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Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.

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Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition.

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Regulation of Cerebral Metabolic Rate

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The brain consumes about one-fifth of total body oxygen utilization

The brain is metabolically one of the most active of all organs in the body. This consumption of O2 provides the energy required for its intense physicochemical activity. The most reliable data on cerebral metabolic rate have been obtained in humans. Cerebral O2 consumption in normal, conscious, young men is approximately 3.5 ml/100 g brain/min (Table 31-1); the rate is similar in young women. The rate of O2 consumption by an entire brain of average weight (1,400 g) is then about 49 ml O2/min. The magnitude of this rate can be appreciated more fully when it is compared with the metabolic rate of the whole body. An average man weighs 70 kg and consumes about 250 ml O2/min in the basal state. Therefore, the brain, which represents only about 2% of total body weight, accounts for 20% of the resting total body O2 consumption. In children, the brain takes up an even larger fraction, as much as 50% in the middle of the first decade of life [15].

Table 31-1. Cerebral Blood Flow and Metabolic Rate in a Normal Young Adult Mana.

Table 31-1

Cerebral Blood Flow and Metabolic Rate in a Normal Young Adult Mana.

O2 is utilized in the brain almost entirely for the oxidation of carbohydrate [16]. The energy equivalent of the total cerebral metabolic rate is, therefore, approximately 20 W, or 0.25 kcal/min. If it is assumed that this energy is utilized mainly for the synthesis of high-energy phosphate bonds, that the efficiency of the energy conservation is approximately 20% and that the free energy of hydrolysis of the terminal phosphate of ATP is approximately 7 kcal/mol, then this energy expenditure can be estimated to support the steady turnover of close to 7 mmol, or approximately 4 × 1021 molecules, of ATP per minute in the entire human brain. The brain normally has no respite from this enormous energy demand. Cerebral O2 consumption continues unabated day and night. Even during sleep there is only a relatively small decrease in cerebral metabolic rate; indeed, it may even be increased in rapid eye movement (REM) sleep (see below).

The main energy-demanding functions of the brain are those of ion flux related to excitation and conduction

The brain does not do mechanical work, like that of cardiac and skeletal muscle, or osmotic work, as the kidney does in concentrating urine. It does not have the complex energy-consuming metabolic functions of the liver nor, despite the synthesis of some hormones and neurotransmitters, is it noted for its biosynthetic activities. Considerable emphasis has been placed on the extent of macromolecular synthesis in the central nervous system, an interest stimulated by the recognition that there are some proteins with short half-lives in brain. However, these represent relatively small numbers of molecules, and in fact, the average protein turnover and the rate of protein synthesis in mature brain are slower than in most other tissues, except perhaps muscle. Clearly, the functions of nervous tissues are mainly excitation and conduction, and these are reflected in the unceasing electrical activity of the brain. The electrical energy ultimately is derived from chemical processes, and it is likely that most of the energy consumption of the brain is used for active transport of ions to sustain and restore the membrane potentials discharged during the processes of excitation and conduction (see Chaps. 5 and 6).

Not all of the O2 consumption of the brain is used for energy metabolism. The brain contains a variety of oxidases and hydroxylases that function in the synthesis and metabolism of a number of neurotransmitters. For example, tyrosine hydroxylase is a mixed-function oxidase that hydroxylates tyrosine to 3,4-dihydroxyphenylalanine (DOPA), and dopamine β-hydroxylase hydroxylates dopamine to form nor-epinephrine. Similarly, tryptophan hydroxylase hydroxylates tryptophan to form 5-hydroxytryptophan in the pathway of serotonin synthesis. The enzymes are oxygenases, which utilize molecular O2 and incorporate it into the hydroxyl group of the hydroxylated products. O2 also is consumed in the metabolism of these monoamine neurotransmitters, which are deaminated oxidatively to their respective aldehydes by monoamine oxidases. All of these enzymes are present in brain, and the reactions catalyzed by them use O2. However, the total turnover rates of these neurotransmitters and the sum total of the maximal velocities of all oxidases involved in their synthesis and degradation can account for only a very small, possibly immeasurable, fraction of the total O2 consumption of brain.

