Dynamic Changes In Glucose Metabolism Research Articles

PET-MRI Applications and Future Prospects in Psychiatry.

This article reviews the synergistic application of positron emission tomography-magnetic resonance imaging (PET-MRI) in neuroscience with relevance for psychiatry, particularly examining neurotransmission, epigenetics, and dynamic imaging methodologies. We begin by discussing the complementary insights that PET and MRI modalities provide into neuroreceptor systems, with a focus on dopamine, opioids, and serotonin receptors, and their implications for understanding and treating psychiatric disorders. We further highlight recent PET-MRI studies using a radioligand that enables the quantification of epigenetic enzymes, specifically histone deacetylases, in the brain in vivo. Imaging epigenetics is used to exemplify the impact the quantification of novel molecular targets may have, including new treatment approaches for psychiatric disorders. Finally, we discuss innovative designs involving functional PET using [18F]FDG (fPET-FDG), which provides detailed information regarding dynamic changes in glucose metabolism. Concurrent acquisitions of fPET-FDG and functional MRI provide a time-resolved approach to studying brain function, yielding simultaneous metabolic and hemodynamic information and thereby opening new avenues for psychiatric research. Collectively, the review underscores the potential of a multimodal PET-MRI approach to advance our understanding of brain structure and function in health and disease, which could improve clinical care based on objective neurobiological features and treatment response monitoring. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.

Whole Blood-based Transcriptional Risk Score for Nonobese Type 2 Diabetes Predicts Dynamic Changes in Glucose Metabolism.

The performance of peripheral blood transcriptional markers in evaluating risk of type 2 diabetes (T2D) with normal body mass index (BMI) is unknown. We developed a whole blood-based transcriptional risk score (wb-TRS) for nonobese T2D and assessed its contributions on disease risk and dynamic changes in glucose metabolism. Using a community-based cohort with blood transcriptome data, we developed the wb-TRS in 1105 participants aged ≥40 years who maintained a normal BMI for up to 10 years, and we validated the wb-TRS in an external dataset. Potential biological significance was explored. The wb-TRS included 144 gene transcripts. Compared to the lowest tertile, wb-TRS in tertile 3 was associated with 8.91-fold (95% CI, 3.53-22.5) higher risk and each 1-unit increment was associated with 2.63-fold (95% CI, 1.87-3.68) higher risk of nonobese T2D. Furthermore, baseline wb-TRS significantly associated with dynamic changes in average, daytime, nighttime, and 24-hour glucose, HbA1c values, and area under the curve of glucose measured by continuous glucose monitoring over 6 months of intervention. The wb-TRS improved the prediction performance for nonobese T2D, combined with fasting glucose, triglycerides, and demographic and anthropometric parameters. Multi-contrast gene set enrichment (Mitch) analysis implicated oxidative phosphorylation, mTORC1 signaling, and cholesterol metabolism involved in nonobese T2D pathogenesis. A whole blood-based nonobese T2D-associated transcriptional risk score was validated to predict dynamic changes in glucose metabolism. These findings suggested several biological pathways involved in the pathogenesis of nonobese T2D.

Widespread fMRI BOLD Signal Overactivations during Cognitive Control in Older Adults Are Not Matched by Corresponding Increases in fPET Glucose Metabolism.

