Fordham University Masthead Logo DigitalResearch@Fordham Chemistry Faculty Publications Chemistry 1999 Circulation and energy metabolism in the brain / Donald D. Clarke and Louis Sokoloff Donald Dudley Clarke PhD Fordham University, [email protected] Louis Sokoloff Follow this and additional works at: https://fordham.bepress.com/chem_facultypubs Part of the Biochemistry Commons Recommended Citation Clarke, Donald Dudley PhD and Sokoloff, Louis, "Circulation and energy metabolism in the brain / Donald D. Clarke and Louis Sokoloff" (1999). Chemistry Faculty Publications. 81. https://fordham.bepress.com/chem_facultypubs/81 This Article is brought to you for free and open access by the Chemistry at DigitalResearch@Fordham. It has been accepted for inclusion in Chemistry Faculty Publications by an authorized administrator of DigitalResearch@Fordham. For more information, please contact [email protected]. F C H A P T E R Circulation and Ene,rgy Metabolism of the Brain Donald D. Clarke and Louis Sokoloff INTERMEDIARY METABOLISM 638 are correlated with blood and cerebrospinal ATP production in brain is highly regulated 638 fluid chemical changes 647 Glycogen is a dynamic but limited energy store in Brain samples are removed for biochemical brain 639 analyses 648 Brain glycolysis is regulated mainly by hexokinase Radioisotope incorporation can identify and and phosphof ructokinase 641 measure routes of metabolism 648 The pyruvate dehydrogenase complex plays a key Oxygen utilization in the cortex is measured by role in regulating oxidation 644 polarographic techniques 648 Energy output and oxygen consumption are Arteriovenous differences identify substances associated with high rates of enzyme activity in consumed or produced by brain 648 t he Krebs cycle 644 Combining cerebral blood flow and arteriovenous The pentose shunt, also termed the hexose differences permits measurement of rates of monophosphate pathway, is active in brain 645 consumption or production of substances by Glutamate in brain is compartmented into brain 649 separate pools 645 REGULATION OF CEREBRAL METABOLIC DIFFERENCES BETWEEN IN VITRO AND IN RATE 6SO VIVO BRAIN METABOLISM 646 The brain consumes about one-fifth of total body In contrast to cells of other tissues. individual oxygen utilization 650 nerve cel ls do not function autonomously 647 The main energy-demanding functions of the The blood-brain ba rrier selectively limits the rates brain are those of ion flux related to excitation of transfer of soluble substances between and conduction 651 blood and brain 647 Continuous cerebral circulation is absolutely required to provide sufficient oxygen 651 CEREBRAL ENERGY METABOLISM Local rates of cerebral blood flow and metabolism IN VIVO 647 can be measured by autoradiography and are Behavioral and central nervous system physiology coupled to local brain function 652 Basic Neurochemistry: Mo lecular, Cellular and Medical Aspects, 6th Ed., ed ited by G. J. Siegel et a!. Published by Lippincott-Raven Publishers, Philadelphia, 1999. Correspondence to Donald D. Clarke, Chemistry Department, Fordham University, Bronx, New York 10458. 638 Part Five Metabolism SUBSTRATES OF CEREBRAL CEREBRAL METABOLIC RATE IN VARIOUS METABOLISM 656 PHYSIOLOGICAL STATES 662 Normally, the substrates are glucose and Cerebral metabolic rate is determined locally by oxygen and the products are carbon dioxide functional activity in discrete regions 662 and water 656 Metabolic rate and nerve conduction are related In brain, glucose utilization is obligatory 657 directly 662 The brain utilizes ketones in states of ketosis 660 It is difficult to define metabolic equivalents of consciousness, mental work and sleep 664 AGE AND DEVELOPMENT INFLUENCE CEREBRAL ENERGY METABOLISM 661 CEREBRAL ENERGY METABOLISM IN Metabolic rate increases during early PATHOLOGICAL STATES 665 development 661 Psychiatric disorders may produce effects related Metabolic rate declines and plateaus after to anxiety 665 maturation 661 Coma and systemic metabolic diseases depress Tissue pathology, but not aging, produces brain metabolism 666 secondary changes in metabolic rate 661 Measurement of local cerebral energy metabolism in humans 667 The biochemical pathways ofenergy metabolism in phosphate bonds (-P) generated during aerobic the brain are in most respects like those of other tis­ metabolism of a single glucose molecule. About sues, but special conditions peculiar to the central !So/o of brain glucose is converted to lactate and nervous system in vivo limit full expression of its does not enter the Krebs cycle, also termed the bioclhemical potentialities. In no tissue are the dis­ citric acid cycle. However, this might be crepancies between in vivo and in vitro properties matched by a corresponding uptake of