Continuous cerebral circulation is absolutely required to provide sufficient oxygen

Not only does the brain utilize O2 at a very rapid rate, but it is absolutely dependent on uninterrupted oxidative metabolism for maintenance of its functional and structural integrity. There is a large Pasteur effect in brain tissue, but even at its maximal rate anaerobic glycolysis is unable to provide sufficient energy. Since the O2 stored in brain is extremely small compared with its rate of utilization, the brain requires continuous replenishment of its O2 by the circulation. If cerebral blood flow is interrupted completely, consciousness is lost within less than 10 sec, or the amount of time required to consume the O2 contained within the brain and its blood content. Loss of consciousness as a result of anoxemia, caused by anoxia or asphyxia, takes only a little longer because of the additional O2 present in the lungs and the still-circulating blood. The average critical level of O2 tension in brain tissues, below which consciousness and the normal EEG pattern are invariably lost, lies between 15 and 20 mm Hg. This seems to be so whether the tissue anoxia is achieved by lowering the cerebral blood flow or the arterial oxygen content. Cessation of cerebral blood flow is followed within a few minutes by irreversible pathological changes within the brain, readily demonstrated by microscopic anatomical techniques. In medical crises, such as cardiac arrest, damage to the brain occurs earliest and is most decisive in determining the degree of recovery.

Cerebral blood flow must be able to maintain the avaricious appetite of the brain for O2. The average rate of blood flow in the human brain as a whole is approximately 57 ml/100 g tissue/min (see Table 31-1). For a whole brain this amounts to almost 800 ml/min, or approximately 15% of the total basal cardiac output. This must be maintained within relatively narrow limits, for the brain cannot tolerate any major drop in its perfusion. A fall in cerebral blood flow to half its normal rate is sufficient to cause loss of consciousness in normal, healthy, young men. There are, fortunately, numerous reflexes and other physiological mechanisms to sustain adequate levels of arterial blood pressure at the head level, such as the baroreceptor reflexes, and to maintain cerebral blood flow, even when arterial pressure falls in times of stress for example, autoregulation. There are also mechanisms to adjust cerebral blood flow to changes in cerebral metabolic demand.

Regulation of cerebral blood flow is achieved mainly by control of the tone or the degree of constriction, or dilation, of the cerebral vessels. This in turn is controlled mainly by local chemical factors, such as PaCO2, PaO2, pH and others still unrecognized. High PaCO2, low PaO2 and low pH, which are products of metabolic activity, tend to dilate the blood vessels and increase cerebral blood flow; changes in the opposite direction constrict the vessels and decrease blood flow [17]. Cerebral blood flow is regulated through such mechanisms to maintain homeostasis of these chemical factors in the local tissue. The rates of production of these chemical factors depend on the rates of energy metabolism; therefore, cerebral blood flow is adjusted to the cerebral metabolic rate [17].

Local rates of cerebral blood flow and metabolism can be measured by autoradiography and are coupled to local brain function

The rates of blood flow and metabolism presented in Table 31-1 and discussed above represent the average values in the brain as a whole. The brain is not homogeneous, however; it is composed of a variety of tissues and discrete structures that often function independently or even inversely with respect to one another. There is little reason to expect that their perfusion and metabolic rates would be similar. Indeed, experiments clearly indicate that they are not. Local cerebral blood flow in laboratory animals has been determined from the local tissue concentrations, measured by a quantitative autoradiographic technique, and from the total history of the arterial concentration of a freely diffusible, chemically inert, radioactive tracer introduced into the circulation [18]. The results reveal that blood-flow rates vary widely throughout the brain, with average values in gray matter approximately four to five times those in white matter [18].