A common observation in fMRI studies using the BOLD signal is that older adults, compared with young adults, show overactivations, particularly during less demanding tasks. The neuronal underpinnings of such overactivations are not known, but a dominant view is that they are compensatory in nature and involve recruitment of additional neural resources. We scanned 23 young (20-37 years) and 34 older (65-86 years) healthy human adults of both sexes with hybrid positron emission tomography/MRI. The radioligand [18F]fluoro-deoxyglucose was used to assess dynamic changes in glucose metabolism as a marker of task-dependent synaptic activity, along with simultaneous fMRI BOLD imaging. Participants performed two verbal working memory (WM) tasks: one involving maintenance (easy) and one requiring manipulation (difficult) of information in WM. Converging activations to the WM tasks versus rest were observed for both imaging modalities and age groups in attentional, control, and sensorimotor networks. Upregulation of activity to WM-demand, comparing the more difficult to the easier task, also converged between both modalities and age groups. For regions in which older adults showed task-dependent BOLD overactivations compared with the young adults, no corresponding increases in glucose metabolism were found. To conclude, findings from the current study show that task-induced changes in the BOLD signal and synaptic activity as measured by glucose metabolism generally converge, but overactivations observed with fMRI in older adults are not coupled with increased synaptic activity, which suggests that these overactivations are not neuronal in origin.SIGNIFICANCE STATEMENT Findings of increased fMRI activations in older compared with younger adults have been suggested to reflect increased use of neuronal resources to cope with reduced brain function. The physiological underpinnings of such compensatory processes are poorly understood, however, and rest on the assumption that vascular signals accurately reflect neuronal activity. Comparing fMRI and simultaneously acquired functional positron emission tomography as an alternative index of synaptic activity, we show that age-related overactivations do not appear to be neuronal in origin. This result is important because mechanisms underlying compensatory processes in aging are potential targets for interventions aiming to prevent age-related cognitive decline.

The Influence of Met Receptor Level on HGF-Induced Glycolytic Reprogramming in Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is known to overexpress a variety of receptor tyrosine kinases, such as the HGF receptor Met. Like other malignancies, HNSCC involves a mutual interaction between the tumor cells and surrounding tissues and cells. We hypothesized that activation of HGF/Met signaling in HNSCC influences glucose metabolism and therefore substantially changes the tumor microenvironment. To determine the effect of HGF, we submitted three established HNSCC cell lines to mRNA sequencing. Dynamic changes in glucose metabolism were measured in real time by an extracellular flux analyzer. As expected, the cell lines exhibited different levels of Met and responded differently to HGF stimulation. As confirmed by mRNA sequencing, the level of Met expression was associated with the number of upregulated HGF-dependent genes. Overall, Met stimulation by HGF leads to increased glycolysis, presumably mediated by higher expression of three key enzymes of glycolysis. These effects appear to be stronger in Methigh-expressing HNSCC cells. Collectively, our data support the hypothesized role of HGF/Met signaling in metabolic reprogramming of HNSCC.

.BETA.3-adrenoceptor-mediated increased circulating transaminase levels in mice treated with its agonist BRL 37344

Treatment with the selective β(3)-adrenoceptor agonist BRL 37344 increased circulating levels of alanine transaminase (ALT) and aspartate transaminase (AST) in mice without causing hepatocellular injury. To clarify whether this was a β(3)-adrenoceptor-mediated effect, the inhibitory effect of the selective β(3)-adrenoceptor antagonist SR 59230A on the increase in circulating transaminase levels induced by BRL 37344 was examined. A single intraperitoneal dose of BRL 37344 alone initially increased insulin and non-esterified fatty acid (NEFA) dose-proportionally at 0.5 hr post-dose, findings considered attributable to β(3)-adrenoceptor-stimulating effects. Levels of the gluconeogenic precursors pyruvate (PA) and lactate (LA) were increased corresponding to the change in insulin. Thereafter, glucose (GLU) level was decreased at 4 and 8 hr post-dose, suggesting disruption of glucose homeostasis. In association with these changes in glucose metabolism, transaminase levels were increased maximally at 4 hr post-dose. The transaminase changes were not accompanied by increases in circulating levels of other hepatocellular enzymes, including guanine deaminase (GUA), glutamate dehydrogenase (GLDH), and lactate dehydrogenase (LDH), or any morphological hepatocellular injury. Intraperitoneal pre-treatment with SR 59230A partly inhibited the effects of BRL 37344 alone, indicating that the increase in levels of circulating ALT by BRL 37344 was attributable to a β(3)-adrenoceptor-stimulating effect. In conclusion, the β(3)-adrenoceptor agonist BRL 37344 was shown to increase circulating transaminase levels in mice accompanied with dynamic changes in glucose metabolism. These findings suggest the possibility that circulating transaminase levels are increased as pharmacological effects of drugs disrupting glucose metabolism, and that hepatotoxic markers should be selected considering these effects to distinguish between acceptable pharmacology and toxicity.

