Elsevier

Brain Research

Volume 815, Issue 2, 9 January 1999, Pages 243-249
Brain Research

Research report
The effects of pharmacological doses of 2-deoxyglucose on cerebral blood flow in healthy volunteers

https://doi.org/10.1016/S0006-8993(98)01137-8Get rights and content

Abstract

The effects of glucose deprivation on cerebral blood flow (CBF) have been extensively investigated during insulin-induced hypoglycemia in laboratory animals. Pharmacological doses of glucose analog, 2-deoxyglucose (2DG), is an alternative glucoprivic agent that in contrast to insulin, directly inhibits glycolysis and glucose utilization. Both glucoprivic conditions markedly increase CBF in laboratory animals. How 2DG affects CBF in humans is still undetermined. In the present study we have employed H215O positron emission tomography (PET) to examine the effects of pharmacological doses of 2DG (40 mg/kg) on regional and global cerebral blood flow in 10 brain areas in 13 healthy volunteers. 2DG administration significantly raised regional CBF (rCBF) in the cingulate gyrus, sensorimotor cortex, superior temporal cortex, occipital cortex, basal ganglia, limbic system and hypothalamus. 2DG produced a trend towards elevated CBF in whole brain and frontal cortex, while no changes were observed in the corpus callosum and thalamus. In addition, 2DG significantly decreased body temperature and mean arterial pressure (MAP). Maximal percent changes in hypothalamic rCBF were significantly correlated with maximal changes in body temperature but not with MAP. These results indicate that cerebral glucoprivation produced by pharmacological doses of 2DG is accompanied by widespread activation of cortical and subcortical blood flow and that the blood flow changes in the hypothalamus may be related to 2DG-induced hypothermia.

Introduction

Cerebral glucose deprivation provides a useful experimental paradigm for the investigation of cerebral blood flow (CBF) in both preclinical and clinical studies. Glucose is the primary energy source for the central nervous system, and glucose deprivation, therefore, influences neuronal functioning throughout the brain. Inhibition of cerebral glucose utilization due to moderate or severe hypoglycemia 8, 18 or blockade of glucose metabolism with pharmacological doses of 2-deoxyglucose (2DG) 6, 18 results in significant increases in CBF in rodents. In humans, the CBF response to insulin-induced hypoglycemia is less robust and consistent, with both increases 11, 23, 31, 37 and little or no change 3, 12, 24, 32 reported. The reasons for these conflicting results are unclear and may be related to degree of hypoglycemia, alterations in cerebral metabolic rate or to the methods employed in the determination of CBF.

Previous data on the cerebral effects of acute glucoprivation in man pertain only to insulin-induced hypoglycemia. Administration of pharmacological doses of 2DG is an alternative paradigm for the assessment of glucoprivic effects on CBF. 2DG is a glucose analog that is transported across the blood-brain barrier into brain tissue where it is phosphorylated to 2-deoxyglucose-6-phosphate (2DG6P) but is not metabolized further down the glycolytic pathway. The 2DG6P then accumulates to levels that inhibit glucose-6-phosphate isomerase and thus blocks glycolysis and oxidative metabolism of glucose [20]. Following the infusion of loading doses of 2DG, blood glucose levels are elevated, presumably mainly due to sympathetic activation, glycogenolysis, reduced body metabolism of glucose, and gluconeogenesis [2]. Thus in contrast to insulin-induced hypoglycemia, 2DG directly inhibits glycolytic flux in the brain while simultaneously producing hyperglycemia [28].

We have previously investigated the effects of pharmacological doses of 2DG on blood flow in 29 brain regions in the conscious unrestrained adult rat and found increases in most regions. The largest increases were observed in the frontal, superior temporal and sensorimotor cortices, cingulate gyrus, basal ganglia, thalamus, limbic regions and the genu of the corpus callosum [6]. Because of the lack of data regarding the effects of 2DG on CBF in humans and its relatively unique mechanism of glucoprivation, we have investigated the influence of this agent on CBF in healthy human subjects by means of positron emission tomography (PET). Because of our previous study in rats 6, 27, we anticipated that 2DG-induced glucoprivation would also increase rCBF in humans and used a region-of-interest (ROI) approach to describe which of the brain areas would be particularly affected. We also examined the 2DG effects on physiologic (temperature, blood pressure, heart rate) and behavioral (self rating of hunger, drowsiness, tension) measures. Finally, as body temperature 16, 33 and blood pressure [40] may be regulated by the hypothalamus, the relationship of 2DG-induced changes in these physiologic variables to hypothalamic rCBF were examined.