A method has been devised to measure glucose consumption in discrete functional and structural components of the brain in intact, conscious laboratory animals [19]. This method also employs quantitative autoradiography to measure local tissue concentrations but utilizes 2-deoxy-d-[14C]glucose as the tracer. The local tissue accumulation of [14C]deoxyglucose as [14C]deoxy-G6P in a given interval of time is related to the amount of glucose that has been phosphorylated by hexokinase over the same interval, and the rate of glucose consumption can be determined from the [14C]deoxy-G6P concentration by appropriate consideration of (i) the relative concentrations of [14C]deoxyglucose and glucose in the plasma, (ii) their rate constants for transport between plasma and brain tissue and (iii) the kinetic constants of hexokinase for deoxyglucose and glucose. The method is based on a kinetic model of the biochemical behavior of 2-deoxyglucose and glucose in brain. The model (diagrammed in Fig. 31-3) has been analyzed mathematically to derive an operational equation that presents the variables to be measured and the procedure to be followed to determine local cerebral glucose utilization.

Figure 31-3. Theoretical basis of radioactive deoxyglucose method for measurement of local cerebral glucose utilization.

Figure 31-3

Theoretical basis of radioactive deoxyglucose method for measurement of local cerebral glucose utilization. A: Theoretical model. Ci represents the total 14C concentration in a single homogeneous tissue of the brain. Cp and Cp represent (more...)

To measure local glucose utilization, a pulse of [14C]deoxyglucose is administered intravenously at time zero and timed arterial blood samples are drawn for determination of the plasma [14C]deoxyglucose and glucose concentrations. At the end of the experimental period, usually about 45 min, the animal is decapitated, the brain is removed and frozen and 20-μm-thick brain sections are autoradiographed on X-ray film along with calibrated [14C]methyl-methacrylate standards. Local tissue concentrations of 14C are determined by quantitative densitometric analysis of the autoradiographs. From the time courses of the arterial plasma [14C]deoxyglucose and glucose concentrations and the final tissue 14C concentrations, determined by quantitative autoradiography, local glucose utilization can be calculated by means of the operational equation for all components of the brain identifiable in the autoradiographs. The procedure is designed so that the autoradiographs reflect mainly the relative local concentrations of [14C]deoxy-G6P. The autoradiographs, therefore, are pictorial representations of the relative rates of glucose utilization in all of the structural components of the brain.

Autoradiographs of the striate cortex in monkey in various functional states are illustrated in Figure 31-4. This method has demonstrated that local cerebral consumption of glucose varies as widely as blood flow throughout the brain (Table 31-2). Indeed, in normal animals, there is remarkably close correlation between local cerebral blood flow and glucose consumption [20]. Changes in functional activity produced by physiological stimulation, anesthesia or deafferentation result in corresponding changes in blood flow and glucose consumption [21] in the structures involved in the functional change. The [14C]deoxyglucose method for the measurement of local glucose utilization has been used to map the functional visual pathways and to identify the locus of the visual cortical representation of the retinal “blind spot” in the brain of rhesus monkey [21] (Fig. 31-4). These results establish that local energy metabolism in the brain is coupled to local functional activity and confirm the long-held belief that local cerebral blood flow is adjusted to metabolic demand in local tissue. The method has been applied to humans by use of 2-[18F]-fluoro-2-deoxy-d-glucose and positron emission tomography (PET), with similar results (see Chap. 54).

Figure 31-4. Autoradiograms of coronal brain sections from rhesus monkeys at the level of the striate cortex.

Figure 31-4

Autoradiograms of coronal brain sections from rhesus monkeys at the level of the striate cortex. A: Animal with normal binocular vision. Note the laminar distribution of the density; the dark band corresponds to layer IV. B: Animal with bilateral visual (more...)

Table 31-2. Representative Values a for Local Cerebral Glucose Utilization in the Normal Conscious Albino Rat and Monkey (μmol/100g/min).

Table 31-2

Representative Values a for Local Cerebral Glucose Utilization in the Normal Conscious Albino Rat and Monkey (μmol/100g/min).

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 1999, American Society for Neurochemistry.
Bookshelf ID: NBK28194


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