Effect of Ketone Bodies on Hyperglycemia and Lactic Acidemia in Hemorrhagic Stress

Katayama, M; Hiraide, Atsushi; Sugimoto, Hisashi; Yoshioka, Toshiharu; Sugimoto, Tsuneaki

doi:10.1177/0148607194018005442

Cited by 25 publications

(14 citation statements)

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“…BHB at a dose of 30 mg × kg -1 × h -1 also inhibited cerebral edema formation, maintained high tissue ATP level, and reduced lactate accumulation without affecting cerebral blood flow in rats subjected to incomplete global cerebral ischemia by bilateral common carotid artery ligation (1). BHB was reported to suppress lactic acidemia and hyperglycemia via alleviation of glycolysis during hemorrhagic shock in rats (2). BHB is converted to acetyl-CoA through pathways other than glycolysis before entering the tricarboxylic acid.…”

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confidence: 95%

β-Hydroxybutyrate, a Cerebral Function Improving Agent, Protects Rat Brain Against Ischemic Damage Caused by Permanent and Transient Focal Cerebral Ischemia

Suzuki

Kitamura

et al. 2002

Japanese Journal of Pharmacology

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130

104

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ABSTRACT-In our previous study, b-hydroxybutyrate (BHB) was found to prolong survival time and to inhibit cerebral edema by improving energy metabolism in the hypoxia, anoxia and global cerebral ischemia models. In this study, the cerebroprotective effect of BHB was examined in rats with permanent (p)-occlusion and transient (t)-occlusion of middle cerebral artery (MCA). BHB (30 mg × kg -1 × h -1 ) was continuously administered through the femoral vein. In rats with p-MCA occlusion, BHB significantly reduced infarct area at 24 h after the occlusion, but not at 72 h after the occlusion. In rats with 2-h t-MCA occlusion followed by 22-h reperfusion, BHB significantly reduced cerebral infarct area, edema formation, lipid peroxidation and neurological deficits. Moreover, in the t-MCA occlusion model, delayed administration of BHB started at 1 h after the initiation of the MCA occlusion also significantly reduced cerebral infarct area. Taking together the results obtained in our previous study into account, these results indicate that BHB decreased cerebral edema formation and infarct area by improving of the cerebral energy metabolism during ischemia and by inhibition of lipid peroxidation after reperfusion.Keywords: b -Hydroxybutyrate, Permanent ischemia, Transient ischemia, Middle cerebral artery occlusion, CerebroprotectionIn the previous study, we have shown b-hydroxybutyrate (BHB), one of the ketone bodies, demonstrated cerebral protective activity in experimental screening models for evaluating ischemic brain damage. BHB (50 mg × kg -1 × h -1 ) prolonged the survival time against N 2 gas-induced hypoxia, KCN-induced anoxia and decapitation-induced complete ischemia (1). BHB at a dose of 30 mg × kg -1 × h -1 also inhibited cerebral edema formation, maintained high tissue ATP level, and reduced lactate accumulation without affecting cerebral blood flow in rats subjected to incomplete global cerebral ischemia by bilateral common carotid artery ligation (1). BHB was reported to suppress lactic acidemia and hyperglycemia via alleviation of glycolysis during hemorrhagic shock in rats (2). BHB is converted to acetyl-CoA through pathways other than glycolysis before entering the tricarboxylic acid. These results suggest that preferential utilization of BHB rather than glucose as an energy substrate might reduce the deleterious accumulation of lactate during ischemia.Cerebral edema and infarction are serious clinical complications in acute human cerebrovascular diseases. Recently, several cerebral ischemic models similar to human cerebrovascular diseases have been developed using rats subjected to middle cerebral artery (MCA) occlusion. Tamura et al. developed the electrocauterization model of MCA occlusion in rats (3), and this model has widely been used to investigate therapeutic approach in permanent cerebral ischemia because of its advantages to produce limited cerebral infarction and to be chronically available. There is another model, the intraluminal suture model in rats, in which a nylon suture is inserted into...

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confidence: 95%

β-Hydroxybutyrate, a Cerebral Function Improving Agent, Protects Rat Brain Against Ischemic Damage Caused by Permanent and Transient Focal Cerebral Ischemia

Suzuki

Kitamura

et al. 2002

Japanese Journal of Pharmacology

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130

104

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“…Ketone bodies have been shown to provide effective neuroprotection from various neuropathological conditions, including Parkinson's and Alzheimer's disease [1] , hypoxia-ischemia [2][3][4][5] , hemorrhagic shock [6] and gly-rely on cerebral ketone metabolism when the substrate is available. Based on the collective evidence from development and neuropathology, we propose that TBI will induce changes in MCT2 expression and that these changes will be age dependent.…”

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Induction of Monocarboxylate Transporter 2 Expression and Ketone Transport following Traumatic Brain Injury in Juvenile and Adult Rats

Prins

Giza²

2006

Dev Neurosci

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Based on recent work demonstrating age-dependent ketogenic neuroprotection after traumatic brain injury (TBI), it was hypothesized that the neuroprotection among early post-weaned animals was related to induced cerebral transport of ketones after injury. Regional changes in monocarboxylate transporter 2 (MCT2) were acutely examined with immunohistochemistry after sham surgery or controlled cortical impact injury among postnatal day 35 and adult rats. Both ages showed elevated MCT2 expression in the ipsilateral cerebral vasculature after TBI. Using Western blotting, MCT2 expression was 80–88% greater in microvessels isolated from postnatal day 35 rats at all time points relative to adults. The increased MCT2 expression was temporally correlated with an age-related increase in cerebral uptake of ketones, when ketones were made available after injury.