Magnesium sulfate enhances exercise performance and manipulates dynamic changes in peripheral glucose utilization

The effect of magnesium supplementation on exercise performance remains controversial. In the present study, the effects of magnesium sulfate on exercise performance and blood glucose metabolism were examined. In order to provide a non-invasive measure of continuous exercise, we developed an auto-blood sampling system was coupled to a microdialysis analyzer to detect the dynamic changes in glucose metabolism in conscious and freely moving gerbils subjected to forced swimming. Gerbils were pretreated with saline or magnesium sulfate (90 mg kg(-1), ip) 30 min before exercise. The duration times were significantly increased by 71% in the magnesium sulfate-treated groups (p < 0.01) when compared with those in the control. Another group of gerbils were subjected to blood sampling assay. A catheter was implanted in the jugular vein of each gerbil for collecting blood samples by the computer-aided blood sampler. The basal levels of plasma glucose, lactate, and magnesium were 6,245 +/- 662, 1,067 +/- 309, and 590 +/- 50 microM, respectively, with no significant difference between groups. Plasma glucose, lactate, and magnesium levels increased to 134 and 204%, 369 and 220%, and 155 and 422% of basal levels during swimming in both the control and magnesium sulfate-treated groups, respectively (p < 0.05). Pretreatment with magnesium sulfate elevated glucose and magnesium levels to 175 and 302% of the basal levels (p < 0.05), respectively, whereas pretreatment with magnesium sulfate reduced the lactate levels 150% of the basal level (p < 0.05) during swimming. Furthermore, the magnesium levels increased to about 152-422% of basal levels during forced swimming and the recovery period (p < 0.05). The present study demonstrates that magnesium sulfate improved the duration time of forced swimming exercise. In addition, magnesium raised glucose levels and attenuated lactate levels during forced swimming. These results indicate that positive effects of magnesium supplementation may contribute to the enhancement of exercise performance in athletes.

Biphasic mechanism of the toxicity induced by 1-methyl-4-phenylpyridinium ion (MPP +) as revealed by dynamic changes in glucose metabolism in rat brain slices

1-Methyl-4-phenylpyridinium (MPP +) is a well-known neurotoxin which causes a clinical syndrome similar to Parkinson's disease. The classical mechanism of MPP + toxicity involves its entry into cells through the dopamine transporter (DAT) to inhibit aerobic glucose metabolism, while recent studies suggest that an oxidative mechanism may contribute to the toxicity of MPP +. However, it has not been adequately determined what role these two mechanisms play in the development of neurotoxicity after MPP + loading in the brain. To clarify this issue, MPP + was added directly to fresh rat brain slices and the dynamic changes in the cerebral glucose metabolic rate (CMRglc) produced by MPP + were serially and two-dimensionally measured using the dynamic positron autoradiography technique with [ 18F]2-fluoro-2-deoxy- d-glucose as a tracer. MPP + dose-dependently increased CMRglc in each of the brain regions examined, reflecting enhanced glycolysis compensating for the decrease in aerobic metabolism. Treatment with DAT inhibitor GBR 12909 significantly attenuated the enhanced glycolysis induced by 10 μM MPP + in the striatum. Treatment with free radical spin trap α-phenyl- N-tert-butylnitrone (PBN) significantly attenuated the enhancement of glycolysis induced by 100 μM MPP + in all brain regions. These results suggest that the mechanism of the toxicity of MPP + is biphasic and consists of a DAT-mediated mechanism selective for dopaminergic regions at a lower concentration of MPP + (10 μM), and an oxidative mechanism that occurs at a higher concentration of MPP + (100 μM) and is not restricted to dopaminergic regions.

