Effect of Ischemia on Quantification of Local Cerebral Glucose Metabolic Rate in Man

Summary:The influence on hippocampal glucose utiliza tion of a transient lO-min forebrain ischemia was quanti fied in male Wi star rats after 2 and 3 weeks as well as after 3 months by application of the [14C]2-deoxyglucose tech nique. Ischemia was induced by occlusion of the carotid arteries and simultaneous lowering of the blood pressure to 40 mm Hg. For identification of the hippocampal ar chitecture, sections were stained for perikarya (cresyl vi olet) and for acetylcholinesterase. The hippocampal re gions clearly showed different responses to the ischemic insult. The necrotic pyramidal cells being almost com pletely removed, significant increases in glucose utiliza tion occurred in most layers of the CAl sector at 2 and 3For over 100 years it has been a well-documented fact that cell populations in the brain do not suc cumb to an ischemic insult uniformly (Sommer, 1880; Bratz, 1899). This concept of selective vulner ability has been addressed in numerous experimen tal studies. Recently, evidence has been presented that accumulation of Ca 2 + on cellular as well as on subcellular levels (Dienel, 1984; Simon et aI., 1984a; Hossmann et aI. , 1985; Sakamoto et aI. , 1986; van Reempts et aI. , 1986; Deshpande et aI., 1987; Dux et aI. , 1987) and excessive excitatory in put due to excitatory amino acids (Benveniste et aI. , 1984; Simon et aI., 1984b; Lodge et aI. , 1986) are interwoven and play a key role in ischemic cell damage. These studies as well as work on postisch emic capillary perfusion (lmdahl and Hossmann, 1986), impaired protein synthesis (Thiel mann et aI., Received November 2, 1989; revised December 12, 1989; ac cepted December 22, 1989. Address correspondence and reprint requests to Dr. T. Beck at Laboratory of Cellular and Molecular Neurobiology, Depart ment of Pathology, Columbia University College of Physicians and Surgeons, 630 W. 168 St., New York, NY 10032, U.S.A.Abbreviations used: NMDA, N-methyl-D-aspartate. 542weeks post ischemia, while widespread reductions pre vailed in all other sectors and the dentate gyrus. At 3 months after the ischemic insult, glucose utilization was reduced in all hippocampal structures including the CAl region. The increases in glucose utilization in the CAl sector are suggested to indicate long-lasting presynaptic hyperexcitation, while the widespread reductions in glu cose utilization demonstrate that neuronal activity is also altered in hippocampal areas that do not show major his tological damage. Key Words: Cerebral ischemia Hippocampus-Local cerebral glucose utilization Long-term recovery.1986), and impaired normalization of pH in the CAl sector (Munekata and Hossmann, 1987) cover a time range that extends up to 7 days post ischemia. The same holds true for the extensive histological work characterizing the temporal profile of isch emic damage in gerbil and rat models of cerebral ischemia (Kirino, 1982; Pulsinelli et aI. , 1982a; Kirino et aI., 1984; Smith et aI., 1984;Schmidt Kastner and Hossmann, 1988), the respective time points ranging from 3 ...

Section: Discussionmentioning

confidence: 99%

Glucose Utilization in Rat Hippocampus after Long-Term Recovery from Ischemia

Beck

Wree

Schleicher

1990

“…The LC was found to be significantly in creased during ischemia, but was unaltered from control during the subsequent recirculation period. However, Hawkins et al (1981) estimated that the LC for fluorodeoxyglucose varied only slightly be tween ischemic and nonischemic regions in stroke patients. It is apparent, therefore, that more de tailed studies are required in order to satisfactorily characterize ischemic and postischemic alterations of the LC.…”

Section: Discussion Lc For the 2dg Modelmentioning

confidence: 99%

“…Hawkins et al (1981) suggested that the rate constants for fluorodeoxyglucose in stroke pa tients differ significantly from those in normal tissue. In the present study, the tissue concentration of unphosphorylated [ 14 C]2DG (C E) was determined directly in each tissue sample taken for metabolite assay and compared with the CE calculated ac cording to the formulation of Sokoloff et al (1977) in order to estimate the possible deviation of rate constants from normal.…”

mentioning

confidence: 99%

Regional Alterations in Glucose Consumption and Metabolite Levels during Postischemic Recovery in Cat Brain