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“…1), a representative type of ketone body, is produced by degradation of fatty acids in the liver. Recent studies have reported the utilization of BHB as an energy substrate in head trauma patients (11) and hemorrhage shock rats (12). Go et al reported that fasting, characterized by features like hypoglycemia and ketosis, protected rats from developing brain infarction following hypoxia-ischemia (13).…”

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confidence: 99%

Effect of β-Hydroxybutyrate, a Cerebral Function Improving Agent, on Cerebral Hypoxia, Anoxia and Ischemia in Mice and Rats

Suzuki

Sato

et al. 2001

Japanese Journal of Pharmacology

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142

116

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ABSTRACT-Although improving energy metabolism in ischemic brain has been accepted for the treatment of cerebrovascular diseases, administration of glucose, as an energy substrate, would aggravate ischemic brain damage via activating anaerobic glycolysis, which leads to lactate accumulation. b-hydroxybutyrate (BHB) is one of the ketone bodies that can be utilized as an energy source during starvation. The purpose of our study was to define the protective effects of BHB on brain damage induced by hypoxia, anoxia and ischemia. The isotonic solution of BHB administered 30 min before the induction of ischemia at doses over 50 mg · kg -1 ·h -1 showed remarkable protective effects against hypoxia and anoxia. BHB administered immediately after a bilateral carotid artery ligation at a dose of 30 mg·kg -1 ·h -1 significantly suppressed the elevation of cerebral water and sodium contents as well as maintaining high ATP and low lactate levels. In contrast, glycerin, a hypertonic agent, substantially reduced the water content but did not show any significant effect on other parameters. We demonstrated that BHB, unlike glycerin, when used as an energy substrate in ischemic brain, has protective effects on cerebral hypoxia, anoxia and ischemia-induced metabolic change.Keywords: b -Hydroxybutyrate, Glycerin, Anti-anoxic effect, Cerebral ischemia, Cerebral energy metabolism The brain is a surprisingly active tissue in terms of glucose metabolism; almost all the energy supplied to maintain its vital functions are derived from glucose oxidation. Restriction of the glucose supply and metabolism under such conditions as hypoxia and ischemia would result in brain damages (cerebral edema and infarct). However, epidemiological data have shown that hyperglycemia was associated with higher risks of strokes and that ischemic cerebral injury was, at least partly, attributed to hyperglycemia as well (1 -3). Furthermore, it has been verified in several animal models that glucose administration accelerated brain damage caused by cerebral ischemia (4 -6). The elevated glucose anaerobic metabolism under hypoxia and ischemia conditions (6 -9) causes tissue lactate accumulation which subsequently leads to an increased H + intracellular concentration level. It is thus conclusive to state that glucose containing solutions have or might have harmful effects in an ischemic brain.Ketone bodies are known for their energy source uses in states of starvation (10). b-Hydroxybutyrate (BHB, Fig. 1), a representative type of ketone body, is produced by degradation of fatty acids in the liver. Recent studies have reported the utilization of BHB as an energy substrate in head trauma patients (11) and hemorrhage shock rats (12). Go et al. reported that fasting, characterized by features like hypoglycemia and ketosis, protected rats from developing brain infarction following hypoxia-ischemia (13). The rats were found to have an increased level of BHB in their blood compared with rats that had a normal *Corresponding author. FAX: +81-543-35-4858 E-mail: motohisa-...

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Effect of Ketone Bodies on Hyperglycemia and Lactic Acidemia in Hemorrhagic Stress

Abstract: These results suggest that administered 3-OHB may suppress glycolysis during hemorrhagic shock.

Cited by 25 publications

References 14 publications

β-Hydroxybutyrate, a Cerebral Function Improving Agent, Protects Rat Brain Against Ischemic Damage Caused by Permanent and Transient Focal Cerebral Ischemia

β-Hydroxybutyrate, a Cerebral Function Improving Agent, Protects Rat Brain Against Ischemic Damage Caused by Permanent and Transient Focal Cerebral Ischemia

Induction of Monocarboxylate Transporter 2 Expression and Ketone Transport following Traumatic Brain Injury in Juvenile and Adult Rats

Effect of β-Hydroxybutyrate, a Cerebral Function Improving Agent, on Cerebral Hypoxia, Anoxia and Ischemia in Mice and Rats

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