Section snippets

Subjects

Thirteen healthy subjects (mean age±S.D.: 31.8±6.2 years; 11 males, 2 females) were recruited through the volunteer pool of the National Institutes of Health (NIH) and participated in the study after giving written informed consent to a protocol approved by an Institutional Review Board. The subjects were in good physical health, as evidenced by physical exam, SMAC, thyroid function test, CBC, urinalysis, HIV antibody test, toxicology screen and ECG. The subjects had no past or current

2DG-induced changes in CBF

2DG administration increased rCBF in the most of the areas that were examined, (Table 1). The increases were statistically significant in the cingulate gyrus (p=0.04), sensorimotor cortex (p=0.04), superior temporal cortex (p=0.03), occipital cortex (p=0.02), basal ganglia (p=0.03), limbic system (p=0.04) and hypothalamus (p<0.01). In the whole brain (p=0.07) and the frontal cortex (p=0.08), 2DG produced marginal effects while no significant effects were observed in the corpus callosum (p=0.58)

Discussion

This is to our knowledge the first report on the influence of 2DG-induced glucoprivation on CBF in human subjects. Bolus administration of pharmacological doses of 2DG (40 mg/kg) resulted in a robust activation of rCBF in cortical and subcortical areas including the cingulate gyrus, sensorimotor cortex, superior temporal cortex, occipital cortex, basal ganglia, limbic system and hypothalamus (mean percent change from baseline 20.5–42). The largest increase in rCBF increase occurred in the

Acknowledgements

The authors gratefully acknowledge contributions of Christopher Bir, Ian Kronish, Thomas Herman, Sara Krause and the nursing staff of 4 East Clinical Care Unit, National Institutes of Health. This study was supported by a grant from the National Association for Research in Schizophrenia and Affective Disorders (NARSAD).

References (40)

  • R.C. Coghill et al.

    Global cerebral blood flow decreases during pain

    J. Cereb. Blood Flow. Metab.

    (1998)
  • M.E. Daube-Witherspoon et al.

    Factors affecting dispersion correction for continuous blood withdrawal and counting systems

    J. Nucl. Med.

    (1992)
  • P. Della Porta et al.

    Cerebral blood flow and metabolism in therapeutic insulin coma

    Metabolism

    (1964)
  • S. Eisenberg et al.

    The cerebral metabolic effects of acutely induced hypoglycemia in human subjects

    Metabolism

    (1962)
  • I. Elman et al.

    Effect of acute metabolic stress on pituitary-adrenal axis activation in patients with schizophrenia

    Am. J. Psychiatry

    (1998)
  • D.S. Goldstein et al.

    Plasma levels of catecholamines and corticotrophin during acute glucopenia induced by 2-deoxy-d-glucose in normal man

    Clin. Auton. Res.

    (1992)
  • J.D. Hardy

    Posterior hypothalamus and the regulation of body temperature

    Fed. Proc.

    (1973)
  • N. Horinaka et al.

    Effects of elevated plasma epinephrine on glucose utilization and blood flow in conscious rat brain

    Am. J. Physiol.

    (1997)
  • N. Horinaka et al.

    Examination of potential mechanisms in the enhancement of cerebral blood flow by hypoglycemia and pharmacological doses of deoxyglucose

    J. Cereb. Blood Flow. Metab.

    (1997)
  • N. Horinaka et al.

    Blockade of cerebral blood flow response to insulin-induced hypoglycemia by caffeine and glibenclamide in conscious rats

    J. Cereb. Blood Flow. Metab.

    (1997)
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