Tanaka

Welsh

Greenberg³

et al. 1985

Summary: Local CMRgl (LCMRgl) and metabolite levels were measured in the same tissue samples fol lowing 4 h of recirculation after 1 h of occlusion of the middle cerebral artery in the caL The rate of glucose utilization was calculated using direct measurement of tissue deoxyglucose-6-phosphate and using a "lumped" constant corrected in each sample for alterations in tissue glucose, Increased LCMRgl (compared with that in sham operated animals) occurred in regions with only minor alterations in levels of lactate and phosphocreatine, By contrast, LCMRgl was markedly depressed in regions Glucose is the principal substrate for energy me tabolism in brain, Measurement of the local CMRgl (LCMRgl) using the radiolabeled glucose analogue [ l4 C]2-deoxyglucose ([ l4 C]2DG) has been a valuable method for evaluating functional activity of brain tissue (Sokoloff, 1981;Greenberg and Reivich, 1983). Among numerous applications of this tech nique, there have been several reports showing a broad spectrum of changes in LCMRgl in animal studies of ischemia, ranging from marked inhibition to pronounced activation (Ginsberg et ai., 1977;Diemer and Siemkowicz, 1980; Welsh et ai., 1980a; Pulsinelli et ai., 1982; Choki et aI., 1983). In addi tion, we recently examined the flow-metabolism couple during the recovery period after cerebral ischemia in the cat (Tanaka et aI., 1985) and found Abbreviations used: 2DO, 2-deoxyglucose; 2DO-6-P, 2-deoxy glucose-6-phosphate; LC, lumped constant; LCMRgl, local CMRgI; MCA, middle cerebral artery; Pc, phosphorylation con stant. 502with major changes in lactate and high-energy phos phates, Interestingly, tissue levels of glucose and un phosphorylated deoxyglucose were abnormally elevated in regions with profound energy failure, These results in dicate an inhibition of glucose utilization in regions dam aged by ischemia, despite the persistent elevation of tissue lactate, Increased glucose metabolism at 4 h post ischemia was detected only in areas with minor anaerobic alteration of metabolite levels, Key Words: Brain glu cose-Deoxyglucose-Energy metabolism-Glucose metabolism-Ischemia-Regional metabolites, that the preservation of a normal flow/metabolism ratio was a critical factor in maintaining tissue via bility.In spite of such important contributions to the study of the metabolic function of brain tissue after ischemia, the [ l4 C]2DG method does not distinguish between aerobic and anaerobic utilization of glu cose and does not provide direct information about the energy state of the tissue. One of the aims of the present study was thus to investigate the rela tionship between the tissue concentration of var ious metabolites (ATP, phosphocreatine, lactate, and glucose) and LCMRgl as determined by the [ 14 C]2DG method during the recirculation period following ischemia. Although measurement of re gional glucose metabolism in human brain has be come feasible utilizing positron emission tomog raphy (Phelps et aI., 1979; Reivich et aI., 1979 Reivich et aI., , 1982, the imaging of regional tissue ...

“…more, the "lumped constant" (LC), a factor cor recting for the differing enzyme affinities of glucose and the metabolic tracer, must be known. These quantities and their variations under normal and pathologic conditions have been determined in sev eral studies (Phelps et aI., 1979;Hawkins et al, 1981;Heiss et al, 1984;Gjedde et al, 1985;Wien hard et aI., 1985) and, in principle, no longer present a problem for the application of the FDG method.…”

mentioning

confidence: 94%

Estimation of Local Cerebral Glucose Utilization by Positron Emission Tomography: Comparison of [¹⁸F]2-Fluoro-2-Deoxy-D-Glucose and [¹⁸F]2-Fluoro-2-Deoxy-D-Mannose in Patients with Focal Brain Lesions

Wienhard¹,

Pawlik²,

Nebeling

et al. 1991

Summary: A comparative PET study of [IBF]2-fluoro-2-deoxy-o-glucose (FDG) and [IBF]2-fluoro-2-deoxy o-mannose (FDM) uptake was performed in 13 patients with focal brain lesions. Differences between FDG and FDM with respect to model rate constants, lumped con stant, and estimated metabolic rate for glucose were de termined on a regional basis. Across whole brain, the transport rate constant Kj was almost unchanged, whereas k:J" describing the transport back from tissue to plasma, was 6% higher, and the phosphorylation rate con stant kj was 9% lower for FDM compared to FDG. This eSF]2-fluoro-2-deoxyglucose (FDG)