Different mechanisms of hypoxic injury on white matter and gray matter as revealed by dynamic changes in glucose metabolism in rats

Fresh rat brain slices were incubated with [ 18F]2-fluoro-2-deoxy- d-glucose ([ 18F]FDG) in oxygenated Krebs–Ringer solution at 36 °C, and the fractional rate constant (= k 3*) of [ 18F]FDG proportional to the cerebral glucose metabolic rate in white matter and gray matter was investigated with positron autoradiography. In both white matter and gray matter, the k 3* value with ≥20 min hypoxia was markedly lower than the unloaded control value, indicating irreversible hypoxic injury. Next, the neuroprotective effect against hypoxia induced by the addition of an N-methyl- d-aspartate receptor antagonist or a free radical scavenger was assessed by determining whether a decrease in the k 3* value after hypoxia loading was prevented. In gray matter, both agents exhibited a neuroprotective effect against 20 min hypoxia. In white matter, however, only the free radical scavenger was effective. These results suggest a similarity in the degree of vulnerability to hypoxia between white matter and gray matter as well as a difference in the developmental mechanism of hypoxic injury, i.e. the involvement of both glutamate and free radicals in gray matter, and the more selective involvement of free radicals in white matter.

Hypoxic tolerance induction in rat brain slices following hypoxic preconditioning due to expression of neuroprotective proteins as revealed by dynamic changes in glucose metabolism

We prepared rat brain slices following sublethal hypoxic pretreatment (preconditioning) and untreated (control) rats, and measured the cerebral glucose metabolic rate (CMRglc) by dynamic positron autoradiography with [ 18F]2-fluoro-2-deoxy- d-glucose before and after originally lethal 20-min hypoxic loading. In the regions of interest such as the frontal cortex, the CMRglc before hypoxic loading did not differ between the preconditioning and control groups. The CMRglc after reoxygenation was markedly lower than that before hypoxic loading in the control group but did not significantly differ from the preloading value in the preconditioning group. Thus, hypoxic tolerance induction by preconditioning was demonstrated using the maintenance of CMRglc as a neuronal viability index. In addition, profiling of gene expression using an Atlas Rat Stress Array suggested the involvement of the expression of genes such as stress protein in hypoxic tolerance induction.

Greater Resistance and Lower Contribution of Free Radicals to Hypoxic Neurotoxicity in Immature Rat Brain Compared to Adult Brain as Revealed by Dynamic Changes in Glucose Metabolism

Seven-day-old rat brain slices were incubated at 36°C in oxygenated Krebs-Ringer solution containing [¹⁸F]2-fluoro-2-deoxy-D-glucose ([¹⁸F]FDG), and serial two-dimensional time-resolved images of [¹⁸F]FDG uptake by the slices were obtained. The Gjedde-Patlak graphical method was applied to the image data, and the duration limit of hypoxia loading that allowed recovery of the fractional rate constant (k3*) of [¹⁸F]FDG (proportional to the cerebral glucose metabolic rate) after hypoxia loading to the unloaded control level was 50 min, and MK-801 as an N-methyl-D-aspartate antagonist had neuroprotective effects, but PBN as a free radical scavenger was ineffective. In our previous study in adult (7-week-old) rat brains [Murata et al., Exp Neurol 2000, 164:269–279], the limit of the hypoxia loading time was 20 min, and both MK-801 and PBN were effective. In the immature rat brains, the ratio of aerobic glucose metabolism to the total glucose metabolism was low compared with the adult rat brains, suggesting only a slight involvement of free radicals in hypoxic neurotoxicity. These data suggest that the higher resistance of immature brains to hypoxia compared to that of adult brains is attributable to a lower involvement of free radicals due to a lower aerobic glucose metabolic rate.

