol/L). Together with our meta-analysis, these data revealed that the degree and duration of ketosis has a major role in determining the corresponding change in CMR glc with ketosis.