Effects of a Single Therapeutic Dose of Glycerol on Cerebral Metabolism in the Brains of Young Mice: Possible Increase in Brain Glucose Transport and Glucose Utilization

Abstract

This is a study of the effects of a single “therapeutic” dose of glycerol [2 g(22 mmol)/kg i.p.] on brain carbohydrate and energy metabolism in normal nursing weanling mice. Findings were correlated with brain water and electrolyte content and with metabolite changes in plasma, red blood cells, and liver. Plasma glycerol levels peaked at 21 mM 7.5 min after injection and returned to the control value, 0.16 mM, by 2 h. Plasma Na+ concentration decreased and plasma protein increased for as long as 2 h after injection. Although red blood cells were freely permeable to glycerol, there was no evidence for glycerol metabolism in these cells. Glycerol levels in liver paralleled those in plasma. Glycerol injection increased liver glucose concentration 23% and doubled hepatic glycerol‐1‐phosphate levels. Liver ATP levels were reduced 24% after glycerol injection. Brain water concentration was significantly reduced from 7.5 min to 30 min after glycerol injection; brain Na+ and K+ levels were unchanged. There was no evidence for glycerol entry into brain (the amount detected in brain tissue could be explained by the glycerol content in the blood of the brain). While plasma glucose increased 33%, brain glucose increased 87%. Concomitantly there were statistically significant increases in fructose‐1,6‐diphosphate, lactate, α‐ketoglutarate, and malate levels. The disproportionately high brain glucose value suggests increased transport of glucose from the blood to the brain. Increases in fructose‐1,6‐diphosphate, lactate, α‐ketoglutarate, and malate are compatible with an increased metabolic flux in the glycolytic pathway and Krebs citric acid cycle. As has been previously shown for urea and/or mannitol, these changes may result from the effects of the hyperosmolar glycerol solution on the blood‐brain barrier and on cerebral glucose utilization. The sustained lowering of plasma Na+ concentration after a single “therapeutic” glycerol injection suggests a need for monitoring plasma Na+ levels in the clinical situation. Possible lowering of hepatic ATP levels by the use of glycerol in humans is another concern.

Comparison of the effects of hypertonic glycerol and urea on brain edema, energy metabolism and blood flow following cerebral microembolism in the rat. Deleterious effect of glycerol treatment.

“…43 However, the entry of glycerol into brain may be enhanced in case of an alteration of the BBB. Present results show that the main metabolic effect of glycerol in embolized rats consisted in important increase in brain lactate level.…”

“…Present results show that the main metabolic effect of glycerol in embolized rats consisted in important increase in brain lactate level. Thurston et al 43 found that injection of glycerol in mice (2 g/kg) increased the brain levels of glucose, lactate, glycolytic and citric acid cycle intermediates, suggesting that glycerol may have increased the metabolic rate for glucose. The enhanced brain glucose concentration observed after glycerol may be the result of de novo glucose synthesis from glycerol.…”

A Developmental Study of Glycerol Oxidation by Rat Brain

“…Their findings are in agreement with earlier studies which showed that there were substantial levels of glycerol kinase in rat brain and that the enzyme had a sufficiently low Kin (2.0-70 /xM) for glycerol to be a major energy substrate provided suffi cient glycerol were present [Tildon et al, 1976;Jenkins and Hajra, 1976], Taken to gether these studies support the concept that glycerol could be readily utilized as a reserve or alternative fuel for brain energy when in tracellular conditions are unfavorable for the utilization of glucose. However, the low levels of free glycerol found in whole brain (<1 /¿M) [Thurston et al, 1981] would seen to argue against the importance of glycerol as an energy substrate.…”

Glycerol oxidation in discrete areas of rat brain from young, adolescent, and adult rats

“…Although little is known about the mechanism of glycerol uptake in the brain (Sloviter et al, 1966;Waterhouse and Coxon, 1970;Allweiss et al, 1972;Goodner et al, 1973;Thurston et al, 1981), there is considerable evidence that glycerol does not readily pass the bloodbrain barrier (Sokoloff, 1960;Waterhouse and Coxon, 1970;Allweiss et al, 1972;Rapoport et al, 1972;Thurston et al, 1981). It is not known whether differential availability of glycerol is observed in different regions of rat brain, although there is some data in the literature suggesting that glycerol injected into the ventricles does not readily penetrate all brain regions (Waterhouse and Coxon, 1970).…”