Hypoxic tolerance induction in rat brain slices following 3-nitropropionic acid pretreatment as revealed by dynamic changes in glucose metabolism

Pretreatment with 3-nitropropionic acid (3-NPA) has been shown to induce tolerance to ischemic/hypoxic brain damage. However, regional differences in tolerance induction by 3-NPA and the degree to which impaired glucose metabolism due to 3-NPA pretreatment itself is directly involved remain unknown. To evaluate these issues using dynamic positron autoradiography with [ 18F]2-fluoro-2-deoxy- d-glucose, the cerebral glucose metabolic rate (CMRglc) was serially measured before and after hypoxia-loading in rat brain slices pretreated with 3-NPA. CMRglc before hypoxia did not significantly differ between the 3-NPA pretreatment group and control group. The 3-NPA-associated recovery of CMRglc after reoxygenation was observed in the frontal cortex, hippocampus, and cerebellum, but not in the striatum and thalamus. Thus, we demonstrated the induction of region-specific hypoxic tolerance after 3-NPA pretreatment using CMRglc maintenance as an index of neuronal viability, and it is unlikely that this induction is associated with the persistence of impaired glucose metabolism due to 3-NPA pretreatment.

Dynamic changes in glucose metabolism accompanying the expression of the neural phenotype after differentiation in PC12 cells

To assess what properties of glucose metabolism are most closely related to expression of the neural phenotype, some parameters of glucose metabolism in PC12 cells before (tumor-type) and after differentiation (neuron-type) were investigated. Neuron-type cells exhibited a 2.7-fold higher level of [ 3H]DG retention than tumor-type cells, accompanied by a higher glucose transport rate and higher levels of hexokinase activity. [ 14C]CO 2 production from [U- 14C]glucose in neuron-type was also more than four-times greater than that in tumor-type cells. The levels of [ 14C]carbon in macromolecules from [ 14C]glucose in neuron-type cells were also much higher (10.6-fold) than those in tumor-type cells, and the levels of incorporation of [ 14C]carbon were almost as high as those of [ 14C]CO 2. From the metabolite analysis, amino acids appeared to be the major compounds converted from glucose. On the other hand, the uptakes of [ 35S]methionine–[ 35S]cysteine and [ 3H]uridine in neuron-type cells were lower than those in tumor-type cells. Following depolarization with 50 mM potassium, [ 14C]CO 2 production increased, but the retention of [ 14C]carbon was not changed in neuron-type cells. The largest change accompanied by acquisition of the neural phenotype was carbon incorporation into the macromolecules derived from glucose. This property may be important for the expression of the neural phenotype as well as the higher levels of both glucose uptake and oxygen consumption.

Posthypoxic Reoxygenation-Induced Neurotoxicity Prevented by Free Radical Scavenger and NMDA/non-NMDA Antagonist in Tandem as Revealed by Dynamic Changes in Glucose Metabolism with Positron Autoradiography

Using a positron autoradiography technique, dynamic changes in the cerebral glucose metabolic rate (CMRglc) induced by hypoxia/reoxygenation were investigated in living brain slices. After incubating fresh rat brain slices (300 μm thick) with [18F]2-fluoro-2-deoxy-d-glucose ([18F]FDG) in oxygenated Krebs–Ringer solution at 36°C, serial two-dimensional time-resolved images of [18F]FDG uptake in the slices were obtained on imaging plates. As compared to the unloaded control values, with hypoxia-loading [18F]FDG uptake increased markedly, suggesting enhanced glycolysis. The net influx constant (K) of [18F]FDG at pre-hypoxia-loading and after reoxygenation with loading hypoxia for various periods of time was quantitatively evaluated by applying the Patlak graphical method to the image data. Regardless of the brain region, with hypoxia of ≤10-min duration, the K value returned to the preloading level, whereas with hypoxia of ≥20 min duration only partial or no recovery was seen, indicating irreversible neuronal damage. The 30-min administration of either N-methyl-d-aspartate (NMDA)/non-NMDA antagonist or a free radical scavenger at the same time as reoxygenation after 20 min hypoxia showed a neuroprotective effect inhibiting the decrease in the post-hypoxia-loading K value. In contrast, no such neuroprotective effect was evident with administration of either of these agents only during hypoxia loading, possibly indicating that immediately after reoxygenation neuronal damage was induced mediated by excitatory amino acids and free radicals in tandem. These results demonstrate that serial quantitative evaluation of CMRglc using this technique may be of use in investigating the brain tissue injury associated with hypoxia/reoxygenation as well as clarifying the underlying mechanisms and protective effect of various drugs against such injury.

