Energy Metabolism Of The Developing Brain

Much like the changes in lipid and protein compositions described earlier, energy metabolism of the brain also undergoes an interesting shift during development. The most dramatic of these changes are changes in blood flow and oxygen consumption and the utilization of glucose as the source of energy. It is well-known from both in vitro and in vivo studies that oxygen consumption by the cerebrum remains at a low level at birth, although oxygen supply to the tissue may be high. Investigations show that relative to the amount of oxygen consumed, the amount of oxygen delivered to the cerebrum during fetal life exceeds that in the newborn and adult by as much as 70%. This may protect the fetus from the stress of labor and delivery, or it may simply be an obligatory adaptation to the low arterial oxygen pressure in the intrauterine environment. After birth, both oxygen supply and oxygen consumption increase rapidly and reach maximum levels at the time of peak development. Oxygen consumption then slowly decreases to the adult level at maturity.

The primary fuel that fulfills the high demand by the brain for metabolic energy is glucose. However, utilization of glucose and the efficiency of the process are not uniform throughout the developmental program. Early immature brain is less aerobic than the mature adult brain and oxidative processes (mito-chondrial metabolism and respiration) are not fully developed in the immature brain. Many years ago, it was shown that newborn rats can withstand anaerobic conditions for as long as 1 hr, but this resistance to hypoxia disappears when the animals are administered iodoacetate, an inhibitor of the glycolytic pathway. This led to the understanding that early in development (before or at birth in rats or humans), glycolytic breakdown of glucose to pyruvate or lactate is a major mode of glucose utilization. However, as is known, comparatively little energy is produced in this pathway (only 2 net moles of ATP are synthesized per mole of glucose utilized compared with 36 mol in the oxidative pathway). After birth, as development proceeds, respiration becomes increasingly important, and the oxidative pathway (complete oxidation of glucose to CO2 and H2O) plays a dominant role in glucose metabolism.

This shift in the metabolic pattern of the brain is understood from the changes in the activities during postnatal development of the enzymes of the glycoly-tic, TCA cycle, and the electron transport systems, with the latter two representing oxidative mechanisms of glucose utilization. For example, it has been found in the rat that the glycolytic enzymes in the brain, (e.g., glyceraldehyde-3-phosphate dehydrogenase, hexokinase, aldolase, and lactate dehydrogenase) already are considerably active after birth and show relatively small increases during the entire postnatal life, whereas the activities of the enzymes of the other two systems show marked variations. In the case of the rat brain, the latter enzymes generally remain at very low levels during the first 10 days after birth, following which their activities rapidly increase and reach maximum levels at about 40 days of age. Figure 10 shows examples with glyceraldehyde-3-phosphate dehydro-genase (glycolytic) and succinate dehydrogenase (TCA

cycle), and Fig. 11 shows an example with cytochrome oxidase (electron transport chain). Activities of many other enzymes of oxidative metabolism (e.g., pyruvate dehydrogenase, citrate synthase, isocitrate dehydro-genase, and fumarase) also change markedly during this period.

The activities of the enzymes of both glycolytic and oxidative pathways develop first in the spinal cord and medulla, then in the hypothalamus, striatum, mid-brain, and the cerebral white matter, and finally in the cerebral cortex and cerebellum (i.e., development is in the caudocephalic direction). This is consistent with the embryological and neurophylogenetic development of the brain regions, which is known to proceed from the medulla to the telencephalon (the end brain), and strongly indicates that the development of morphological and neurological maturity in the various regions of the brain is correlated with the development of their aerobic potential. Particularly interesting in this context is the development of the pyruvate dehydrogenase complex since this enzyme has a key regulatory role in controlling the flux of glucose carbon via pyruvate into the TCA cycle for energy metabolism in all tissues including the brain. Indeed, in the brain of species born neurologically mature (the prenatal brain developers such as guinea pig), pyruvate dehydrogenase activity is fully developed at birth, whereas in the brain of the purely postnatal brain developers such as the rat (which are born

Figure 10 Changes in the activities of glyceraldehyde-3-phosphate dehydrogenase (•, moles substrate/kg protein of forebrain/hr) and succinate dehydrogenase (O, moles substrate/g whole brain/hr) in the developing rat brain. Values are plotted as percentages of maximal activities (reproduced with permission from Pergamon Press).

Figure 10 Changes in the activities of glyceraldehyde-3-phosphate dehydrogenase (•, moles substrate/kg protein of forebrain/hr) and succinate dehydrogenase (O, moles substrate/g whole brain/hr) in the developing rat brain. Values are plotted as percentages of maximal activities (reproduced with permission from Pergamon Press).

0 30 60 90 120

Days after birth

Figure 11 Changes in activities of cytochrome oxidase (O ) and b-hydroxybutyrate dehydogenase (•) in the developing rat brain (reproduced with permission of the American Society of Biological Chemists).

neurologically immature), the activity of the enzyme is low. The subsequent neurological development of the latter species is correlated with the development of the pyruvate dehydrogenase activity in their brains.

An important aspect of energy metabolism in the neonatal brain concerns the utilization of ketone bodies, b-hydroxybutyrate and acetoacetate, as an additional source of energy. Probably because of an underdeveloped blood-brain barrier, the neonatal brain can take up ketone bodies and utilize them for the production of energy. During the early postnatal period, the ketone bodies are preferred to glucose as substrates for synthesis of phospholipids and sphin-golipids to meet the requirements for growth and myelination. The ketone bodies thus form an important fuel metabolite for the rat brain during early periods after birth.

The pattern of cerebral metabolism of glucose also changes during development. Thus, in the adult brain of most mammalian species, the rate of glucose utilization ranges between 0.3 and 1.0 mmol/kg tissue/min, and most of this metabolism (>90%) is carried through the glycolysis — TCA cycle — electron transport pathway. In contrast, in neonates, the hexose monophosphate (HMP) shunt represents a significant mechanism for the metabolism of a portion of total glucose. It has been estimated that the HMP shunt is responsible for as much as 50% of total brain glucose utilization during the first 4 weeks of life in the rat. Since production of ribose and NADPH is characteristic of the shunt, it is very likely that this pathway is utilized by the developing brain to meet its own demand for rapid synthesis of nucleic acids and large amounts of lipids, respectively. As the brain matures, the activity of the shunt gradually decreases, as reflected by a decrease with age in the activity of glucose-6-phosphate dehydrogenase, the first enzyme of the shunt, relative to the activities of the glycolytic and the TCA cycle enzymes.

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Pregnancy Diet Plan

Pregnancy Diet Plan

The first trimester is very important for the mother and the baby. For most women it is common to find out about their pregnancy after they have missed their menstrual cycle. Since, not all women note their menstrual cycle and dates of intercourse, it may cause slight confusion about the exact date of conception. That is why most women find out that they are pregnant only after one month of pregnancy.

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