ketone greater or the extrapolations from in vitro data to bodies. The total net gain of-Pis 33 equivalents conclusions about in vivo metabolic functions more per mole of glucose utilized. The steady-state hazardous. Valid identification of normally used concentration of ATP is high and represents the substrates and products of cerebral energy sum of very rapid synthesis and utilization. On metabolism, as well as reliable estimations of their average, half of the terminal phosphate groups rates of utilization and production, can be obtained turn over in about 3 sec; this is probably much only in the intact animal; in vitro studies identify faster in certain regions [2]. The level of-Pis pathways ofintermediary metabolism, mechanisms kept constant by regulation of ADP phosphoryl­ and potential rather than actual performance. ation in relation to ATP hydrolysis. The active Although the brain is said to be unique adenylyl kinase reaction, which forms equivalent among tissues in its high rate of oxidative amounts of ATP and AMP from ADP, prevents metabolism, the overall cerebral metabolic rate any great accumulation of ADP. Only a small for 0 2 (CMR02) is of the same order as the un­ amount of AMP is present under steady-state stressed heart and renal cortex [I). Regional conditions; thus, a relatively small decrease in fluxes in the brain may greatly exceed CMR02, ATP may lead to a relatively large increase in however, and these are closely coupled to AMP, which is a positive modulator of many re­ changes in metabolic demand. actions that lead to increased ATP synthesis. Such an amplification factor provides a sensitive control for maintenance of ATP levels [3). Be­ INTERMEDIARY METABOLISM tween 37 and 42°C, the brain metabolic rate in­ creases about So/o per degree. The concentration of creatine phosphate ATP production in brain is highly regulated (CRP) in brain is even higher than that of ATP, and creatine phosphokinase (CPK) is extremely Oxidative steps of carbohydrate metabolism active. The CRP level is exquisitely sensitive to normally contribute 36 of the 38 high-energy changes in oxygenation, providing - P for ADP Chapter 31 Brain Circulation and Metabolism 639 , phosphorylation and, thus, maintaining ATP The enzymes which synthesize and catab­ levels. The CPK system also may function in reg­ olize glycogen in other tissues are found in ulating mitochondrial activity. In neurons with a brain also, but their kinetic and regulatory very heterogeneous mitochondrial distribution, properties do differ [5). Glycogen metabolism the CRP shuttle may play a critical role in energy in brain, unlike in other tissues, is controlled transport [4]. The BB isoenzyme ofCPK is char­ locally. It is isolated from the tumult of sys­ acteristic of, but not confined to, brain. Thus, its temic activity, evidently by the blood-brain presence in body fluids does not necessarily in­ barrier (BBB). Although glucocorticoid hor­ dicate disruption of neural tissue. mones that penetrate the BBB increase glyco­ gen turnover, circulating protein hormones Glycogen is a dynamic but limited and biogenic amines have no effect. Beyond the energy store in brain BBB, cells are sensitive to local amine concen­ trations; drugs that cross the BBB and modify Although present in relatively low concentration local amine concentrations or membrane re­ in brain (3.3 mmoVkg brain in rat), glycogen is a ceptors thus cause metabolic changes (see unique energy reserve that requires no energy Chap. 32). (ATP) for initiation of its metabolism. As with Separate systems for the synthesis and glucose, glycogen levels in brain appear to vary degradation of glycogen provide a greater degree with plasma glucose concentrations. Biopsies of control than if glycogen were degraded by have shown that human brain contains much more glycogen than rodent brain, but the effects simply reversing its synthesis (Fig. 31-1). The of anesthesia and pathological changes in the amount of glucose-6-phosphate ( G6P), the ini­ biopsied tissue may have contributed. Glycogen tial synthetic substrate, usually varies inversely granules are seen in electron micrographs of glia with the rate of brain glycolysis because of and neurons ofimmature animals but only in as­ greater facilitation of the phosphofructokinase trocytes of adults. Barbiturates decrease brain step relative to transport and phosphorylation of metabolism and increase the number ofgranules glucose. Thus, a decline in G6P during energy seen, particularly in astrocytes of synaptic re­ need slows glycogen formation. gions; however, biochemical studies show that The glucosyl group of uridine diphospho­ neurons do contain glycogen and that enzymes glucose (UDP-glucose) is transferred to the ter­ for its synthesis and metabolism