Neurotoxicity after hypoxia/during ischemia due to glutamate with/without free radicals as revealed by dynamic changes in glucose metabolism

Fresh rat brain slices were incubated with [ 18F]2-fluoro-2-deoxy- d-glucose ([ 18F]FDG) in oxygenated Krebs–Ringer solution at 36°C, and serial two-dimensional time-resolved images of [ 18F]FDG uptake in the slices were obtained on imaging plates. The fractional rate constant of [ 18F]FDG (proportional to the cerebral glucose metabolic rate) from pre-loading of ischemia (O 2 and glucose deprivation)/hypoxia (O 2 deprivation) to the reperfused/reoxygenated post-loading phase was quantitatively evaluated by applying the Gjedde–Patlak graphical method to the image data. Against ischemia an N-methyl- d-aspartate antagonist and hypothermia, but not a free radical scavenger, showed a protective effect when administered during ischemia, whereas no such effect was achieved with any of the above agents when administered after reperfusion. Against hypoxia, there was no protective effect with any of the above agents when administered during hypoxia, although an effect was noted with each when administered after reoxygenation. Excitatory amino acids during ischemia loading were found to be the main factor in the neuronal damage associated with ischemia, while in hypoxia, excitatory amino acids working in tandem with free radicals immediately after reoxygenation were implicated.

Hypoxic but not ischemic neurotoxicity of free radicals revealed by dynamic changes in glucose metabolism of fresh rat brain slices on positron autoradiography.

Dynamic changes in the regional cerebral glucose metabolic rate induced by hypoxia/reoxygenation or ischemia/reperfusion were investigated with a positron autoradiography technique. Fresh rat brain slices were incubated with [18F]2-fluoro-2-deoxy-D-glucose ([18F]FDG) in oxygenated Krebs-Ringer solution at 36 degrees C, and serial two-dimensional time-resolved images of [18F]FDG uptake in the slices were obtained. In the case of loading hypoxia (oxygen deprivation)/pseudoischemia (oxygen and glucose deprivation) for various periods of time, the net influx constant (K) of [18F]FDG at preloading and after reoxygenation/pseudoreperfusion (post-loading) was quantitatively evaluated by applying the Patlak graphical method to the image data. Regardless of the brain region, with hypoxia lasting > or =20 minutes, the postloading K value was decreased compared with the unloaded control, whereas with pseudoischemia of < or =40 minutes, approximately the same level as the unloaded control was maintained. Next, the neuroprotective effect against hypoxia/pseudoischemia loading induced by the addition of a free radical scavenger or an N-methyl-D-aspartate (NMDA) antagonist was assessed by determining whether a decrease in the postloading K value was prevented. Whereas with 20-minute hypoxia, both agents exhibited a neuroprotective effect, in the case of 50-minute pseudoischemia, only the NMDA antagonist did so, with the free radical scavenger being ineffective. These results demonstrate that hypoxia causes irreversible neuronal damage within a shorter period than ischemia, with both free radicals and glutamate suggested to be involved in tandem in the neurotoxicity induced by hypoxia, whereas glutamate alone is involved in ischemic neurotoxicity.

Dynamic changes in glucose metabolism induced by thiamine deficiency and its replenishment as revealed by a positron autoradiography technique using rat living brain slices.

Dynamic changes in the cerebral glucose metabolic rate (CMRglc) before and after thiamine replenishment were investigated in living brain slices obtained from pyrithiamine-treated (PT) and pair-fed control rats by use of a positron autoradiography technique. Fresh rat brain slices (300 microm thick) were incubated with [18F]2-fluoro-2-deoxy-D-glucose ([18F]FDG) in oxygenated Krebs-Ringer solution at 36 degrees C, during which serial two-dimensional images of [18F]FDG uptake in the slices were constructed on the imaging plates. The net influx constant (=K) of [18F]FDG was determined by a Patlak graphical method of the image data. Prior to thiamine pyrophosphate (TPP)-loading, the K value in the neurologically symptomatic PT was higher in all brain regions except the thalamus and mammillary body than the control, suggesting compensatory enhanced glycolysis. The rapid decrease in this heightened net influx constant immediately after TPP-loading was surmised to be due to activation of pyruvate oxidation with lactate as the substrate, with this inhibiting the glycolysis. From > or = 150 min after TPP-loading, the K value continued to show low values in the thalamus and mammillary body, which are regarded as the responsible sites for Korsakoff syndrome, whereas in all other sites recovery to control values was observed. These findings suggest that using this technique the quantitative evaluation of serial local changes in CMRglc from thiamine deficiency to after its replenishment may be useful in elucidating the pathophysiology and prognosis of Wernicke's encephalopathy.

Dynamic changes in glucose metabolism of living rat brain slices induced by hypoxia and neurotoxic chemical-loading revealed by positron autoradiography.

Fresh rat brain slices were incubated with 2-deoxy-2-[18F]-fluoro-D-glucose ([18F]FDG) in oxygenated Krebs-Ringer solution at 36 degrees C, and serial two-dimensional time-resolved images of [18F]FDG uptake were obtained from these specimens on imaging plates. The fractional rate constant (= k3*) of [18F]FDG proportional to the cerebral glucose metabolic rate (CMRglc) was evaluated by applying the Gjedde-Patlak graphical method to the image data. With hypoxia loading (oxygen deprivation) or glucose metabolism inhibitors acting on oxidative phosphorylation, the k3* value increased dramatically suggesting enhanced glycolysis. After relieving hypoxia < or = 10-min, the k3* value returned to the pre-loading level. In contrast, with > or = 20-min hypoxia only partial or no recovery was observed, indicating that irreversible neuronal damage had been induced. However, after loading with tetrodotoxin (TTX), the k3* value also decreased but returned to the pre-loading level even after 70-min TTX-loading, reflecting a transient inhibition of neuronal activity. This technique provides a new means of quantifying dynamic changes in the regional CMRglc in living brain slices in response to various interventions such as hypoxia and neurotoxic chemical-loading as well as determining the viability and prognosis of brain tissues.

Dynamic changes in glucose metabolism by lactate loading as revealed by a positron autoradiography technique using rat living brain slices

To demonstrate the preference of lactate over glucose as an energy substrate in normal brain tissue under normoxic condition, the dynamic changes in glucose uptake by lactate loading were investigated in living rat brain slices using a positron autoradiography technique. Fresh rat brain slices were incubated with [ 18F]2-fluoro-2-deoxy- d-glucose ([ 18F]FDG) in oxygenated Krebs–Ringer solution containing 10 mM glucose at 36°C. During incubation, serial two-dimensional imaging of [ 18F]FDG uptake in the slices was constructed on the imaging plates. Lactate loading (20 mM) reversibly suppressed the [ 18F]FDG accumulation up to 80 min. Compared with the pre-loading and the unloaded control values, [ 18F]FDG uptake was suppressed to 25–45% in cerebral regions and 6–7% in cerebellum. The lactate concentration in the surrounding medium decreased after lactate loading. Hence brain tissue preferentially uses lactate over glucose under normoxic and euglycemic condition.